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Nguyen AK, Blacksmith MS, Kidd JM. Duplications and Retrogenes Are Numerous and Widespread in Modern Canine Genomic Assemblies. Genome Biol Evol 2024; 16:evae142. [PMID: 38946312 PMCID: PMC11259980 DOI: 10.1093/gbe/evae142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 05/08/2024] [Accepted: 06/24/2024] [Indexed: 07/02/2024] Open
Abstract
Recent years have seen a dramatic increase in the number of canine genome assemblies available. Duplications are an important source of evolutionary novelty and are also prone to misassembly. We explored the duplication content of nine canine genome assemblies using both genome self-alignment and read-depth approaches. We find that 8.58% of the genome is duplicated in the canFam4 assembly, derived from the German Shepherd Dog Mischka, including 90.15% of unplaced contigs. Highlighting the continued difficulty in properly assembling duplications, less than half of read-depth and assembly alignment duplications overlap, but the mCanLor1.2 Greenland wolf assembly shows greater concordance. Further study shows the presence of multiple segments that have alignments to four or more duplicate copies. These high-recurrence duplications correspond to gene retrocopies. We identified 3,892 candidate retrocopies from 1,316 parental genes in the canFam4 assembly and find that ∼8.82% of duplicated base pairs involve a retrocopy, confirming this mechanism as a major driver of gene duplication in canines. Similar patterns are found across eight other recent canine genome assemblies, with metrics supporting a greater quality of the PacBio HiFi mCanLor1.2 assembly. Comparison between the wolf and other canine assemblies found that 92% of retrocopy insertions are shared between assemblies. By calculating the number of generations since genome divergence, we estimate that new retrocopy insertions appear, on average, in 1 out of 3,514 births. Our analyses illustrate the impact of retrogene formation on canine genomes and highlight the variable representation of duplicated sequences among recently completed canine assemblies.
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Affiliation(s)
- Anthony K Nguyen
- Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
| | - Matthew S Blacksmith
- Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
| | - Jeffrey M Kidd
- Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
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2
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Mao Y, Harvey WT, Porubsky D, Munson KM, Hoekzema K, Lewis AP, Audano PA, Rozanski A, Yang X, Zhang S, Yoo D, Gordon DS, Fair T, Wei X, Logsdon GA, Haukness M, Dishuck PC, Jeong H, Del Rosario R, Bauer VL, Fattor WT, Wilkerson GK, Mao Y, Shi Y, Sun Q, Lu Q, Paten B, Bakken TE, Pollen AA, Feng G, Sawyer SL, Warren WC, Carbone L, Eichler EE. Structurally divergent and recurrently mutated regions of primate genomes. Cell 2024; 187:1547-1562.e13. [PMID: 38428424 PMCID: PMC10947866 DOI: 10.1016/j.cell.2024.01.052] [Citation(s) in RCA: 27] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 11/26/2023] [Accepted: 01/31/2024] [Indexed: 03/03/2024]
Abstract
We sequenced and assembled using multiple long-read sequencing technologies the genomes of chimpanzee, bonobo, gorilla, orangutan, gibbon, macaque, owl monkey, and marmoset. We identified 1,338,997 lineage-specific fixed structural variants (SVs) disrupting 1,561 protein-coding genes and 136,932 regulatory elements, including the most complete set of human-specific fixed differences. We estimate that 819.47 Mbp or ∼27% of the genome has been affected by SVs across primate evolution. We identify 1,607 structurally divergent regions wherein recurrent structural variation contributes to creating SV hotspots where genes are recurrently lost (e.g., CARD, C4, and OLAH gene families) and additional lineage-specific genes are generated (e.g., CKAP2, VPS36, ACBD7, and NEK5 paralogs), becoming targets of rapid chromosomal diversification and positive selection (e.g., RGPD gene family). High-fidelity long-read sequencing has made these dynamic regions of the genome accessible for sequence-level analyses within and between primate species.
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Affiliation(s)
- Yafei Mao
- Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA; Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.
| | - William T Harvey
- Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
| | - David Porubsky
- Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
| | - Katherine M Munson
- Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
| | - Kendra Hoekzema
- Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
| | - Alexandra P Lewis
- Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
| | - Peter A Audano
- Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
| | - Allison Rozanski
- Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
| | - Xiangyu Yang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Shilong Zhang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - DongAhn Yoo
- Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
| | - David S Gordon
- Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA
| | - Tyler Fair
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA
| | - Xiaoxi Wei
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Glennis A Logsdon
- Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
| | - Marina Haukness
- UC Santa Cruz Genomics Institute, University of California, Santa Cruz, Santa Cruz, CA, USA
| | - Philip C Dishuck
- Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
| | - Hyeonsoo Jeong
- Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
| | - Ricardo Del Rosario
- McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Vanessa L Bauer
- BioFrontiers Institute, Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Bouder, CO, USA
| | - Will T Fattor
- BioFrontiers Institute, Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Bouder, CO, USA
| | - Gregory K Wilkerson
- Department of Veterinary Sciences, Michale E. Keeling Center for Comparative Medicine and Research, The University of Texas MD Anderson Cancer Center, Bastrop, TX, USA; Department of Clinical Sciences, North Carolina State University, Raleigh, NC, USA
| | - Yuxiang Mao
- Institute of Neuroscience, State Key Laboratory of Neuroscience, Center for Excellence in Brain Science & Intelligence Technology, Chinese Academy of Sciences, Shanghai, China; Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai, China
| | - Yongyong Shi
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China; Institute of Neuroscience, State Key Laboratory of Neuroscience, Center for Excellence in Brain Science & Intelligence Technology, Chinese Academy of Sciences, Shanghai, China; Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai, China
| | - Qiang Sun
- Institute of Neuroscience, State Key Laboratory of Neuroscience, Center for Excellence in Brain Science & Intelligence Technology, Chinese Academy of Sciences, Shanghai, China; Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai, China
| | - Qing Lu
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Benedict Paten
- UC Santa Cruz Genomics Institute, University of California, Santa Cruz, Santa Cruz, CA, USA
| | | | - Alex A Pollen
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA
| | - Guoping Feng
- McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Sara L Sawyer
- BioFrontiers Institute, Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Bouder, CO, USA
| | - Wesley C Warren
- Department of Animal Sciences, Bond Life Sciences Center, University of Missouri, Columbia, MO, USA; Department of Surgery, School of Medicine, University of Missouri, Columbia, MO, USA; Institute of Data Science and Informatics, University of Missouri, Columbia, MO, USA
| | - Lucia Carbone
- Department of Medicine, Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR, USA; Division of Genetics, Oregon National Primate Research Center, Beaverton, OR, USA; Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA; Department of Medical Informatics and Clinical Epidemiology, Oregon Health and Science University, Portland, OR, USA
| | - Evan E Eichler
- Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA.
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3
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Zhang W, Lin S, Zeng B, Chen X, Chen L, Chen M, Guo W, Lin Y, Yu L, Hou J, Li Y, Li S, Jin X, Cai W, Zhang K, Nie Q, Chen H, Li J, He P, Cai Q, Qiu Y, Wang C, Fu F. High leukocyte mitochondrial DNA copy number contributes to poor prognosis in breast cancer patients. BMC Cancer 2023; 23:377. [PMID: 37098487 PMCID: PMC10131463 DOI: 10.1186/s12885-023-10838-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 04/12/2023] [Indexed: 04/27/2023] Open
Abstract
BACKGROUND Compelling evidence has indicated a significant association between leukocyte mitochondrial DNA copy number (mtDNAcn) and prognosis of several malignancies in a cancer-specific manner. However, whether leukocyte mtDNAcn can predict the clinical outcome of breast cancer (BC) patients has not been well investigated. METHODS The mtDNA copy number of peripheral blood leukocytes from 661 BC patients was measured using a Multiplex AccuCopy™Kit based on a multiplex fluorescence competitive PCR principle. Kaplan-Meier curves and Cox proportional hazards regression model were applied to investigate the association of mtDNAcn with invasive disease-free survival (iDFS), distant disease-free survival (DDFS), breast cancer special survival (BCSS), and overall survival (OS) of patients. The possible mtDNAcn-environment interactions were also evaluated by the Cox proportional hazard regression models. RESULTS BC patients with higher leukocyte mtDNA-CN exhibited a significantly worse iDFS than those with lower leukocyte mtDNAcn (5-year iDFS: fully-adjusted model: HR = 1.433[95%CI 1.038-1.978], P = 0.028). Interaction analyses showed that mtDNAcn was significantly associated with hormone receptor status (adjusted p for interaction: 5-year BCSS: 0.028, 5-year OS: 0.022), so further analysis was mainly in the HR subgroup. Multivariate Cox regression analysis demonstrated that mtDNAcn was an independent prognostic factor for both BCSS and OS in HR-positive patients (HR+: 5-year BCSS: adjusted HR (aHR) = 2.340[95% CI 1.163-4.708], P = 0.017 and 5-year OS: aHR = 2.446 [95% CI 1.218-4.913], P = 0.011). CONCLUSIONS For the first time, our study demonstrated that leukocyte mtDNA copy number might influence the outcome of early-stage breast cancer patients depending on intrinsic tumor subtypes in Chinese women.
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Grants
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
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Affiliation(s)
- Wenzhe Zhang
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Songping Lin
- Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, 362000, Fujian Province, China
| | - Bangwei Zeng
- Nosocomial Infection Control Branch, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
| | - Xiaobin Chen
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Lili Chen
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Minyan Chen
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Wenhui Guo
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Yuxiang Lin
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Liuwen Yu
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Jialin Hou
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Yan Li
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Shengmei Li
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Xuan Jin
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Weifeng Cai
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Kun Zhang
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Qian Nie
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Hanxi Chen
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Jing Li
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Peng He
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Qindong Cai
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Yibin Qiu
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Chuan Wang
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China.
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China.
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China.
| | - Fangmeng Fu
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China.
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China.
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China.
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4
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Mao Y, Harvey WT, Porubsky D, Munson KM, Hoekzema K, Lewis AP, Audano PA, Rozanski A, Yang X, Zhang S, Gordon DS, Wei X, Logsdon GA, Haukness M, Dishuck PC, Jeong H, Del Rosario R, Bauer VL, Fattor WT, Wilkerson GK, Lu Q, Paten B, Feng G, Sawyer SL, Warren WC, Carbone L, Eichler EE. Structurally divergent and recurrently mutated regions of primate genomes. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.07.531415. [PMID: 36945442 PMCID: PMC10028934 DOI: 10.1101/2023.03.07.531415] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/10/2023]
Abstract
To better understand the pattern of primate genome structural variation, we sequenced and assembled using multiple long-read sequencing technologies the genomes of eight nonhuman primate species, including New World monkeys (owl monkey and marmoset), Old World monkey (macaque), Asian apes (orangutan and gibbon), and African ape lineages (gorilla, bonobo, and chimpanzee). Compared to the human genome, we identified 1,338,997 lineage-specific fixed structural variants (SVs) disrupting 1,561 protein-coding genes and 136,932 regulatory elements, including the most complete set of human-specific fixed differences. Across 50 million years of primate evolution, we estimate that 819.47 Mbp or ~27% of the genome has been affected by SVs based on analysis of these primate lineages. We identify 1,607 structurally divergent regions (SDRs) wherein recurrent structural variation contributes to creating SV hotspots where genes are recurrently lost (CARDs, ABCD7, OLAH) and new lineage-specific genes are generated (e.g., CKAP2, NEK5) and have become targets of rapid chromosomal diversification and positive selection (e.g., RGPDs). High-fidelity long-read sequencing has made these dynamic regions of the genome accessible for sequence-level analyses within and between primate species for the first time.
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Affiliation(s)
- Yafei Mao
- Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - William T Harvey
- Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
| | - David Porubsky
- Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
| | - Katherine M Munson
- Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
| | - Kendra Hoekzema
- Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
| | - Alexandra P Lewis
- Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
| | - Peter A Audano
- Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
| | - Allison Rozanski
- Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
| | - Xiangyu Yang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Shilong Zhang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - David S Gordon
- Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
- Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA
| | - Xiaoxi Wei
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Glennis A Logsdon
- Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
| | - Marina Haukness
- UC Santa Cruz Genomics Institute, University of California, Santa Cruz, Santa Cruz, CA, USA
| | - Philip C Dishuck
- Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
| | - Hyeonsoo Jeong
- Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
| | - Ricardo Del Rosario
- McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Vanessa L Bauer
- BioFrontiers Institute, Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO, USA
| | - Will T Fattor
- BioFrontiers Institute, Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO, USA
| | - Gregory K Wilkerson
- Department of Veterinary Sciences, Michale E. Keeling Center for Comparative Medicine and Research, The University of Texas MD Anderson Cancer Center, Bastrop, TX, USA
- Department of Clinical Sciences, North Carolina State University, Raleigh, NC, USA
| | - Qing Lu
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Benedict Paten
- UC Santa Cruz Genomics Institute, University of California, Santa Cruz, Santa Cruz, CA, USA
| | - Guoping Feng
- McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Sara L Sawyer
- BioFrontiers Institute, Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO, USA
| | - Wesley C Warren
- Department of Animal Sciences, Bond Life Sciences Center, University of Missouri, Columbia, MO, USA
- Department of Surgery, School of Medicine, University of Missouri, Columbia, MO, USA
- Institute of Data Science and Informatics, University of Missouri, Columbia, MO, USA
| | - Lucia Carbone
- Department of Medicine, Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR, USA
- Division of Genetics, Oregon National Primate Research Center, Beaverton, OR, USA
- Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA
- Department of Medical Informatics and Clinical Epidemiology, Oregon Health and Science University, Portland, OR, USA
| | - Evan E Eichler
- Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
- Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA
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5
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Si N, Zhang Z, Huang X, Wang C, Guo P, Pan B, Jiang H. De novo 22q11.2 deletions and auricular findings in two Chinese patients with microtia. Mol Genet Genomic Med 2021; 10:e1862. [PMID: 34971493 PMCID: PMC8801138 DOI: 10.1002/mgg3.1862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 08/20/2021] [Accepted: 12/14/2021] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND Congenital microtia is a common craniofacial malformation resulting from both environmental and genetic factors. Recurrent chromosomal imbalances were observed in patients with microtia. The 22q11.2 deletion is one of the most common microdeletions in human beings. The cell division cycle 45 gene (CDC45) embedded in the proximal 22q11.2 deleted region is involved in craniofacial development. However, only a few studies have focused on the 22q11.2 deletion as genetic etiology in microtia patients and studied its associated external ear deformity characteristics in detail. METHODS In this research, a total of 65 patients from north China with sporadic microtia were studied. Copy number variations of CDC45 were screened using AccuCopy assay. The 22q11.2 deletion harboring CDC45 was identified by whole-genome sequencing and targeted next-generation sequencing. A parental test was carried out to determine the origin of the deletion. RESULTS CDC45 copy number loss was identified in two patients with microtia. A set of qPCR assays demonstrated two patients carried a typical proximal 22q11.2 deletion between the low-copy repeats on chromosome 22q11.2 (LCR22A and LCR22D), encompassing CDC45. The 22q11.2 deletions were de novo in each patient. In-depth auricular phenotype assessment showed these two patients have a distinct concha-type ear malformation while other microtia patients have lobule-type microtia among the 65 microtia patient cohort in this study. CONCLUSION Here we present two additional Chinese microtia patients with de novo 22q11.2 proximal deletion harboring CDC45 and further report these patients' distinct ear malformation.
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Affiliation(s)
- Nuo Si
- Plastic Surgery Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, China
| | - Zeya Zhang
- Plastic Surgery Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, China
| | - Xin Huang
- Plastic Surgery Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, China
| | - Chanchen Wang
- Plastic Surgery Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, China
| | - Peipei Guo
- Plastic Surgery Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, China
| | - Bo Pan
- Plastic Surgery Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, China
| | - Haiyue Jiang
- Plastic Surgery Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, China
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A rare familial rearrangement of chromosomes 9 and 15 associated with intellectual disability: a clinical and molecular study. Mol Cytogenet 2021; 14:47. [PMID: 34607577 PMCID: PMC8489072 DOI: 10.1186/s13039-021-00565-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 03/09/2021] [Indexed: 11/22/2022] Open
Abstract
Background There are many reports on rearrangements occurring separately in the regions of chromosomes 9p and 15q affected in the case under study. 15q duplication syndrome is caused by the presence of at least one extra maternally derived copy of the Prader–Willi/Angelman critical region. Trisomy 9p is the fourth most frequent chromosome anomaly with a clinically recognizable syndrome often accompanied by intellectual disability. Here we report a new case of a patient with maternally derived unique complex sSMC resulting in partial trisomy of both chromosomes 9 and 15 associated with intellectual disability. Case presentation We characterise a supernumerary derivative chromosome 15: 47,XY,+der(15)t(9;15)(p21.2;q13.2), likely resulting from 3:1 malsegregation during maternal gametogenesis. Chromosomal analysis showed that a phenotypically normal mother is a carrier of balanced translocation t(9;15)(p21.1;q13.2). Her 7-year-old son showed signs of intellectual disability and a number of physical abnormalities including bilateral cryptorchidism and congenital megaureter. The child’s magnetic resonance imaging showed changes in brain volume and in structural and functional connectivity revealing phenotypic changes caused by the presence of the extra chromosome material, whereas the mother’s brain MRI was normal. Sequence analyses of the microdissected der(15) chromosome detected two breakpoint regions: HSA9:25,928,021-26,157,441 (9p21.2 band) and HSA15:30,552,104-30,765,905 (15q13.2 band). The breakpoint region on chromosome HSA9 is poor in genetic features with several areas of high homology with the breakpoint region on chromosome 15. The breakpoint region on HSA15 is located in the area of a large segmental duplication. Conclusions We discuss the case of these phenotypic and brain MRI features in light of reported signatures for 9p partial trisomy and 15 duplication syndromes and analyze how the genomic characteristics of the found breakpoint regions have contributed to the origin of the derivative chromosome. We recommend MRI for all patients with a developmental delay, especially in cases with identified rearrangements, to accumulate more information on brain phenotypes related to chromosomal syndromes. Supplementary Information The online version contains supplementary material available at 10.1186/s13039-021-00565-y.
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7
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Zhen Q, Zhang Y, Yu Y, Yang H, Zhang T, Li X, Mo X, Li B, Wu J, Liang Y, Ge H, Xu Q, Chen W, Qian W, Xu H, Chen G, Bai B, Zhang J, Lu Y, Chen S, Zhang H, Zhang Y, Chen X, Li X, Jin X, Lin X, Yong L, Fang M, Zhao J, Lu Y, Wu S, Jiang D, Shi J, Cao H, Qiu Y, Li S, Kang X, Shen J, Ma H, Sun S, Fan Y, Chen W, Bai M, Jiang Q, Li W, Lv C, Li S, Chen M, Li F, Li Y, Sun L. Three Novel Structural Variations at MHC and IL12B Predisposing to Psoriasis. Br J Dermatol 2021; 186:307-317. [PMID: 34498260 DOI: 10.1111/bjd.20752] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/07/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND Structural variations (SVs, defined as DNA variants ≥50 bp) have been associated with various complex human diseases. However, research to screen the whole genome for SVs predisposing to psoriasis is still lacking. OBJECTIVES This study aimed to investigate the association of SVs and psoriasis. METHODS We performed a genome-wide screen on SVs using an imputation method on 5 independent cohorts with 45,386 subjects from the Chinese Han population. Fine mapping analysis, genetic interaction analysis and RNA expression analysis were conducted to explore the mechanism of SVs. RESULTS We obtained 4,535 SVs in total and identified 2 novel deletions (esv3608550, OR=2.73, P<2.00×10-308 ; esv3608542, OR=0.47, P=7.40×10-28 ) at 6q21.33 (MHC), 1 novel Alu element insertion (esv3607339, OR=1.22, P=1.18×10-35 ) at 5q33.3 (IL12B), and confirmed 1 previously reported deletion (esv3587563, OR=1.30, P=9.52×10-60 ) at 1q21.2 (LCE) for psoriasis. Fine mapping analysis including SNPs and small Insertions/Deletions (InDels) revealed that esv3608550 and esv3608542 were independently associated with psoriasis, and a novel independent SNP (rs9378188, OR=1.65, P=3.46×10-38 ) was identified at 6q21.33. By genetic interaction analysis and RNA expression analysis, we speculate that the association of 2 deletions at 6q21.33 with psoriasis might relate to their influence on the expression of HLA-C. CONCLUSIONS Our study constructed the most comprehensive SV map for psoriasis thus far and enriched the genetic architecture and pathogenesis of psoriasis as well as highlighted the nonnegligible impact of SVs on complex diseases.
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Affiliation(s)
- Q Zhen
- Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.,Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China, 230032.,Anhui Provincial Institute of Translational Medicine, Hefei, 230032, China
| | - Y Zhang
- Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Y Yu
- Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.,Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China, 230032.,Anhui Provincial Institute of Translational Medicine, Hefei, 230032, China
| | - H Yang
- Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - T Zhang
- Department of Biology, University of Copenhagen, Ole MaalØes Vej 5, 2200, Copenhagen, Denmark
| | - X Li
- Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - X Mo
- Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - B Li
- Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.,The Comprehensive Lab, College of Basic, Anhui Medical University
| | - J Wu
- Department of Dermatology, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University
| | - Y Liang
- Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - H Ge
- Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.,Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China, 230032.,Anhui Provincial Institute of Translational Medicine, Hefei, 230032, China
| | - Q Xu
- Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.,Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China, 230032.,Anhui Provincial Institute of Translational Medicine, Hefei, 230032, China
| | - W Chen
- Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.,Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China, 230032.,Anhui Provincial Institute of Translational Medicine, Hefei, 230032, China
| | - W Qian
- Institute of Dermalology, Guangzhou Medical University, Guangzhou, 510095, China
| | - H Xu
- Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - G Chen
- Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.,Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China, 230032.,Anhui Provincial Institute of Translational Medicine, Hefei, 230032, China
| | - B Bai
- Department of Dermatology at No.2 Hospital, Harbin Medical University, Harbin, Heilongjiang, 150001, China
| | - J Zhang
- Department of Dermatology, The 195 Hospital of Chinese People's Liberation Army, Xianning, Hubei, 437100, China
| | - Y Lu
- Dermatology Department of the First Affiliated Hospital, Nanjng Medical University, Nanjing, Jiangsu, 210029, China
| | - S Chen
- Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.,Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China, 230032.,Anhui Provincial Institute of Translational Medicine, Hefei, 230032, China
| | - H Zhang
- Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.,Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China, 230032.,Anhui Provincial Institute of Translational Medicine, Hefei, 230032, China
| | - Y Zhang
- Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - X Chen
- Department of Dermatology at Chengdu Second People's Hospital, Sichuan, Chengdu, 610017, China
| | - X Li
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China
| | - X Jin
- School of Medicine, South China University of Technology, Guangzhou, 510006, Guangdong, China
| | - X Lin
- Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, 20 Chazhong Road, Fuzhou, 350005, China
| | - L Yong
- Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.,Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China, 230032.,Anhui Provincial Institute of Translational Medicine, Hefei, 230032, China
| | - M Fang
- Key Laboratory of Healthy Mariculture for the East China Sea, Ministry of Agriculture, Fisheries College, Jimei University, Xiamen, Fujian, 361021, China
| | - J Zhao
- Department of Dermatology, People's Hospital of Xinjiang Uygur Autonomous Region, Xinjiang, Urumqi, 830001, China
| | - Y Lu
- Department of Dermatology at Chengdu Second People's Hospital, Sichuan, Chengdu, 610017, China
| | - S Wu
- Urology Institute of Shenzhen University, The Luohu Affiliated Hospital of Shenzhen University
| | - D Jiang
- Key Laboratory of Healthy Mariculture for the East China Sea, Ministry of Agriculture, Fisheries College, Jimei University, Xiamen, Fujian, 361021, China
| | - J Shi
- Department of Dermatology at the Second Affiliated Hospital, Baotou Medical College, University Of Science and Technology Of The Inner Mongolia, Baotou, Inner Mongolia, 014030, China
| | - H Cao
- Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Y Qiu
- Department of Dermatology, Jining No. 1 People's Hospital, Shandong, 272011, China
| | - S Li
- Department of Dermatology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - X Kang
- Department of Dermatology, People's Hospital of Xinjiang Uygur Autonomous Region, Xinjiang, Urumqi, 830001, China
| | - J Shen
- Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - H Ma
- Department of Dematology, the 2rd Hospital of Xi'an Jiaotong University. Xi'an, Shanxi, 710004, China
| | - S Sun
- Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Y Fan
- Department of Dermatology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - W Chen
- Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, 20 Chazhong Road, Fuzhou, 350005, China
| | - M Bai
- Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Q Jiang
- Donggang Center Hospital, Dandong, Liaoning, 118300
| | - W Li
- Collaborative Innovation Center for Birth Defect Research and Transformation of Shandong Province, Jining Medical University, Jining, Shandong, 272067, China
| | - C Lv
- Dalian Dermatosis Hospital, Dalian, Liaoning, 116021, China
| | - S Li
- Department of Dermatology at No, Hospital of Jilin University, Changchun, Jilin, 130021, China
| | - M Chen
- Dermatology Hospital, Peking Union Medical College
| | - F Li
- Department of Dermatology, The Second Hospital of Jilin University, Changchun, 130041, China
| | - Y Li
- Department of Dermatology, The 195 Hospital of Chinese People's Liberation Army, Xianning, Hubei, 437100, China
| | - L Sun
- Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.,Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China, 230032.,Anhui Provincial Institute of Translational Medicine, Hefei, 230032, China
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8
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Huang S, Zhang T, Wang Y, Wang L, Yan Z, Teng Y, Li Z, Lou Q, Liu S, Cai J, Chen Y, Li M, Huang H, Xu Z, Zou Y. Association of DYNC1H1 gene SNP/CNV with disease susceptibility, GCs efficacy, HRQOL, anxiety, and depression in Chinese SLE patients. J Clin Lab Anal 2021; 35:e23892. [PMID: 34272765 PMCID: PMC8373356 DOI: 10.1002/jcla.23892] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 06/18/2021] [Accepted: 06/20/2021] [Indexed: 12/17/2022] Open
Abstract
Background Systemic lupus erythematosus is a heterogeneous autoimmune disease characterized by multi‐system injuries and overproduction of autoantibodies. There are many genetic studies on SLE, but no report has considered the relationship between cytoplasmic dynein and SLE susceptibility. Objectives Our study intends to investigate whether DYNC1H1 gene SNP/CNV is related to SLE susceptibility, GCs efficacy, HRQOL, anxiety, and depression in Chinese SLE patients. Methods A total of 502 cases and 544 healthy controls were recruited into the case‐control study, and 472 subjects from the case group were followed up for 12 weeks to evaluate GCs efficacy, HRQOL, anxiety, and depression. Multiplex SNaPshot technique was applied to genotype the seven SNPs of DYNC1H1, and AccuCopyTM method was conducted to quantify the copy number of DYNC1H1. Anxiety and depression were evaluated using HAMA and HAMD‐24 scales, respectively. The SF‐36 scale was used to assess HRQOL. Results The significant association between SNP rs1190606 and SLE susceptibility was displayed in the dominant model (PBH = 0.004) as well as its allele model (PBH = 0.004). We also found that SNP rs2273440 was related to photosensitization symptom in SLE patients (PBH = 0.032). In the follow‐up study, SNP rs11160668 was connected with the improvement of BP in male patients (PBH = 0.011). However, no association of DYNC1H1 gene with GCs efficacy, anxiety, and depression was found. No CNV in DYNC1H1 was detected. Conclusions The study suggests that DYNC1H1 gene polymorphisms may have an effect on SLE susceptibility and BP improvement of HRQOL in Chinese SLE patients.
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Affiliation(s)
- Shunwei Huang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China.,The Key Laboratory of Anhui Medical Autoimmune Diseases, Hefei, China
| | - Tingyu Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China.,The Key Laboratory of Anhui Medical Autoimmune Diseases, Hefei, China
| | - Yuhua Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China.,The Key Laboratory of Anhui Medical Autoimmune Diseases, Hefei, China
| | - Linlin Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China.,The Key Laboratory of Anhui Medical Autoimmune Diseases, Hefei, China
| | - Ziye Yan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China.,The Key Laboratory of Anhui Medical Autoimmune Diseases, Hefei, China
| | - Ying Teng
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China.,The Key Laboratory of Anhui Medical Autoimmune Diseases, Hefei, China
| | - Zhen Li
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China.,The Key Laboratory of Anhui Medical Autoimmune Diseases, Hefei, China
| | - Qiuyue Lou
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China.,The Key Laboratory of Anhui Medical Autoimmune Diseases, Hefei, China
| | - Shuang Liu
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jing Cai
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yangfan Chen
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Mu Li
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Hailiang Huang
- Department of Laboratory Medicine, School of Public Health, Anhui Medical University, Hefei, China
| | - Zhouzhou Xu
- Department of Rheumatology and Immunology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yanfeng Zou
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China.,The Key Laboratory of Anhui Medical Autoimmune Diseases, Hefei, China
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9
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Chen S, Lu L, Xian J, Shi C, Chen J, Rao B, Qiu F, Lu J, Yang L. Prognostic Value of Germline Copy Number Variants and Environmental Exposures in Non-small Cell Lung Cancer. Front Genet 2021; 12:681857. [PMID: 34178039 PMCID: PMC8226327 DOI: 10.3389/fgene.2021.681857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 05/18/2021] [Indexed: 11/13/2022] Open
Abstract
Germline copy number variant (gCNV) has been studied as a genetic determinant for prognosis of several types of cancer, but little is known about how it affects non-small cell lung cancer (NSCLC) prognosis. We aimed to develop a prognostic nomogram for NSCLC based on gCNVs. Promising gCNVs that are associated with overall survival (OS) of NSCLC were sorted by analyzing the TCGA data and were validated in a small Chinese population. Then the successfully verified gCNVs were determined in a training cohort (n = 570) to develop a prognostic nomogram, and in a validation cohort (n = 465) to validate the nomogram. Thirty-five OS-related gCNVs were sorted and were reduced to 15 predictors by the Lasso regression analysis. Of them, only CNVR395.1 and CNVR2239.1 were confirmed to be associated with OS of NSCLC in the Chinese population. High polygenic risk score (PRS), which was calculated by the hazard effects of CNVR395.1 and CNVR2239.1, exerted a significantly higher death rate in the training cohort (HR = 1.41, 95%CI: 1.16-1.74) and validation cohort (HR = 1.42, 95%CI: 1.13-1.77) than low PRS. The nomogram incorporating PRS and surrounding factors, achieved admissible concordance indexes of 0.678 (95%CI: 0.664-0.693) and 0.686 (95%CI: 0.670-0.702) in predicting OS in the training and validation cohorts, respectively, and had well-fitted calibration curves. Moreover, an interaction between PRS and asbestos exposure was observed on affecting OS (P interaction = 0.042). Our analysis developed a nomogram that achieved an admissible prediction of NSCLC survival, which would be beneficial to the personalized intervention of NSCLC.
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Affiliation(s)
- Shizhen Chen
- The State Key Laboratory of Respiratory Disease, Institute of Public Health, Guangzhou Medical University, Guangzhou, China
| | - Liming Lu
- The State Key Laboratory of Respiratory Disease, Institute of Public Health, Guangzhou Medical University, Guangzhou, China
| | - Jianfeng Xian
- The State Key Laboratory of Respiratory Disease, Institute of Public Health, Guangzhou Medical University, Guangzhou, China
| | - Changhong Shi
- The State Key Laboratory of Respiratory Disease, Institute of Public Health, Guangzhou Medical University, Guangzhou, China
| | - Jinbin Chen
- The State Key Laboratory of Respiratory Disease, Institute of Public Health, Guangzhou Medical University, Guangzhou, China
| | - Boqi Rao
- The State Key Laboratory of Respiratory Disease, Institute of Public Health, Guangzhou Medical University, Guangzhou, China
| | - Fuman Qiu
- The State Key Laboratory of Respiratory Disease, Institute of Public Health, Guangzhou Medical University, Guangzhou, China
| | - Jiachun Lu
- The State Key Laboratory of Respiratory Disease, Institute of Public Health, Guangzhou Medical University, Guangzhou, China
- The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Lei Yang
- The State Key Laboratory of Respiratory Disease, Institute of Public Health, Guangzhou Medical University, Guangzhou, China
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10
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Pu J, Wang J, Qin Z, Wang A, Zhang Y, Wu X, Wu Y, Li W, Xu Z, Lu Y, Tang Q, Wei H. IGF2BP2 Promotes Liver Cancer Growth Through an m6A-FEN1-Dependent Mechanism. Front Oncol 2020; 10:578816. [PMID: 33224879 PMCID: PMC7667992 DOI: 10.3389/fonc.2020.578816] [Citation(s) in RCA: 108] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 10/07/2020] [Indexed: 12/22/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in China. N6-methyladenosine (m6A) plays an important role in posttranscriptional gene regulation. METTL3 and IGF2BP2 are key genes in the m6A signal pathway and have recently been shown to play important roles in cancer development and progression. In our work, higher METTL3 and IGF2BP2 expression were found in HCC tissues and were associated with a poor prognosis. In addition, IGF2BP2 overexpression promoted HCC proliferation in vitro and in vivo. Mechanistically, IGF2BP2 directly recognized and bound to the m6A site on FEN1 mRNA and enhanced FEN1 mRNA stability. Overall, our study revealed that METTL3 and IGF2BP2, acting as an oncogene, maintained FEN1 expression through an m6A-IGF2BP2-dependent mechanism in HCC cells, and indicated a potential biomarker panel for prognostic prediction in liver cancer.
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Affiliation(s)
- Jian Pu
- Department of General Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi, China
| | - Jianchu Wang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi, China
| | - Zebang Qin
- Graduate College of Youjiang Medical University for Nationalities, Guangxi, China
| | - Anmin Wang
- Graduate College of Youjiang Medical University for Nationalities, Guangxi, China
| | - Ya Zhang
- Graduate College of Youjiang Medical University for Nationalities, Guangxi, China
| | - Xianjian Wu
- Graduate College of Youjiang Medical University for Nationalities, Guangxi, China
| | - Yi Wu
- Graduate College of Youjiang Medical University for Nationalities, Guangxi, China
| | - Wenchuan Li
- Department of Hepatobiliary Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi, China
| | - Zuoming Xu
- Department of Hepatobiliary Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi, China
| | - Yuan Lu
- Graduate College of Youjiang Medical University for Nationalities, Guangxi, China
| | - Qianli Tang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi, China
| | - Huamei Wei
- Department of Pathology, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi, China
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11
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Robertson MJ, Kent K, Tharp N, Nozawa K, Dean L, Mathew M, Grimm SL, Yu Z, Légaré C, Fujihara Y, Ikawa M, Sullivan R, Coarfa C, Matzuk MM, Garcia TX. Large-scale discovery of male reproductive tract-specific genes through analysis of RNA-seq datasets. BMC Biol 2020; 18:103. [PMID: 32814578 PMCID: PMC7436996 DOI: 10.1186/s12915-020-00826-z] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 07/08/2020] [Indexed: 12/15/2022] Open
Abstract
Background The development of a safe, effective, reversible, non-hormonal contraceptive method for men has been an ongoing effort for the past few decades. However, despite significant progress on elucidating the function of key proteins involved in reproduction, understanding male reproductive physiology is limited by incomplete information on the genes expressed in reproductive tissues, and no contraceptive targets have so far reached clinical trials. To advance product development, further identification of novel reproductive tract-specific genes leading to potentially druggable protein targets is imperative. Results In this study, we expand on previous single tissue, single species studies by integrating analysis of publicly available human and mouse RNA-seq datasets whose initial published purpose was not focused on identifying male reproductive tract-specific targets. We also incorporate analysis of additional newly acquired human and mouse testis and epididymis samples to increase the number of targets identified. We detected a combined total of 1178 genes for which no previous evidence of male reproductive tract-specific expression was annotated, many of which are potentially druggable targets. Through RT-PCR, we confirmed the reproductive tract-specific expression of 51 novel orthologous human and mouse genes without a reported mouse model. Of these, we ablated four epididymis-specific genes (Spint3, Spint4, Spint5, and Ces5a) and two testis-specific genes (Pp2d1 and Saxo1) in individual or double knockout mice generated through the CRISPR/Cas9 system. Our results validate a functional requirement for Spint4/5 and Ces5a in male mouse fertility, while demonstrating that Spint3, Pp2d1, and Saxo1 are each individually dispensable for male mouse fertility. Conclusions Our work provides a plethora of novel testis- and epididymis-specific genes and elucidates the functional requirement of several of these genes, which is essential towards understanding the etiology of male infertility and the development of male contraceptives.
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Affiliation(s)
- Matthew J Robertson
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.,Center for Precision Environmental Health, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA
| | - Katarzyna Kent
- Department of Pathology and Immunology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.,Department of Biology and Biotechnology, University of Houston-Clear Lake, 2700 Bay Area Blvd., Houston, TX, 77058, USA.,Center for Drug Discovery, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA
| | - Nathan Tharp
- Department of Pathology and Immunology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.,Department of Biology and Biotechnology, University of Houston-Clear Lake, 2700 Bay Area Blvd., Houston, TX, 77058, USA.,Center for Drug Discovery, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA
| | - Kaori Nozawa
- Department of Pathology and Immunology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.,Center for Drug Discovery, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA
| | - Laura Dean
- Department of Pathology and Immunology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.,Department of Biology and Biotechnology, University of Houston-Clear Lake, 2700 Bay Area Blvd., Houston, TX, 77058, USA.,Center for Drug Discovery, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA
| | - Michelle Mathew
- Department of Pathology and Immunology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.,Department of Biology and Biotechnology, University of Houston-Clear Lake, 2700 Bay Area Blvd., Houston, TX, 77058, USA.,Center for Drug Discovery, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA
| | - Sandra L Grimm
- Center for Precision Environmental Health, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.,Department of Molecular and Cellular Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA
| | - Zhifeng Yu
- Department of Pathology and Immunology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.,Center for Drug Discovery, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA
| | - Christine Légaré
- Department Obstetrics, Gynecology and Reproduction, Faculty Medicine, Université Laval, Quebec, QC, Canada.,Reproduction, Mother and Youth Health Division, Centre de recherche du CHU de Québec-Université Laval, 2705 boul Laurier, Quebec, QC, G1V 4G2, Canada
| | - Yoshitaka Fujihara
- Department of Pathology and Immunology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.,Center for Drug Discovery, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.,Department of Experimental Genome Research, Research Institute for Microbial Diseases, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.,Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center, 6-1 Kishibeshinmachi, Suita, Osaka, 564-8565, Japan
| | - Masahito Ikawa
- Department of Experimental Genome Research, Research Institute for Microbial Diseases, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Robert Sullivan
- Department Obstetrics, Gynecology and Reproduction, Faculty Medicine, Université Laval, Quebec, QC, Canada.,Reproduction, Mother and Youth Health Division, Centre de recherche du CHU de Québec-Université Laval, 2705 boul Laurier, Quebec, QC, G1V 4G2, Canada
| | - Cristian Coarfa
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA. .,Center for Precision Environmental Health, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA. .,Department of Molecular and Cellular Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.
| | - Martin M Matzuk
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.,Department of Pathology and Immunology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.,Center for Drug Discovery, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.,Department of Molecular and Cellular Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA
| | - Thomas X Garcia
- Department of Pathology and Immunology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA. .,Department of Biology and Biotechnology, University of Houston-Clear Lake, 2700 Bay Area Blvd., Houston, TX, 77058, USA. .,Center for Drug Discovery, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.
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12
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Wang Y, Li L, Yang Y, Feng J, Wang L, Zhang H. Copy Number Variation in MUC5AC and Susceptibility to Allergic Rhinitis: A Low-Coverage Whole-Genome Sequencing and Validation Cohort Study. Genet Test Mol Biomarkers 2020; 24:173-180. [PMID: 32208937 DOI: 10.1089/gtmb.2019.0166] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Background: The contribution of genetic copy number variations (CNVs) to allergic rhinitis (AR) remains unknown. The aim of this study was to identify genetic CNVs related to AR in the Han Chinese population. Methods: A case/parent trio of patients of Han Chinese descent affected with AR was examined using low-coverage whole-genome sequencing. Select CNVs were also explored for AR association in a validation cohort of 696 diagnosed AR patients and 528 matched controls. AccuCopy™, a multiplex fluorescence competitive polymerase chain reaction (PCR) assay, was used for genotyping of the CNV and was further validated with real-time PCR. Results: In the case/parent trio study, 67 CNVs were found in the Database of Genomic Variants and shared by patients within the family; 7 of these CNVs had a frequency higher than 0.05. A duplication at 11P15.5 was found involving three mucin-encoding genes (MUC2, MUC5AC, and MUC5B) previously identified as candidate genes for asthma and other chronic inflammatory upper airway diseases. In the validation cohort, no CNVs for MUC2 or MUC5B were identified. However, in the case group, 36.21% of individuals had a duplication of MUC5AC, and 28.03% of controls had MUC5AC duplication (χ2 = 9.123; p = 0.0025). The association of MUC5AC copy number with AR was significant in a multivariable logistic regression analysis after adjusting for age and sex (Padj = 0.0010; OR = 2.073; 95% CI, 1.625-2.805). Real-time PCR validation confirmed duplication of MUC5AC, and the CNV genotype detected with the AccuCopy assay was validated for 58 (96.67%) individuals. Furthermore, individuals with a high MUC5AC copy number showed enhanced total blood eosinophil counts in both the total sample group and the case group (Spearman's ρ: 0.162, p < 0.001; Spearman's ρ: 0.240, p < 0.001). Conclusions: MUC5AC copy number is associated with AR susceptibility. Additional validation and functional studies are warranted to elucidate the effect of MUC5AC CNV on gene expression and AR risk.
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Affiliation(s)
- Yan Wang
- Department of Otolaryngology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Linge Li
- Department of Otolaryngology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Yuping Yang
- Department of Otolaryngology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Juan Feng
- Department of Otolaryngology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Lingling Wang
- Department of Otolaryngology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Hua Zhang
- Department of Otolaryngology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
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13
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Mei X, Qi D, Zhang T, Zhao Y, Jin L, Hou J, Wang J, Lin Y, Xue Y, Zhu P, Liu Z, Huang L, Nie J, Si W, Ma J, Ye J, Finnell RH, Saiyin H, Wang H, Zhao J, Zhao S, Xu W. Inhibiting MARSs reduces hyperhomocysteinemia-associated neural tube and congenital heart defects. EMBO Mol Med 2020; 12:e9469. [PMID: 32003121 PMCID: PMC7059139 DOI: 10.15252/emmm.201809469] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Revised: 12/16/2019] [Accepted: 12/19/2019] [Indexed: 02/05/2023] Open
Abstract
Hyperhomocysteinemia is a common metabolic disorder that imposes major adverse health consequences. Reducing homocysteine levels, however, is not always effective against hyperhomocysteinemia-associated pathologies. Herein, we report the potential roles of methionyl-tRNA synthetase (MARS)-generated homocysteine signals in neural tube defects (NTDs) and congenital heart defects (CHDs). Increased copy numbers of MARS and/or MARS2 were detected in NTD and CHD patients. MARSs sense homocysteine and transmit its signal by inducing protein lysine (N)-homocysteinylation. Here, we identified hundreds of novel N-homocysteinylated proteins. N-homocysteinylation of superoxide dismutases (SOD1/2) provided new mechanistic insights for homocysteine-induced oxidative stress, apoptosis and Wnt signalling deregulation. Elevated MARS expression in developing and proliferating cells sensitizes them to the effects of homocysteine. Targeting MARSs using the homocysteine analogue acetyl homocysteine thioether (AHT) reversed MARS efficacy. AHT lowered NTD and CHD onsets in retinoic acid-induced and hyperhomocysteinemia-induced animal models without affecting homocysteine levels. We provide genetic and biochemical evidence to show that MARSs are previously overlooked genetic determinants and key pathological factors of hyperhomocysteinemia, and suggest that MARS inhibition represents an important medicinal approach for controlling hyperhomocysteinemia-associated diseases.
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14
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Li D, Lin C, Li N, Du Y, Yang C, Bai Y, Feng Z, Su C, Wu R, Song S, Yan P, Chen M, Jain A, Huang L, Zhang Y, Li X. PLAGL2 and POFUT1 are regulated by an evolutionarily conserved bidirectional promoter and are collaboratively involved in colorectal cancer by maintaining stemness. EBioMedicine 2019; 45:124-138. [PMID: 31279780 PMCID: PMC6642334 DOI: 10.1016/j.ebiom.2019.06.051] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 06/25/2019] [Accepted: 06/26/2019] [Indexed: 02/07/2023] Open
Abstract
Background Our previous study revealed that PLAGL2 or POFUT1 can promote tumorigenesis and maintain significant positive correlations in colorectal cancer (CRC). However, the mechanism leading to the co-expression and the underlying functional and biological implications remain unclear. Methods Clinical tumor tissues and TCGA dataset were utilized to analyze the co-expression of PLAGL2 and POFUT1. Luciferase reporter assays, specially made bidirectional promoter vectors and ectopic expression of 3’UTR were employed to study the mechanisms of co-expression. In vitro and in vivo assays were performed to further confirm the oncogenic function of both. The sphere formation assay, immunofluorescence, Western blot and qRT-PCR were performed to investigate the effect of both genes in colorectal cancer stem cells (CSCs). Findings PLAGL2 and POFUT1 maintained co-expression in CRC (r = 0.91, p < .0001). An evolutionarily conserved bidirectional promoter, rather than post-transcriptional regulation by competing endogenous RNAs, caused the co-expression of PLAGL2 and POFUT1 in CRC. The bidirectional gene pair PLAGL2/POFUT1 was subverted in CRC and acted synergistically to promote colorectal tumorigenesis by maintaining stemness of colorectal cancer stem cells through the Wnt and Notch pathways. Finally, PLAGL2 and POFUT1 share transcription factor binding sites, and introducing mutations into promoter regions with shared transcription regulatory elements led to a decrease in the PLAGL2/POFUT1 promoter activity in both directions. Interpretation Our team identified for the first time a bidirectional promoter pair oncogene, PLAGL2-POFUT1, in CRC. The two genes synergistically promote the progression of CRC and affect the characteristics of CSCs, which can offer promising intervention targets for clinicians and researchers. Fund National Nature Science Foundation of China, the Hunan province projects of Postgraduate Independent Exploration and Innovation of Central South University.
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Affiliation(s)
- Daojiang Li
- Department of gastroenterological surgery, The Third XiangYa Hospital of Central South University, Changsha, Hunan 410013, China; Department of Colorectal and Anal Surgery of Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Changwei Lin
- Department of gastroenterological surgery, The Third XiangYa Hospital of Central South University, Changsha, Hunan 410013, China
| | - Nanpeng Li
- Department of gastroenterological surgery, The Third XiangYa Hospital of Central South University, Changsha, Hunan 410013, China
| | - Yuheng Du
- Department of gastroenterological surgery, The Third XiangYa Hospital of Central South University, Changsha, Hunan 410013, China
| | - Chunxing Yang
- Department of gastroenterological surgery, The Third XiangYa Hospital of Central South University, Changsha, Hunan 410013, China
| | - Yang Bai
- Department of gastroenterological surgery, The Third XiangYa Hospital of Central South University, Changsha, Hunan 410013, China
| | - Zhicai Feng
- Department of Burns and Plastic Surgery, the 3rd Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
| | - Chen Su
- Department of gastroenterological surgery, The Third XiangYa Hospital of Central South University, Changsha, Hunan 410013, China
| | - Runliu Wu
- Department of gastroenterological surgery, The Third XiangYa Hospital of Central South University, Changsha, Hunan 410013, China
| | - Shenglei Song
- Department of gastroenterological surgery, The Third XiangYa Hospital of Central South University, Changsha, Hunan 410013, China
| | - Peicheng Yan
- Department of gastroenterological surgery, The Third XiangYa Hospital of Central South University, Changsha, Hunan 410013, China
| | - Miao Chen
- Department of gastroenterological surgery, The Third XiangYa Hospital of Central South University, Changsha, Hunan 410013, China
| | - Arad Jain
- College of Arts and Science, University of Virginia, Charlottesville, Virginia 22904, United States of America
| | - Lihua Huang
- Center for Experimental Medicine, The Third XiangYa Hospital of Central South University, Changsha, Hunan 410013, China
| | - Yi Zhang
- Department of gastroenterological surgery, The Third XiangYa Hospital of Central South University, Changsha, Hunan 410013, China
| | - Xiaorong Li
- Department of gastroenterological surgery, The Third XiangYa Hospital of Central South University, Changsha, Hunan 410013, China; Center for Experimental Medicine, The Third XiangYa Hospital of Central South University, Changsha, Hunan 410013, China.
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15
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Zhang M, Gu Y, Huang S, Lou Q, Xie Q, Xu Z, Chen Y, Pan F, Xu S, Liu S, Tao J, Liu S, Cai J, Chen P, Qian L, Wang C, Liang C, Huang H, Pan H, Su H, Cheng J, Zhang Y, Hu W, Zou Y. Copy number variations and polymorphisms in HSP90AB1 and risk of systemic lupus erythematosus and efficacy of glucocorticoids. J Cell Mol Med 2019; 23:5340-5348. [PMID: 31124601 PMCID: PMC6653051 DOI: 10.1111/jcmm.14410] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 05/04/2019] [Accepted: 05/08/2019] [Indexed: 11/26/2022] Open
Abstract
The aim of our study was to assess the associations of HSP90AB1 copy number variations (CNVs) with systemic lupus erythematosus (SLE) risk and glucocorticoids (GCs) efficacy, as well as the relationship between HSP90AB1 single‐nucleotide polymorphisms (SNPs) and GCs efficacy. HSP90AB1 CNVs and SLE risk were analysed in 519 patients and 538 controls. Patients treated with GCs were followed up for 12 weeks and were divided into sensitive and insensitive groups to investigate the effects of CNVs (419 patients) and SNPs (457 patients) on the efficacy of GCs. Health‐related quality of life (HRQoL) was also measured by SF‐36 at baseline and week 12 to explore the relationship between CNVs/SNPs and HRQoL improvements in Chinese SLE patients. Our results indicated a statistically significant association between HSP90AB1 CNVs and SLE (PBH = 0.039), and this association was more pronounced in the female subgroup (PBH = 0.039). However, we did not detect association of HSP90AB1 CNVs/SNPs with efficacy of GCs. But we found a marginal association between SNP rs13296 and improvement in Role‐emotional, while this association was not strong enough to survive in the multiple testing corrections. Collectively, our findings suggest that the copy number of HSP90AB1 is associated with SLE susceptibility. But copy number and polymorphisms of HSP90AB1 may not be associated with efficacy of GCs.
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Affiliation(s)
- Man Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China.,The Key Laboratory of Anhui Medical Autoimmune Diseases, Hefei, China
| | - Yuanyuan Gu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China.,The Key Laboratory of Anhui Medical Autoimmune Diseases, Hefei, China
| | - Shunwei Huang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China.,The Key Laboratory of Anhui Medical Autoimmune Diseases, Hefei, China
| | - Qiuyue Lou
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China.,The Key Laboratory of Anhui Medical Autoimmune Diseases, Hefei, China
| | - Qiaomei Xie
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China.,The Key Laboratory of Anhui Medical Autoimmune Diseases, Hefei, China
| | - Zhiwei Xu
- School of Public Health and Social Work, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia
| | - Yangfan Chen
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Faming Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China.,The Key Laboratory of Anhui Medical Autoimmune Diseases, Hefei, China
| | - Shengqian Xu
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Shengxiu Liu
- Institute of Dermatology and Department of Dermatology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jinhui Tao
- Department of Rheumatology and Immunology, Anhui Medical University Affiliated Provincial Hospital, Hefei, China
| | - Shuang Liu
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jing Cai
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Peiling Chen
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Long Qian
- Department of Rheumatology and Immunology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Chunhuai Wang
- Department of Rheumatology and Immunology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Chunmei Liang
- Department of Laboratory Medicine, School of Public Health, Anhui Medical University, Hefei, China
| | - Hailiang Huang
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China
| | - Haifeng Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China.,The Key Laboratory of Anhui Medical Autoimmune Diseases, Hefei, China
| | - Hong Su
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China.,The Key Laboratory of Anhui Medical Autoimmune Diseases, Hefei, China
| | - Jian Cheng
- School of Public Health and Social Work, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia
| | - Yuzhou Zhang
- School of Public Health and Social Work, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia
| | - Wenbiao Hu
- School of Public Health and Social Work, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia
| | - Yanfeng Zou
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China.,The Key Laboratory of Anhui Medical Autoimmune Diseases, Hefei, China
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16
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Bai Y, Yang C, Wu R, Huang L, Song S, Li W, Yan P, Lin C, Li D, Zhang Y. YTHDF1 Regulates Tumorigenicity and Cancer Stem Cell-Like Activity in Human Colorectal Carcinoma. Front Oncol 2019; 9:332. [PMID: 31131257 PMCID: PMC6509179 DOI: 10.3389/fonc.2019.00332] [Citation(s) in RCA: 201] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Accepted: 04/11/2019] [Indexed: 01/05/2023] Open
Abstract
YTH N6-methyladenosine (m6A) RNA binding protein 1 (YTHDF1) is a core factor in RNA methylation modification. Recent studies have shown that m6A is closely related to multiple tumors, thus YTHDF1 may also play a role in tumorigenesis. This study, aimed to explore the role of YTHDF1 in the colorectal cancer (CRC). In this study, we identified YTHDF1 as being highly expressed at the mRNA and protein levels in TCGA, GEO CRC and primary CRC. Furthermore, the YTHDF1 gene copy number was positively correlated with YTHDF1 mRNA expression in CRC. Knocking down the expression of YTHDF1 significantly inhibited the CRC cell's tumorigenicity in vitro and murine xenograft tumor growth in vivo. Furthermore, silencing of YTHDF1 inhibited the colonosphere formation ability in vitro. Mechanistically, we found that silencing YTHDF1 significantly inhibited Wnt/β-catenin pathway activity in CRC cells. Together, YTHDF1 is overexpressed in CRC and plays a vital oncogenic role in CRC, and this novel finding may provide a potential therapeutic target for CRC.
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Affiliation(s)
- Yang Bai
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Chunxing Yang
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Runliu Wu
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Lihua Huang
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Shenlei Song
- Center for Medical Experiments, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Wanwan Li
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Peichen Yan
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Changwei Lin
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Daojiang Li
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Yi Zhang
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, China
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17
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Xie X, Chen C, Liang Q, Wu X, Wang X, Wu W, Ding Q. Characterization of two large duplications of
F9
associated with mild and severe haemophilia B, respectively. Haemophilia 2019; 25:475-483. [PMID: 30866119 DOI: 10.1111/hae.13704] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Revised: 09/06/2018] [Accepted: 01/23/2019] [Indexed: 02/01/2023]
Affiliation(s)
- Xiaoling Xie
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital Shanghai Jiaotong University School of Medicine Shanghai China
| | - Changming Chen
- Department of Laboratory Medicine, Ruijin Hospital Shanghai Jiaotong University School of Medicine Shanghai China
| | - Qian Liang
- Department of Laboratory Medicine, Ruijin Hospital Shanghai Jiaotong University School of Medicine Shanghai China
| | - Xi Wu
- Department of Laboratory Medicine, Ruijin Hospital Shanghai Jiaotong University School of Medicine Shanghai China
| | - Xuefeng Wang
- Department of Laboratory Medicine, Ruijin Hospital Shanghai Jiaotong University School of Medicine Shanghai China
- Collaborative Innovation Center of Hematology Shanghai Jiaotong University School of Medicine Shanghai China
| | - Wenman Wu
- Collaborative Innovation Center of Hematology Shanghai Jiaotong University School of Medicine Shanghai China
- Faculty of Medical Laboratory Science, Ruijin Hospital Shanghai Jiaotong University School of Medicine Shanghai China
| | - Qiulan Ding
- Department of Laboratory Medicine, Ruijin Hospital Shanghai Jiaotong University School of Medicine Shanghai China
- Collaborative Innovation Center of Hematology Shanghai Jiaotong University School of Medicine Shanghai China
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18
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Lu Y, Wu X, Dai J, Ding Q, Wu W, Wang X. The characteristics and spectrum of F9 mutations in Chinese sporadic haemophilia B pedigrees. Haemophilia 2019; 25:316-323. [PMID: 30648777 DOI: 10.1111/hae.13681] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 07/06/2018] [Accepted: 12/20/2018] [Indexed: 01/01/2023]
Abstract
INTRODUCTION Sporadic haemophilia B (HB) without obvious familial history poses challenges for genetic diagnosis and counselling. AIM To identify the F9 variants in sporadic HB patients and probe the origin of these de novo mutations. METHOD A total of 294 unrelated HB pedigrees sought genetic diagnosis were analysed in this single-centre study. The F9 gene was analysed by direct sequencing, and AccuCopy technique was adopted to screen for gene copy number variations. Six short tandem repeats approximal or within F9 gene were applied for linkage analysis. Mosaicism of sequence variant was determined by ddNTP Primer Extension method. RESULTS Sporadic HB patients constituted 36% (61/294) of cases enrolled in current study. The sporadic and familial HB patients shared similar spectrum of F9 variants, with single nucleotide substitution as predominant form of disease-causing mutation and no mutation prone hotspot sites, including CpG dinucleotide sequences, had been identified. Majority of the mothers of sporadic HB patients were F9 mutation carriers (70%, 43/61), and most of them (95%, 41/43) had the inherited bleeding trait traced back to maternal grandfathers. Although most de novo mutations occur in germ cells, 2 maternal grandfathers, who had somatic mosaic mutations of F9, were also revealed to be the source of genetic variations identified in patients. In our cohort, FIX inhibitor incidence was 1%, developed only in patients carrying null mutations. CONCLUSION The diversity of F9 genetic variants and possible mosaicism of de novo mutation demand extensive study and more cautious in genetic counselling of sporadic HB.
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Affiliation(s)
- Yeling Lu
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xi Wu
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Dai
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qiulan Ding
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wenman Wu
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xuefeng Wang
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Chen K, Dong SS, Wu N, Wu ZH, Zhou YX, Li K, Zhang F, Xiao JH. A novel multiplex fluorescent competitive PCR for copy number variation detection. Genomics 2018; 111:1745-1751. [PMID: 30529537 DOI: 10.1016/j.ygeno.2018.11.029] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Revised: 11/09/2018] [Accepted: 11/28/2018] [Indexed: 10/27/2022]
Abstract
The copy number variation (CNV) is an important genetic marker in cancer and other diseases. To detect CNVs of specific genetic loci, the multiplex ligation-dependent probe amplification (MLPA) is an appropriate approach, but the experimental optimization and probe synthesis are still great challenges. The multiplex competitive PCR is an alternative method for CNV detection. However, the construction of internal competitive template and establishment of a stable multiplex PCR system are the main limiting factors for this method. Here, we introduce a novel multiplex fluorescent competitive PCR (NMFC-PCR) for detecting CNVs. In this method, the blunt hairpin primers are used to rapidly establish a stable multiplex PCR system due to the reduction of non-specific amplification, and limited cycles' amplification is used to obtain the internal competitive template instead of artificial synthesis. With this method, we tested 21 clinical samples with potential LIM homeobox 1 (LHX1) or T-box 6 (TBX6) deletion. Every three segments located on the LHX1 and TBX6 were selected as the target regions, while two segments located on X-chromosome and five segments located on autosome were selected as the reference regions for detecting CNVs. The results showed that the gender information of 21 samples can be accurately inferred by the copy number ratio (CNR) of X-chromosomal reference region to autosomal reference region (X/A), and 2 samples had one copy of LHX1 and 9 samples had one copy of TBX6. To evaluate the accuracy of NMFC-PCR, 5 random samples with CNV were also detected by array-based comparative genomic hybridization (aCGH), and the results of aCGH were consistent with the NMFC-PCR results. To further assess the performance of NMFC-PCR, 60 normal samples were simultaneously tested. The results showed that the gender results were exactly the same as known information, and CNVs of LHX1 or TBX6 were not found. In conclusion, the method is a cheap, efficient, accurate, and convenient competitive PCR method for CNV detection.
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Affiliation(s)
- Ke Chen
- College of Environmental Science and Engineering, Donghua University, Shanghai, China
| | - Shuang-Shuang Dong
- Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering at School of Life Sciences, Institute of Reproduction and Development, Fudan University, Shanghai, China; Key Laboratory of Reproduction Regulation of NHFPC, Collaborative Innovation Center of Genetics and Development, Fudan University, Shanghai, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China
| | - Nan Wu
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China; Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences, Beijing, China
| | - Zhi-Hong Wu
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China; Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences, Beijing, China
| | - Yu-Xun Zhou
- Institute of Biological Sciences and Biotechnology, Donghua University, Shanghai, China
| | - Kai Li
- Institute of Biological Sciences and Biotechnology, Donghua University, Shanghai, China
| | - Feng Zhang
- Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering at School of Life Sciences, Institute of Reproduction and Development, Fudan University, Shanghai, China; Key Laboratory of Reproduction Regulation of NHFPC, Collaborative Innovation Center of Genetics and Development, Fudan University, Shanghai, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.
| | - Jun-Hua Xiao
- Institute of Biological Sciences and Biotechnology, Donghua University, Shanghai, China.
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Li W, Wang Y, Li B, Tang B, Sun H, Lai J, He N, Li B, Meng H, Liao W, Liu X. 16p11.2 deletion in patients with paroxysmal kinesigenic dyskinesia but without intellectual disability. Brain Behav 2018; 8:e01134. [PMID: 30307717 PMCID: PMC6236233 DOI: 10.1002/brb3.1134] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Revised: 09/09/2018] [Accepted: 09/12/2018] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION Mutations of the PRRT2 gene are the most common cause for paroxysmal kinesigenic dyskinesia. However, patients with negative PRRT2 mutations are not rare. The aim of this study is to determine whether copy number variant of PRRT2 gene is another potential pathogenic mechanism in the patients with paroxysmal kinesigenic dyskinesia with negative PRRT2 point and frameshift mutations. METHODS We screened PRRT2 copy number variants using the AccuCopy™ method in 29 patients with paroxysmal kinesigenic dyskinesia with negative PRRT2 point and frameshift mutations. Next-generation sequencing was used to determine the chromosomal deletion sites in patients with PRRT2 copy number variants, and to exclude mutations in other known causative genes for paroxysmal kinesigenic dyskinesia. RESULTS Two sporadic patients with negative PRRT2 point and frameshift mutations (6.9%) were identified to have de novo PRRT2 copy number deletions (591 and 832 Kb deletions located in 16p11.2). The two patients presented with pure paroxysmal kinesigenic dyskinesia and paroxysmal kinesigenic dyskinesia and benign infantile convulsions, respectively. They had normal intelligence and neuropsychiatric development, in contrast to those previously reported with 16p11.2 deletions complicated with neuropsychiatric disorders. No correlation between the deletion ranges and phenotypic variations was found. CONCLUSION 16p11.2 deletions play causative roles in paroxysmal kinesigenic dyskinesia, especially for sporadic cases. Our findings extend the phenotype of 16p11.2 deletions to pure paroxysmal kinesigenic dyskinesia. Screening for 16p11.2 deletions should thus be included in genetic evaluations for patients with paroxysmal kinesigenic dyskinesia.
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Affiliation(s)
- Wen Li
- Institute of Neuroscience, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province, the Ministry of Education of China, Guangzhou, China
| | - Yifan Wang
- Institute of Neuroscience, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province, the Ministry of Education of China, Guangzhou, China
| | - Bin Li
- Institute of Neuroscience, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province, the Ministry of Education of China, Guangzhou, China
| | - Bin Tang
- Institute of Neuroscience, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province, the Ministry of Education of China, Guangzhou, China
| | - Hui Sun
- Institute of Neuroscience, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province, the Ministry of Education of China, Guangzhou, China
| | - Jinxing Lai
- Institute of Neuroscience, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province, the Ministry of Education of China, Guangzhou, China
| | - Na He
- Institute of Neuroscience, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province, the Ministry of Education of China, Guangzhou, China
| | - Bingmei Li
- Institute of Neuroscience, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province, the Ministry of Education of China, Guangzhou, China
| | - Heng Meng
- Department of Neurology, the First Affiliated Hospital and Clinical Neuroscience Institute, Jinan University, Guangzhou, China
| | - Weiping Liao
- Institute of Neuroscience, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province, the Ministry of Education of China, Guangzhou, China
| | - Xiaorong Liu
- Institute of Neuroscience, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province, the Ministry of Education of China, Guangzhou, China
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21
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Yan YX, Li JJH, Xiao HB, Wang S, He Y, Wu LJ. Association analysis of copy number variations in type 2 diabetes-related susceptible genes in a Chinese population. Acta Diabetol 2018; 55:909-916. [PMID: 29858661 DOI: 10.1007/s00592-018-1168-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Accepted: 05/25/2018] [Indexed: 01/19/2023]
Abstract
AIMS Copy number variations (CNVs) have been implicated as an important genetic marker of common disease. In this study, we explored genetic effects of common CNVs in Type 2 diabetes (T2D) related susceptible genes in Chinese population. METHODS Seven common CNV loci were selected from genes enclosing the susceptible single nucleotide polymorphisms (SNPs) of T2D confirmed by genome-wide association studies (GWAS) and replication studies conducted in east Asia population. The CNVs and SNPs were genotyped in 504 T2D patients and 494 non-T2D controls. Cumulative effect of the positive CNV loci was measured using genetic risk score (GRS). Multiplicative and additive interaction between candidate CNV loci and SNPs were assessed. RESULTS Compared with the common two copies, the deletion of nsv6360 (adjusted OR = 2.28, 95% CI 1.37-3.78, P = 0.001), nsv8414 (adjusted OR = 1.89, 95% CI 1.16-3.08, P = 0.006) and nsv1898 (adjusted OR = 1.84, 95% CI 1.19-2.84, P = 0.005) were significantly associated with increased risk of T2D (P < 0.007). Significant dose-response relationship was observed between GRS and the risk of T2D (χ2 for trend = 19.51, P < 0.001). In addition, significant additive interactions between nsv8414 and rs17584499 in PTPRD (AP = 0.60, 95% CI 0.12-1.07) and nsv1898 and rs16955379 in CMIP (AP = 0.46, 95% CI 0.01-0.91) were observed. CONCLUSIONS There were three CNV loci (nsv6360, nsv8414 and nsv1898) associated with T2D, and a significant cumulative effect of these loci on the risk of T2D. The comprehensive effects of both CNVs and SNPs may provide a more useful tool for the identification of genetic susceptibility for T2D.
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Affiliation(s)
- Yu-Xiang Yan
- Department of Epidemiology and Biostatistics, School of Public Health, Capital Medical University, No. 10 Xitoutiao, You An Men, Beijing, 100069, People's Republic of China.
- Municipal Key Laboratory of Clinical Epidemiology, Beijing, People's Republic of China.
| | - Jia-Jiang-Hui Li
- Department of Epidemiology and Biostatistics, School of Public Health, Capital Medical University, No. 10 Xitoutiao, You An Men, Beijing, 100069, People's Republic of China
| | - Huan-Bo Xiao
- Department of Preventive Medicine, Yanjing Medical College, Capital Medical University, Beijing, People's Republic of China
| | - Shuo Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Capital Medical University, No. 10 Xitoutiao, You An Men, Beijing, 100069, People's Republic of China
| | - Yan He
- Department of Epidemiology and Biostatistics, School of Public Health, Capital Medical University, No. 10 Xitoutiao, You An Men, Beijing, 100069, People's Republic of China
- Municipal Key Laboratory of Clinical Epidemiology, Beijing, People's Republic of China
| | - Li-Juan Wu
- Department of Epidemiology and Biostatistics, School of Public Health, Capital Medical University, No. 10 Xitoutiao, You An Men, Beijing, 100069, People's Republic of China.
- Municipal Key Laboratory of Clinical Epidemiology, Beijing, People's Republic of China.
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22
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23
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Low responsiveness to a hepatitis B virus vaccine in a Chinese population lacks association with ITGAL, CD58, TNFSF15, CCL15, TGFB3, and BCL6 gene variants. INFECTION GENETICS AND EVOLUTION 2018; 64:126-130. [PMID: 29902581 DOI: 10.1016/j.meegid.2018.06.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Revised: 03/14/2018] [Accepted: 06/06/2018] [Indexed: 12/27/2022]
Abstract
It is known that multiple genetic variants can affect immune responses to the hepatitis B virus (HBV) vaccine. A case-control study was undertaken to examine the possible association of low responsiveness to the HBV vaccine in a Chinese population with genetic polymorphisms in integrin subunit alpha L, CD58, tumor necrosis factor superfamily member 15, C-C motif chemokine ligand 15, transforming growth factor beta 3, and B-cell lymphoma 6 protein. The copy numbers of these six genes were detected in 129 low responders, 129 middle responders and 129 high responders to HBV vaccination. There were no significant differences in the copy numbers of these six genes between the groups. Thus, these findings indicated that the copy number variations of these genes may not be the reason for the low responsiveness to the HBV vaccine in a Chinese population.
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Yan Y, Yang X, Liu Y, Shen Y, Tu W, Dong Q, Yang D, Ma Y, Yang Y. Copy number variation of functional RBMY1 is associated with sperm motility: an azoospermia factor-linked candidate for asthenozoospermia. Hum Reprod 2018; 32:1521-1531. [PMID: 28498920 DOI: 10.1093/humrep/dex100] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Accepted: 04/28/2017] [Indexed: 02/05/2023] Open
Abstract
STUDY QUESTION What is the influence of copy number variation (CNV) in functional RNA binding motif protein Y-linked family 1 (RBMY1) on spermatogenic phenotypes? SUMMARY ANSWER The RBMY1 functional copy dosage is positively correlated with sperm motility, and dosage insufficiency is an independent risk factor for asthenozoospermia. WHAT IS KNOWN ALREADY RBMY1, a multi-copy gene expressed exclusively in the adult testis, is one of the most important candidates for male infertility in the azoospermia factor (AZF) region of the Y-chromosome. RBMY1 encodes an RNA-binding protein that serves as a pre-mRNA splicing regulator during spermatogenesis, and male mice deficient in Rbmy are sterile. STUDY DESIGN, SIZE, DURATION A total of 3127 adult males were recruited from 2009 to 2016; of this group, the dosage of RBMY1 functional copy were investigated in 486 fertile males. In the remaining 2641 males with known spermatogenesis status, 1070 Y-chromosome haplogroup (Y-hg) O3* or O3e carriers without chromosomal aberration or known AZF structure mutations responsible for spermatogenic impairment, including 506 men with normozoospermia and 564 men with oligozoospermia or/and asthenozoospermia, were screened, and the RBMY1 functional copy dosage and copy conversion were determined to explore their associations with sperm phenotypes. The correlation between RBMY1 dosage and its mRNA level or RBMY1 protein level and the correlation between sperm RBMY1 level and motility were analysed in 15 testis tissue samples and eight semen samples. Ten additional semen samples were used to confirm the subcellular localization of RBMY1 in individual sperm. PARTICIPANTS/MATERIALS, SETTING, METHODS All the Han volunteers donating whole blood, semen and testis tissue were from southwest China. RBMY1 copy number, copy conversion, mRNA/protein amount and protein location in sperm were detected using the AccuCopy® assay method, paralog ratio test, quantitative PCR, western blotting and immunofluorescence staining methods, respectively. MAIN RESULTS AND THE ROLE OF CHANCE This study identified Y-hg-independent CNV of functional RBMY1 in the enrolled population. A difference in the distribution of RBMY1 copy number was observed between the group with normal sperm motility and the group with asthenozoospermia. A positive correlation between the RBMY1 copy dosage and sperm motility was identified, and the males with fewer than six copies of RBMY1 showed an elevated risk for asthenozoospermia relative to those with six RBMY1 copies, the most common dosage in the population. The RBMY1 copy dosage was positively correlated with its mRNA and protein level in the testis. Sperm with high motility were found to carry more RBMY1 protein than those with relatively low motility. The RBMY1 protein was confirmed to predominantly localize in the neck and mid-piece region of sperm as well as the principal piece of the sperm tail. Our population study completes a chain of evidence suggesting that RBMY1 influences the susceptibility of males to asthenozoospermia by modulating sperm motility. LIMITATIONS REASONS FOR CAUTION High sequence similarity between the RBMY1 functional copies and a large number of pseudogenes potentially reduces the accuracy of the copy number detection. The mechanism underlying the CNV in RBMY1 is still unclear, and the effect of the structural variations in the RBMY1 copy cluster on the copy dosage of other protein-coding genes located in the region cannot be excluded, which may potentially bias our observations. WIDER IMPLICATIONS OF THE FINDINGS Asthenozoospermia is a multi-factor complex disease with a limited number of proven susceptibility genes. This study identified a novel genomic candidate independently contributing to the condition, enriching our understanding of the role of AZF-linked genes in male reproduction. Our finding provides insight into the physiological and pathological characteristics of RBMY1 in terms of sperm motility, supplies persuasive evidence of the significance of RBMY1 copy number analysis in the clinical counselling of male infertility resulting from asthenozoospermia. STUDY FUNDING/COMPETING INTEREST(S) This work was funded by the National Natural Science Foundation of China (Nos. 81370748 and 30971598). The authors have no conflicts of interest.
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Affiliation(s)
- Yuanlong Yan
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 1, Keyuan Road 4, Gaopeng Street, Chengdu, Sichuan 610041, China
| | - Xiling Yang
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 1, Keyuan Road 4, Gaopeng Street, Chengdu, Sichuan 610041, China
| | - Yunqiang Liu
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 1, Keyuan Road 4, Gaopeng Street, Chengdu, Sichuan 610041, China
| | - Ying Shen
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 1, Keyuan Road 4, Gaopeng Street, Chengdu, Sichuan 610041, China
| | - Wenling Tu
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 1, Keyuan Road 4, Gaopeng Street, Chengdu, Sichuan 610041, China
| | - Qiang Dong
- Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Dong Yang
- Reproductive Medicine Institute, Chengdu Women's and Children's Central Hospital, Chengdu, Sichuan 610031, China
| | - Yongyi Ma
- Jinjiang Maternal and Child Health Hospital, Chengdu, Sichuan 610016, China
| | - Yuan Yang
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 1, Keyuan Road 4, Gaopeng Street, Chengdu, Sichuan 610041, China
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Lu Y, Xin Y, Dai J, Wu X, You G, Ding Q, Wu W, Wang X. Spectrum and origin of mutations in sporadic cases of haemophilia A in China. Haemophilia 2018; 24:291-298. [PMID: 29381227 DOI: 10.1111/hae.13402] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/11/2017] [Indexed: 02/06/2023]
Affiliation(s)
- Y. Lu
- Department of Laboratory Medicine; Ruijin Hospital; Shanghai Jiao Tong University School of Medicine; Shanghai China
| | - Y. Xin
- Department of Laboratory Medicine; The Fourth Affiliated Hospital; Harbin Medical University; Harbin China
| | - J. Dai
- Department of Laboratory Medicine; Ruijin Hospital; Shanghai Jiao Tong University School of Medicine; Shanghai China
| | - X. Wu
- Department of Laboratory Medicine; Ruijin Hospital; Shanghai Jiao Tong University School of Medicine; Shanghai China
| | - G. You
- Department of Laboratory Medicine; Shanghai Children's Medical Center; Shanghai Jiao Tong University School of Medicine; Shanghai China
| | - Q. Ding
- Department of Laboratory Medicine; Ruijin Hospital; Shanghai Jiao Tong University School of Medicine; Shanghai China
| | - W. Wu
- Department of Laboratory Medicine; Ruijin Hospital; Shanghai Jiao Tong University School of Medicine; Shanghai China
| | - X. Wang
- Department of Laboratory Medicine; Ruijin Hospital; Shanghai Jiao Tong University School of Medicine; Shanghai China
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Lin S, Lin X, Zhang Z, Jiang M, Rao Y, Nie Q, Zhang X. Copy Number Variation in SOX6 Contributes to Chicken Muscle Development. Genes (Basel) 2018; 9:genes9010042. [PMID: 29342086 PMCID: PMC5793193 DOI: 10.3390/genes9010042] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 01/11/2018] [Accepted: 01/12/2018] [Indexed: 11/16/2022] Open
Abstract
Copy number variations (CNVs), which cover many functional genes, are associated with complex diseases, phenotypic diversity and traits that are economically important to raising chickens. The sex-determining region Y-box 6 (Sox6) plays a key role in fast-twitch muscle fiber differentiation of zebrafish and mice, but it is still unknown whether SOX6 plays a role in chicken skeletal muscle development. We identified two copy number polymorphisms (CNPs) which were significantly related to different traits on the genome level in chickens by AccuCopy® and CNVplex® analyses. Notably, five white recessive rock (CN = 1, CN = 3) variant individuals and two Xinghua (CN = 3) variant individuals contain a CNP13 (chromosome5: 10,500,294-10,675,531) which overlaps with SOX6. There is a disordered region in SOX6 proteins 265-579 aa coded by a partial CNV overlapping region. A quantitative real-time polymerase chain reaction showed that the expression level of SOX6 mRNA was positively associated with CNV and highly expressed during the skeletal muscle cell differentiation in chickens. After the knockdown of the SOX6, the expression levels of IGFIR1, MYF6, SOX9, SHOX and CCND1 were significantly down-regulated. All of them directly linked to muscle development. These results suggest that the number of CNVs in the CNP13 is positively associated with the expression level of SOX6, which promotes the proliferation and differentiation of skeletal muscle cells by up-regulating the expression levels of the muscle-growth-related genes in chickens as in other animal species.
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Affiliation(s)
- Shudai Lin
- Guangdong Provincial Key Laboratory of Agro-Animal Genomics and Molecular Breeding, Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, College of Animal Science of South China Agricultural University, Guangzhou 510642, China.
| | - Xiran Lin
- Guangdong Provincial Key Laboratory of Agro-Animal Genomics and Molecular Breeding, Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, College of Animal Science of South China Agricultural University, Guangzhou 510642, China.
| | - Zihao Zhang
- Guangdong Provincial Key Laboratory of Agro-Animal Genomics and Molecular Breeding, Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, College of Animal Science of South China Agricultural University, Guangzhou 510642, China.
| | - Mingya Jiang
- Guangdong Provincial Key Laboratory of Agro-Animal Genomics and Molecular Breeding, Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, College of Animal Science of South China Agricultural University, Guangzhou 510642, China.
| | - Yousheng Rao
- Department of Biological Technology, Nanchang Normal University, Nanchang 330029, China.
| | - Qinghua Nie
- Guangdong Provincial Key Laboratory of Agro-Animal Genomics and Molecular Breeding, Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, College of Animal Science of South China Agricultural University, Guangzhou 510642, China.
| | - Xiquan Zhang
- Guangdong Provincial Key Laboratory of Agro-Animal Genomics and Molecular Breeding, Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, College of Animal Science of South China Agricultural University, Guangzhou 510642, China.
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You G, Chi K, Lu Y, Ding Q, Dai J, Xi X, Wang H, Wang X. Identification and characterisation of a novel aberrant pattern of intron 1 inversion with concomitant large insertion and deletion within the F8 gene. Thromb Haemost 2017; 112:264-70. [DOI: 10.1160/th13-10-0892] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2013] [Accepted: 03/07/2014] [Indexed: 01/16/2023]
Abstract
SummaryIntron 1 inversion (Inv1) is a recurrent causative mutation of haemophilia A (HA) and is responsible for 1–5% of severe HA. Inv1 occurs as a result of intra-chromosomal homologous recombination between int1h-1 within intron 1 and int1h-2 located in approximately 125 kb telomeric to the F8 gene. In this report, we presented a previously undescribed aberrant type of Inv1 with complex genomic rearrangement in a pedigree with severe HA. The breakpoints of the rearrangement were identified by the genome walking technique; copy number variations (CNVs) of the F8 gene and X chromosome were detected by AccuCopy technique, Affymetrix CytoScan HD CNV assay and quantitative PCR (qPCR); the F8 transcripts related to the aberrant Inv1 were analysed by reverse transcription PCR (RT-PCR). We have characterised the exact breakpoints of the complex rearrangement, and determined the location and size of the insertion and deletion. The rearrangements can be summarised as an aberrant pattern of Inv1 with a deletion of 2.56 kb and a duplication of 227.3 kb inserted in the rejoining junction within the F8 gene. Our results suggested that this complex genomic rearrangement was generated by two distinct repair mechanisms of fork stalling and template switching/microhomology-mediated break-induced replication (FoSTeS/MMBIR) and nonallelic homologous recombination (NAHR).
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Ding Q, You G, Dai J, Xi X, Wang H, Wu X, Lu Y, Wang X. Characterisation of large F9 deletions in seven unrelated patients with severe haemophilia B. Thromb Haemost 2017; 112:459-65. [DOI: 10.1160/th13-12-1060] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2013] [Accepted: 03/25/2014] [Indexed: 01/05/2023]
Abstract
SummaryLarge deletions in the F9 gene are detected in approximately 5% of patients with severe haemophilia B, but only a few deletion breakpoints have been characterised precisely until now. In this study we identified a total of seven large F9 deletions in the index patients and nine female carriers by the AccuCopy technique. We also successfully characterised the exact breakpoints for each large deletion including four deletions encompassing the entire F9 gene by the genome walking method combined with primer walking strategy. The extents of deletion regions ranged from 11.1 to 884 kb. Microhomologies ranged from 2 to 6 bp were identified in the breakpoint junctions of six deletions. The other deletion occurred between two highly homologous sequences of the same long interspersed nuclear element 1 (LINE/L1). Non-homologous end joining (NHEJ) and microhomology-mediated break-induced replication (MMBIR) may be the main causative mechanisms for the six large deletions with microhomologies. Non-allelic homologous recombination (NAHR) may mediate the deletion occurred between the two tandem LINEs in the other large deletion. Repetitive elements and non-B DNA forming motifs identified in the junction regions may contribute to DNA breakage leading to large deletions.
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Zheng Z, Yu R, Gao C, Jian X, Quan S, Xing G, Liu S, Liu Z. Low copy number of FCGR3B is associated with lupus nephritis in a Chinese population. Exp Ther Med 2017; 14:4497-4502. [PMID: 29104657 DOI: 10.3892/etm.2017.5069] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2015] [Accepted: 02/27/2017] [Indexed: 12/16/2022] Open
Abstract
Lupus nephritis (LN) is a polygenic disease caused by an interaction between hereditary and environmental factors. Numerous gene copy number variations have been identified to contribute to this disease. Previously, immunoglobulin (Ig)G Fcγ receptor 3B (FCGR3B) copy number variation (CNV) was reported to be associated with LN in the Caucasian population. However, the effect of FCGR3B CNV on LN in the Chinese population remains unknown. The present study aimed to investigate whether CNVs of FCGR3B are associated with LN in the Henan Chinese population. FCGR3B CNVs were determined in 142 LN patients and 328 healthy controls. A modified methodology based on competitive polymerase chain reaction, a Multiplex AccuCopy™ kit was used to detect FCGR3B copy number. Clinical and laboratory data was collected retrospectively from medical records. To evaluate associations between FCGR3B CNVs and LN susceptibility, the present study calculated the odds ratios using a logistic regression analysis. The current study identified that the distribution of FCGR3B copy number was significantly different between LN and healthy controls (P=0.031). A low copy number (<2) of FCGR3B was significantly enriched in LN patients (P=0.042), and was a risk factor for LN (odds ratio=2.059; 95% confidence interval, 1.081-3.921; P=0.028). However, a high copy number (>2) had no effect on LN. There were no associations between FCGR3B CNV and clinical phenotypes of LN. The results from the present study demonstrate that a low copy number of FCGR3B is a risk factor for LN in a Chinese population.
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Affiliation(s)
- Zhaohui Zheng
- Department of Rheumatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Ruohan Yu
- Department of Rheumatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Congcong Gao
- Department of Rheumatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Xianan Jian
- Department of Rheumatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Songxia Quan
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Guolan Xing
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Shengyun Liu
- Department of Rheumatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Zhangsuo Liu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
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Zhang X, Li X, Han R, Chen M, Yuan Y, Hu X, Wang M, Li R, Yang X, Xia Q, Ma Y, Yang J, Tong J, Xu S, Xu J, Shuai Z, Pan F. Copy number variations of the IL-22 gene are associated with ankylosing spondylitis: A case-control study in Chinese Han population. Hum Immunol 2017; 78:547-552. [PMID: 28716697 DOI: 10.1016/j.humimm.2017.07.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Revised: 06/28/2017] [Accepted: 07/11/2017] [Indexed: 12/17/2022]
Abstract
IL-22 provides a new insight into the mechanisms of autoimmunity, and copy number variations (CNVs) are associated with autoimmune diseases. This study aims to explore the association of IL-22 gene CNVs with ankylosing spondylitis (AS) susceptibility. The copy numbers of IL-22 gene (2 fragments: IL-22_1, IL-22_2) were examined by AccuCopy™ methods in a cohort of 649 AS patients and 628 controls. Association of IL-22 CNVs and AS susceptibility was analyzed, and AS risk was estimated by Odds Ratio (ORs) and 95% confidence intervals (CIs), and the Benjamini-Hochberg method was applied to regulate the false discovery rate (FDR). We found one copy of IL-22 gene was significantly associated with AS [OR=0.345, 95%CI (0.144, 0.827), P=0.013, PFDR=0.026] in the IL-22_2 fragment, and this association still exist after adjustment of age and sex [OR=0.344, 95%CI (0.143, 0.825), P=0.017, PFDR=0.034]. In the stratification analysis by gender, the statistical difference was detected in males in the IL-22_2 fragment [OR=0.306, 95%CI (0.121, 0.778), P=0.009, PFDR=0.018; adjusted OR=0.306, 95%CI (0.120, 0.777), P=0.013, PFDR=0.026]. We suggest that IL-22 CNVs are associated with AS and that lower copy number might be a protective factor for AS, especially in male patients.
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Affiliation(s)
- Xu Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Xiaona Li
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Renfang Han
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Mengya Chen
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Yaping Yuan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Xingxing Hu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Mengmeng Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Rui Li
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Xiao Yang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Qing Xia
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Yubo Ma
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Jiajia Yang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Jingjing Tong
- Department of Rheumatism and Immunity, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Shengqian Xu
- Department of Rheumatism and Immunity, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Jianhua Xu
- Department of Rheumatism and Immunity, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Zongwen Shuai
- Department of Rheumatism and Immunity, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Faming Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China.
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The research on association of copy number variation in chromosome 9p21 region with atherothrombotic stroke in the Han Chinese population. J Neurol Sci 2017; 377:88-94. [PMID: 28477716 DOI: 10.1016/j.jns.2017.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Revised: 03/01/2017] [Accepted: 04/03/2017] [Indexed: 11/23/2022]
Abstract
BACKGROUND/PURPOSE The copy number variants (CNVs) contain more genetic information compared with SNPs. The aim of this study was to elucidate whether the CNVs in Chromosome 9p21 region are associated with increased risk of Atherothrombotic stroke (ATS) in a Han Chinese population. METHODS A case-controlled association study was conducted in which only patients with ATS were enrolled. The CNVs were detected by the method of multiplex competitive amplification. The differences in distribution of CNVs between cases and controls were analyzed using univariate and multivariate logistic regression analysis. Subgroup analyses were also carried out to determine whether the effect of the CNVs was specific to age and gender among the subjects. RESULTS A total of 274 ATS patients and 282 health controls were included in the present study. 4 genes (ANRIL, CDKN2A, CDKN2B, and MTAP) including eight gene fragments in all were analyzed for CNV. The results showed that the copied number of most CNV in the 4 genes is two. There was no significant difference of CNV frequency between groups. CONCLUSIONS The obtained data suggested a negative association between CNV of the four genes and ATS. It is necessary to perform sequencing analyses across the entire 9p21 region for detecting rare or uncommon CNV.
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Li F, Li X, Zou GZ, Gao YF, Ye J. Association between TLR7 copy number variations and hepatitis B virus infection outcome in Chinese. World J Gastroenterol 2017; 23:1602-1607. [PMID: 28321161 PMCID: PMC5340812 DOI: 10.3748/wjg.v23.i9.1602] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Revised: 12/27/2016] [Accepted: 01/17/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To explore whether copy number variations (CNVs) of toll-like receptor 7 (TLR7) are associated with susceptibility to chronic hepatitis B virus (HBV) infection.
METHODS This study included 623 patients (495 males and 128 females) with chronic hepatitis B virus infection (CHB) and 300 patients (135 females and 165 males) with acute hepatitis B virus infection (AHB) as controls. All CHB patients were further categorized according to disease progression after HBV infection (CHB, liver cirrhosis, or hepatocellular carcinoma). Copy numbers of the TLR7 gene were measured using the AccuCopy method. χ2 tests were used to evaluate the association between TLR7 CNVs and infection type. P values, odds ratios, and 95% confidence intervals (CIs) were used to estimate the effects of risk.
RESULTS Among male patients, there were significant differences between the AHB group and CHB group in the distribution of TLR7 CNVs. Low copy number of TLR7 was significantly associated with chronic HBV infection (OR = 0.329, 95%CI: 0.229-0.473, P < 0.001). Difference in TLR7 copy number was also found between AHB and CHB female patients, with low copy number again associated with an increased risk of chronic HBV infection (OR = 0.292, 95%CI: 0.173-0.492, P < 0.001). However, there were no significant differences in TLR7 copy number among the three types of chronic HBV infection (CHB, liver cirrhosis, or hepatocellular carcinoma). In addition, there was no association between TLR7 copy number and titer of the HBV e antigen.
CONCLUSION Low TLR7 copy number is a risk factor for chronic HBV infection but is not associated with later stages of disease progression.
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Ji J, Qin Y, Wang R, Huang Z, Zhang Y, Zhou R, Song L, Ling X, Hu Z, Miao D, Shen H, Xia Y, Wang X, Lu C. Copy number gain of VCX, X-linked multi-copy gene, leads to cell proliferation and apoptosis during spermatogenesis. Oncotarget 2016; 7:78532-78540. [PMID: 27705943 PMCID: PMC5340235 DOI: 10.18632/oncotarget.12397] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Accepted: 09/25/2016] [Indexed: 11/25/2022] Open
Abstract
Male factor infertility affects one-sixth of couples worldwide, and non-obstructive azoospermia (NOA) is one of the most severe forms. In recent years there has been increasing evidence to implicate the participation of X chromosome in the process of spermatogenesis. To uncover the roles of X-linked multi-copy genes in spermatogenesis, we performed systematic analysis of X-linked gene copy number variations (CNVs) and Y chromosome haplogrouping in 447 idiopathic NOA patients and 485 healthy controls. Interestingly, the frequency of individuals with abnormal level copy of Variable charge, X-linked (VCX) was significantly different between cases and controls after multiple test correction (p = 5.10 × 10-5). To discriminate the effect of gain/loss copies in these genes, we analyzed the frequency of X-linked multi-copy genes in subjects among subdivided groups. Our results demonstrated that individuals with increased copy numbers of Nuclear RNA export factor 2 (NXF2) (p = 9.21 × 10-8) and VCX (p = 1.97 × 10-4) conferred the risk of NOA. In vitro analysis demonstrated that increasing copy number of VCX could upregulate the gene expression and regulate cell proliferation and apoptosis. Our study establishes a robust association between the VCX CNVs and NOA risk.
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Affiliation(s)
- Juan Ji
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, China
- Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
- Department of Children Health Care, Nanjing Maternity and Child Health Care Hospital Affiliated to Nanjing Medical University, Nanjing, China
| | - Yufeng Qin
- Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA
| | - Rong Wang
- Research Center for Bone and Stem Cells, Department of Anatomy, Histology, and Embryology, Nanjing Medical University, Nanjing, China
| | - Zhenyao Huang
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, China
- Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Yan Zhang
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, China
- Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Ran Zhou
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, China
- Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Ling Song
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, China
- Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Xiufeng Ling
- Department of Children Health Care, Nanjing Maternity and Child Health Care Hospital Affiliated to Nanjing Medical University, Nanjing, China
| | - Zhibin Hu
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, China
- Department of Epidemiology and Biostatistics and Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Dengshun Miao
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, China
- Research Center for Bone and Stem Cells, Department of Anatomy, Histology, and Embryology, Nanjing Medical University, Nanjing, China
| | - Hongbing Shen
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, China
- Department of Epidemiology and Biostatistics and Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Yankai Xia
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, China
- Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Xinru Wang
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, China
- Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Chuncheng Lu
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, China
- Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
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AccuCopy quantification combined with pre-amplification of long-distance PCR for fast analysis of intron 22 inversion in haemophilia A. Clin Chim Acta 2016; 458:78-83. [DOI: 10.1016/j.cca.2016.04.015] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Revised: 03/30/2016] [Accepted: 04/13/2016] [Indexed: 12/15/2022]
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Guo S, Li Y, Wang Y, Chu H, Chen Y, Liu Q, Guo G, Tu W, Wu W, Zou H, Yang L, Xiao R, Ma Y, Zhang F, Xiong M, Jin L, Zhou X, Wang J. Copy Number Variation of HLA-DQA1 and APOBEC3A/3B Contribute to the Susceptibility of Systemic Sclerosis in the Chinese Han Population. J Rheumatol 2016; 43:880-6. [PMID: 27036383 DOI: 10.3899/jrheum.150945] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/26/2016] [Indexed: 12/31/2022]
Abstract
OBJECTIVE Systemic sclerosis (SSc) is a systemic connective tissue disease caused by a genetic aberrant. The involvement of the copy number variations (CNV) in the pathogenesis of SSc is unclear. We tried to identify some CNV that are involved with the susceptibility to SSc. METHODS A genome-wide CNV screening was performed in 20 patients with SSc. Five SSc-associated common CNV that included HLA-DRB5, HLA-DQA1, IRGM, CDC42EP3, and APOBEC3A/3B were identified from the screening and were then validated in 365 patients with SSc and 369 matched healthy controls. RESULTS Three hundred forty-four CNV (140 gains and 204 losses) and 2 CNV hotspots (6q21.3 and 22q11.2) were found in the SSc genomes (covering 24.2 megabases), suggesting that CNV were ubiquitous in the SSc genome and played important roles in the pathogenesis of SSc. The high copy number of HLA-DQA1 was a significantly protective factor for SSc (OR 0.07, p = 2.99 × 10(-17)), while the high copy number of APOBEC3A/B was a significant risk factor (OR 3.45, p = 6.4 × 10(-18)), adjusted with sex and age. The risk prediction model based on genetic factors in logistic regression showed moderate prediction ability, with area under the curve = 0.80 (95% CI 0.77-0.83), which demonstrated that APOBEC3A/B and HLA-DQA1 were powerful biomarkers for SSc risk evaluation and contributed to the susceptibility to SSc. CONCLUSION CNV of HLA-DQA1 and APOBEC3A/B contribute to the susceptibility to SSc in a Chinese Han population.
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Affiliation(s)
- Shicheng Guo
- From the State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Institute of Rheumatology, Immunology and Allergy, Fudan University; Shanghai Traditional Chinese Medicine (TCM)-Integrated Hospital; Division of Dermatology, and Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai; Yiling Hospital, Shijiazhuang; Division of Rheumatology, Teaching Hospital of Chengdu University of TCM, Chengdu; Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, China; School of Public Health, and Medical School at Houston, University of Texas, Houston, Texas, USA.S. Guo, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, and Institute of Rheumatology, Immunology and Allergy, Fudan University; Y. Li, MS, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Y. Wang, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; H. Chu, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Y. Chen, PhD, State Key Laboratory o
| | - Yuan Li
- From the State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Institute of Rheumatology, Immunology and Allergy, Fudan University; Shanghai Traditional Chinese Medicine (TCM)-Integrated Hospital; Division of Dermatology, and Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai; Yiling Hospital, Shijiazhuang; Division of Rheumatology, Teaching Hospital of Chengdu University of TCM, Chengdu; Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, China; School of Public Health, and Medical School at Houston, University of Texas, Houston, Texas, USA.S. Guo, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, and Institute of Rheumatology, Immunology and Allergy, Fudan University; Y. Li, MS, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Y. Wang, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; H. Chu, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Y. Chen, PhD, State Key Laboratory o
| | - Yi Wang
- From the State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Institute of Rheumatology, Immunology and Allergy, Fudan University; Shanghai Traditional Chinese Medicine (TCM)-Integrated Hospital; Division of Dermatology, and Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai; Yiling Hospital, Shijiazhuang; Division of Rheumatology, Teaching Hospital of Chengdu University of TCM, Chengdu; Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, China; School of Public Health, and Medical School at Houston, University of Texas, Houston, Texas, USA.S. Guo, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, and Institute of Rheumatology, Immunology and Allergy, Fudan University; Y. Li, MS, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Y. Wang, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; H. Chu, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Y. Chen, PhD, State Key Laboratory o
| | - Haiyan Chu
- From the State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Institute of Rheumatology, Immunology and Allergy, Fudan University; Shanghai Traditional Chinese Medicine (TCM)-Integrated Hospital; Division of Dermatology, and Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai; Yiling Hospital, Shijiazhuang; Division of Rheumatology, Teaching Hospital of Chengdu University of TCM, Chengdu; Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, China; School of Public Health, and Medical School at Houston, University of Texas, Houston, Texas, USA.S. Guo, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, and Institute of Rheumatology, Immunology and Allergy, Fudan University; Y. Li, MS, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Y. Wang, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; H. Chu, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Y. Chen, PhD, State Key Laboratory o
| | - Yulin Chen
- From the State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Institute of Rheumatology, Immunology and Allergy, Fudan University; Shanghai Traditional Chinese Medicine (TCM)-Integrated Hospital; Division of Dermatology, and Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai; Yiling Hospital, Shijiazhuang; Division of Rheumatology, Teaching Hospital of Chengdu University of TCM, Chengdu; Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, China; School of Public Health, and Medical School at Houston, University of Texas, Houston, Texas, USA.S. Guo, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, and Institute of Rheumatology, Immunology and Allergy, Fudan University; Y. Li, MS, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Y. Wang, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; H. Chu, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Y. Chen, PhD, State Key Laboratory o
| | - Qingmei Liu
- From the State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Institute of Rheumatology, Immunology and Allergy, Fudan University; Shanghai Traditional Chinese Medicine (TCM)-Integrated Hospital; Division of Dermatology, and Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai; Yiling Hospital, Shijiazhuang; Division of Rheumatology, Teaching Hospital of Chengdu University of TCM, Chengdu; Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, China; School of Public Health, and Medical School at Houston, University of Texas, Houston, Texas, USA.S. Guo, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, and Institute of Rheumatology, Immunology and Allergy, Fudan University; Y. Li, MS, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Y. Wang, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; H. Chu, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Y. Chen, PhD, State Key Laboratory o
| | - Gang Guo
- From the State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Institute of Rheumatology, Immunology and Allergy, Fudan University; Shanghai Traditional Chinese Medicine (TCM)-Integrated Hospital; Division of Dermatology, and Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai; Yiling Hospital, Shijiazhuang; Division of Rheumatology, Teaching Hospital of Chengdu University of TCM, Chengdu; Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, China; School of Public Health, and Medical School at Houston, University of Texas, Houston, Texas, USA.S. Guo, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, and Institute of Rheumatology, Immunology and Allergy, Fudan University; Y. Li, MS, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Y. Wang, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; H. Chu, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Y. Chen, PhD, State Key Laboratory o
| | - Wenzhen Tu
- From the State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Institute of Rheumatology, Immunology and Allergy, Fudan University; Shanghai Traditional Chinese Medicine (TCM)-Integrated Hospital; Division of Dermatology, and Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai; Yiling Hospital, Shijiazhuang; Division of Rheumatology, Teaching Hospital of Chengdu University of TCM, Chengdu; Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, China; School of Public Health, and Medical School at Houston, University of Texas, Houston, Texas, USA.S. Guo, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, and Institute of Rheumatology, Immunology and Allergy, Fudan University; Y. Li, MS, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Y. Wang, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; H. Chu, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Y. Chen, PhD, State Key Laboratory o
| | - Wenyu Wu
- From the State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Institute of Rheumatology, Immunology and Allergy, Fudan University; Shanghai Traditional Chinese Medicine (TCM)-Integrated Hospital; Division of Dermatology, and Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai; Yiling Hospital, Shijiazhuang; Division of Rheumatology, Teaching Hospital of Chengdu University of TCM, Chengdu; Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, China; School of Public Health, and Medical School at Houston, University of Texas, Houston, Texas, USA.S. Guo, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, and Institute of Rheumatology, Immunology and Allergy, Fudan University; Y. Li, MS, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Y. Wang, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; H. Chu, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Y. Chen, PhD, State Key Laboratory o
| | - Hejian Zou
- From the State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Institute of Rheumatology, Immunology and Allergy, Fudan University; Shanghai Traditional Chinese Medicine (TCM)-Integrated Hospital; Division of Dermatology, and Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai; Yiling Hospital, Shijiazhuang; Division of Rheumatology, Teaching Hospital of Chengdu University of TCM, Chengdu; Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, China; School of Public Health, and Medical School at Houston, University of Texas, Houston, Texas, USA.S. Guo, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, and Institute of Rheumatology, Immunology and Allergy, Fudan University; Y. Li, MS, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Y. Wang, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; H. Chu, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Y. Chen, PhD, State Key Laboratory o
| | - Li Yang
- From the State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Institute of Rheumatology, Immunology and Allergy, Fudan University; Shanghai Traditional Chinese Medicine (TCM)-Integrated Hospital; Division of Dermatology, and Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai; Yiling Hospital, Shijiazhuang; Division of Rheumatology, Teaching Hospital of Chengdu University of TCM, Chengdu; Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, China; School of Public Health, and Medical School at Houston, University of Texas, Houston, Texas, USA.S. Guo, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, and Institute of Rheumatology, Immunology and Allergy, Fudan University; Y. Li, MS, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Y. Wang, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; H. Chu, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Y. Chen, PhD, State Key Laboratory o
| | - Rong Xiao
- From the State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Institute of Rheumatology, Immunology and Allergy, Fudan University; Shanghai Traditional Chinese Medicine (TCM)-Integrated Hospital; Division of Dermatology, and Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai; Yiling Hospital, Shijiazhuang; Division of Rheumatology, Teaching Hospital of Chengdu University of TCM, Chengdu; Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, China; School of Public Health, and Medical School at Houston, University of Texas, Houston, Texas, USA.S. Guo, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, and Institute of Rheumatology, Immunology and Allergy, Fudan University; Y. Li, MS, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Y. Wang, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; H. Chu, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Y. Chen, PhD, State Key Laboratory o
| | - Yanyun Ma
- From the State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Institute of Rheumatology, Immunology and Allergy, Fudan University; Shanghai Traditional Chinese Medicine (TCM)-Integrated Hospital; Division of Dermatology, and Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai; Yiling Hospital, Shijiazhuang; Division of Rheumatology, Teaching Hospital of Chengdu University of TCM, Chengdu; Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, China; School of Public Health, and Medical School at Houston, University of Texas, Houston, Texas, USA.S. Guo, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, and Institute of Rheumatology, Immunology and Allergy, Fudan University; Y. Li, MS, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Y. Wang, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; H. Chu, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Y. Chen, PhD, State Key Laboratory o
| | - Feng Zhang
- From the State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Institute of Rheumatology, Immunology and Allergy, Fudan University; Shanghai Traditional Chinese Medicine (TCM)-Integrated Hospital; Division of Dermatology, and Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai; Yiling Hospital, Shijiazhuang; Division of Rheumatology, Teaching Hospital of Chengdu University of TCM, Chengdu; Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, China; School of Public Health, and Medical School at Houston, University of Texas, Houston, Texas, USA.S. Guo, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, and Institute of Rheumatology, Immunology and Allergy, Fudan University; Y. Li, MS, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Y. Wang, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; H. Chu, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Y. Chen, PhD, State Key Laboratory o
| | - Momiao Xiong
- From the State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Institute of Rheumatology, Immunology and Allergy, Fudan University; Shanghai Traditional Chinese Medicine (TCM)-Integrated Hospital; Division of Dermatology, and Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai; Yiling Hospital, Shijiazhuang; Division of Rheumatology, Teaching Hospital of Chengdu University of TCM, Chengdu; Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, China; School of Public Health, and Medical School at Houston, University of Texas, Houston, Texas, USA.S. Guo, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, and Institute of Rheumatology, Immunology and Allergy, Fudan University; Y. Li, MS, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Y. Wang, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; H. Chu, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Y. Chen, PhD, State Key Laboratory o
| | - Li Jin
- From the State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Institute of Rheumatology, Immunology and Allergy, Fudan University; Shanghai Traditional Chinese Medicine (TCM)-Integrated Hospital; Division of Dermatology, and Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai; Yiling Hospital, Shijiazhuang; Division of Rheumatology, Teaching Hospital of Chengdu University of TCM, Chengdu; Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, China; School of Public Health, and Medical School at Houston, University of Texas, Houston, Texas, USA.S. Guo, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, and Institute of Rheumatology, Immunology and Allergy, Fudan University; Y. Li, MS, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Y. Wang, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; H. Chu, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Y. Chen, PhD, State Key Laboratory o
| | - Xiaodong Zhou
- From the State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Institute of Rheumatology, Immunology and Allergy, Fudan University; Shanghai Traditional Chinese Medicine (TCM)-Integrated Hospital; Division of Dermatology, and Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai; Yiling Hospital, Shijiazhuang; Division of Rheumatology, Teaching Hospital of Chengdu University of TCM, Chengdu; Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, China; School of Public Health, and Medical School at Houston, University of Texas, Houston, Texas, USA.S. Guo, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, and Institute of Rheumatology, Immunology and Allergy, Fudan University; Y. Li, MS, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Y. Wang, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; H. Chu, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Y. Chen, PhD, State Key Laboratory o
| | - Jiucun Wang
- From the State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Institute of Rheumatology, Immunology and Allergy, Fudan University; Shanghai Traditional Chinese Medicine (TCM)-Integrated Hospital; Division of Dermatology, and Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai; Yiling Hospital, Shijiazhuang; Division of Rheumatology, Teaching Hospital of Chengdu University of TCM, Chengdu; Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, China; School of Public Health, and Medical School at Houston, University of Texas, Houston, Texas, USA.S. Guo, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, and Institute of Rheumatology, Immunology and Allergy, Fudan University; Y. Li, MS, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Y. Wang, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; H. Chu, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; Y. Chen, PhD, State Key Laboratory o
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Thomas A, Ivaškevičius V, Zawadzki C, Goudemand J, Biswas A, Oldenburg J. Characterization of a novel large deletion caused by double-stranded breaks in 6-bp microhomologous sequences of intron 11 and 12 of the F13A1 gene. Hum Genome Var 2016; 3:15059. [PMID: 27081562 PMCID: PMC4760118 DOI: 10.1038/hgv.2015.59] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Revised: 11/08/2015] [Accepted: 11/09/2015] [Indexed: 12/22/2022] Open
Abstract
Coagulation Factor XIII is a heterotetrameric protransglutaminase which stabilizes preformed fibrin clots by covalent crosslinking them. Inherited homozygous or compound heterozygous deficiency of coagulation Factor XIII (FXIII) is a rare severe bleeding disorder affecting 1 in 2 million individuals. Most of the patients with inherited FXIII deficiency described in the literature carry F13A1 gene point mutations (missense, nonsense and splice site defects), whereas large deletions (>0.5 kb in size) are underrepresented. In this article we report for the first time the complete characterization of a novel homozygous F13A1 large deletion covering the entire exon 12 in a young patient with a severe FXIII-deficient phenotype from France. Using primer walking on genomic DNA we have identified the deletion breakpoints in the region between g.6.143,016–g.6.148,901 caused by small 6-bp microhomologies at the 5´ and 3´ breakpoints. Parents of the patient were heterozygous carriers. Identification of this large deletion offers the possibility of prenatal diagnosis for the mother in this family who is heterozygous for this deletion.
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Affiliation(s)
- Anne Thomas
- Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn , Bonn, Germany
| | - Vytautas Ivaškevičius
- Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn , Bonn, Germany
| | | | - Jenny Goudemand
- Institut d'Hématologie, Hŏpital Cardiologique , Lille, France
| | - Arijit Biswas
- Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn , Bonn, Germany
| | - Johannes Oldenburg
- Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn , Bonn, Germany
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Autism-like behaviours and germline transmission in transgenic monkeys overexpressing MeCP2. Nature 2016; 530:98-102. [PMID: 26808898 DOI: 10.1038/nature16533] [Citation(s) in RCA: 222] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2015] [Accepted: 12/14/2015] [Indexed: 11/08/2022]
Abstract
Methyl-CpG binding protein 2 (MeCP2) has crucial roles in transcriptional regulation and microRNA processing. Mutations in the MECP2 gene are found in 90% of patients with Rett syndrome, a severe developmental disorder with autistic phenotypes. Duplications of MECP2-containing genomic segments cause the MECP2 duplication syndrome, which shares core symptoms with autism spectrum disorders. Although Mecp2-null mice recapitulate most developmental and behavioural defects seen in patients with Rett syndrome, it has been difficult to identify autism-like behaviours in the mouse model of MeCP2 overexpression. Here we report that lentivirus-based transgenic cynomolgus monkeys (Macaca fascicularis) expressing human MeCP2 in the brain exhibit autism-like behaviours and show germline transmission of the transgene. Expression of the MECP2 transgene was confirmed by western blotting and immunostaining of brain tissues of transgenic monkeys. Genomic integration sites of the transgenes were characterized by a deep-sequencing-based method. As compared to wild-type monkeys, MECP2 transgenic monkeys exhibited a higher frequency of repetitive circular locomotion and increased stress responses, as measured by the threat-related anxiety and defensive test. The transgenic monkeys showed less interaction with wild-type monkeys within the same group, and also a reduced interaction time when paired with other transgenic monkeys in social interaction tests. The cognitive functions of the transgenic monkeys were largely normal in the Wisconsin general test apparatus, although some showed signs of stereotypic cognitive behaviours. Notably, we succeeded in generating five F1 offspring of MECP2 transgenic monkeys by intracytoplasmic sperm injection with sperm from one F0 transgenic monkey, showing germline transmission and Mendelian segregation of several MECP2 transgenes in the F1 progeny. Moreover, F1 transgenic monkeys also showed reduced social interactions when tested in pairs, as compared to wild-type monkeys of similar age. Together, these results indicate the feasibility and reliability of using genetically engineered non-human primates to study brain disorders.
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Clinical manifestations and mutation spectrum of 57 subjects with congenital factor XI deficiency in China. Blood Cells Mol Dis 2016; 58:29-34. [PMID: 27067486 DOI: 10.1016/j.bcmd.2016.01.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2015] [Revised: 01/12/2016] [Accepted: 01/15/2016] [Indexed: 11/23/2022]
Abstract
Congenital factor XI (FXI) deficiency is a rare bleeding disorder with unpredictable bleeding tendency. Few studies in a large cohort have been reported regarding associations between FXI activity (FXI:C) or genotypes and bleeding symptoms currently. This study characterized clinical manifestations and mutation spectrum of 57 subjects with FXI deficiency in China. Clinical data were collected and mutations were identified by direct sequencing and determined by mRNA analysis. The result revealed bleeding symptoms were only found in 12 patients (12/57, 21.1%) with severely reduced FXI:C, and prolonged bleeding post injury/surgery as well as easy bruising were the commonest bleeding manifestations presented in respective 5 cases (5/12, 41.7%). A total number of 37 mutations were identified including 19 missense mutations, 9 nonsense mutations, 6 splice site mutations and 3 small deletions. Among them, 4 missense mutations, 5 splice mutations, 3 small deletions and a nonsense mutation were newly detected. W228*, G400V, Q263* and c.1136-4delGTTG with a total frequency of 48.3% were the most four common mutations in Chinese patients. RT-PCR analysis was carried out and confirmed that both c.596-8T>A and c.1136-4delGTTG were pathogenic due to frameshift resulting in respective truncated proteins. Our findings suggested clinical manifestations had little to do with FXI:C or genotypes, which required further study. This study, the largest investigation of FXI deficiency in China revealed that the F11 mutation spectrum of Chinese population was distinct from those of other populations earlier established.
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Synaptic P-Rex1 signaling regulates hippocampal long-term depression and autism-like social behavior. Proc Natl Acad Sci U S A 2015; 112:E6964-72. [PMID: 26621702 DOI: 10.1073/pnas.1512913112] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Autism spectrum disorders (ASDs) are a group of highly inheritable mental disorders associated with synaptic dysfunction, but the underlying cellular and molecular mechanisms remain to be clarified. Here we report that autism in Chinese Han population is associated with genetic variations and copy number deletion of P-Rex1 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 1). Genetic deletion or knockdown of P-Rex1 in the CA1 region of the hippocampus in mice resulted in autism-like social behavior that was specifically linked to the defect of long-term depression (LTD) in the CA1 region through alteration of AMPA receptor endocytosis mediated by the postsynaptic PP1α (protein phosphase 1α)-P-Rex1-Rac1 (Ras-related C3 botulinum toxin substrate 1) signaling pathway. Rescue of the LTD in the CA1 region markedly alleviated autism-like social behavior. Together, our findings suggest a vital role of P-Rex1 signaling in CA1 LTD that is critical for social behavior and cognitive function and offer new insight into the etiology of ASDs.
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Wang L, Yang X, Cai G, Xin L, Xia Q, Zhang X, Li X, Wang M, Wang K, Xia G, Xu S, Xu J, Zou Y, Pan F. Association study of copy number variants in FCGR3A and FCGR3B gene with risk of ankylosing spondylitis in a Chinese population. Rheumatol Int 2015; 36:437-42. [DOI: 10.1007/s00296-015-3384-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Accepted: 10/07/2015] [Indexed: 01/17/2023]
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Ding N, Yang X, Zhang L, Cai G, Xia Q, Fan D, Li X, Hu Y, Liu L, Xin L, Wang L, Xu S, Xu J, Zou Y, Ding C, Pan F. Association of β-defensin gene copy number variations with ankylosing spondylitis in Chinese population: A case–control study. Mod Rheumatol 2015; 26:146-50. [DOI: 10.3109/14397595.2015.1056930] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
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Cai G, Xia Q, Fan D, Li X, Ding N, Hu Y, Yang X, Liu L, Xin L, Wang L, Xu S, Xu J, Zou Y, Ding C, Pan F. Association between DEFB103 gene copy number variation and ankylosing spondylitis: a case-control study. ACTA ACUST UNITED AC 2015. [PMID: 26224324 DOI: 10.1111/tan.12630] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
In this brief communication, we investigate the role of DEFB103 gene copy number variation (CNV) in ankylosing spondylitis (AS) susceptibility. A total of 807 Chinese individuals including 406 AS patients and 401 controls were enrolled. The DEFB103 copy number was measured by two sets of probes to obtain a stable result in a custom-by-design Multiplex AccuCopy(™) kit (Genesky Biotechnologies Inc., Shanghai, China) based on a multiplex fluorescence competitive polymerase chain reaction (PCR) principle. The copy number of DEFB103 ranged from 2 to 6 in both AS patients and controls. Mann-Whitney U test and chi-squared test were performed to analyze the difference of DEFB103 copy number between AS patients and controls while no statistical difference has been found. We considered the copy number of DEFB103 gene may not associate with susceptibility to AS.
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Affiliation(s)
- G Cai
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China
| | - Q Xia
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China
| | - D Fan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China
| | - X Li
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China
| | - N Ding
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China
| | - Y Hu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China
| | - X Yang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China
| | - L Liu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China
| | - L Xin
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China
| | - L Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China
| | - S Xu
- Department of Rheumatism and Immunity, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - J Xu
- Department of Rheumatism and Immunity, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Y Zou
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China
| | - C Ding
- Department of Rheumatism and Immunity, The First Affiliated Hospital of Anhui Medical University, Hefei, China.,Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia
| | - F Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China.,Department of Rheumatism and Immunity, The First Affiliated Hospital of Anhui Medical University, Hefei, China.,Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia
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Huang N, Wen Y, Guo X, Li Z, Dai J, Ni B, Yu J, Lin Y, Zhou W, Yao B, Jiang Y, Sha J, Conrad DF, Hu Z. A Screen for Genomic Disorders of Infertility Identifies MAST2 Duplications Associated with Nonobstructive Azoospermia in Humans. Biol Reprod 2015. [PMID: 26203179 DOI: 10.1095/biolreprod.115.131185] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Since the cytogenetic identification of azoospermia factor regions 40 years ago, the Y chromosome has dominated research on the genetics of male infertility. We hypothesized that hotspots of structural rearrangement, which are dispersed across the genome, may mediate rare, recurrent copy number variations (CNVs), leading to severe infertility. We tested this hypothesis by contrasting patterns of rare CNVs in 970 Han Chinese men with idiopathic nonobstructive azoospermia and 1661 ethnicity-matched controls. Our results strongly support our previous claim that sperm production is modulated by genetic variation across the entire genome. The X chromosome in particular was enriched for loci modulating spermatogenesis--rare X-linked deletions larger than 100 kb were twice as common in patients compared with controls (odds ratio [OR] = 2.05, P = 0.01). At rearrangement hotspots across the genome, we observed a 2.4-fold enrichment of singleton CNVs in patients (P < 0.02), and we identified 117 testis genes, such as SYCE1, contained within 47 hotspots that may plausibly mediate genomic disorders of fertility. In our discovery sample we observed 3 case-specific duplications of the autosomal gene MAST2, and in a replication phase we found another 11 duplications in 1457 patients and 1 duplication in 1590 controls (P < 5 × 10(-5), combined data). With a large, polygenic genetic basis, new ways of establishing the pathogenicity of rare, large-effect mutations will be needed to fully reap the benefit of genome data in the management of azoospermia.
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Affiliation(s)
- Ni Huang
- Department of Genetics, Washington University School of Medicine, St. Louis, Missouri Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri
| | - Yang Wen
- State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, China Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Xuejiang Guo
- State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, China Department of Histology and Embryology, Nanjing Medical University, Nanjing, China
| | - Zheng Li
- Shanghai Human Sperm Bank, Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Juncheng Dai
- State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, China Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Bixian Ni
- State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, China Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Jun Yu
- State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, China Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Yuan Lin
- State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, China Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Wen Zhou
- State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, China Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Bing Yao
- Department of Andrology, Nanjing Jinling Hospital, Nanjing, China
| | - Yue Jiang
- State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, China Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Jiahao Sha
- State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, China Department of Histology and Embryology, Nanjing Medical University, Nanjing, China
| | - Donald F Conrad
- Department of Genetics, Washington University School of Medicine, St. Louis, Missouri Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri
| | - Zhibin Hu
- State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, China Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
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Zhang X, Xu Y, Liu D, Geng J, Chen S, Jiang Z, Fu Q, Sun K. A modified multiplex ligation-dependent probe amplification method for the detection of 22q11.2 copy number variations in patients with congenital heart disease. BMC Genomics 2015; 16:364. [PMID: 25952753 PMCID: PMC4424574 DOI: 10.1186/s12864-015-1590-5] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Accepted: 04/27/2015] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Copy number variations (CNVs) of chromosomal region 22q11.2 are associated with a subset of patients with congenital heart disease (CHD). Accurate and efficient detection of CNV is important for genetic analysis of CHD. The aim of the study was to introduce a novel approach named CNVplex®, a high-throughput analysis technique designed for efficient detection of chromosomal CNVs, and to explore the prevalence of sub-chromosomal imbalances in 22q11.2 loci in patients with CHD from a single institute. RESULTS We developed a novel technique, CNVplex®, for high-throughput detection of sub-chromosomal copy number aberrations. Modified from the multiplex ligation-dependent probe amplification (MLPA) method, it introduced a lengthening ligation system and four universal primer sets, which simplified the synthesis of probes and significantly improved the flexibility of the experiment. We used 110 samples, which were extensively characterized with chromosomal microarray analysis and MLPA, to validate the performance of the newly developed method. Furthermore, CNVplex® was used to screen for sub-chromosomal imbalances in 22q11.2 loci in 818 CHD patients consecutively enrolled from Shanghai Children's Medical Center. In the methodology development phase, CNVplex® detected all copy number aberrations that were previously identified with both chromosomal microarray analysis and MLPA, demonstrating 100% sensitivity and specificity. In the validation phase, 22q11.2 deletion and 22q11.2 duplication were detected in 39 and 1 of 818 patients with CHD by CNVplex®, respectively. Our data demonstrated that the frequency of 22q11.2 deletion varied among sub-groups of CHD patients. Notably, 22q11.2 deletion was more commonly observed in cases with conotruncal defect (CTD) than in cases with non-CTD (P<0.001). With higher resolution and more probes against selected chromosomal loci, CNVplex® also identified several individuals with small CNVs and alterations in other chromosomes. CONCLUSIONS CNVplex® is sensitive and specific in its detection of CNVs, and it is an alternative to MLPA for batch screening of pathogenetic CNVs in known genomic loci.
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Affiliation(s)
- Xiaoqing Zhang
- Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, Peoples Republic of China.
| | - Yuejuan Xu
- Department of Pediatric Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, Peoples Republic of China.
| | - Deyuan Liu
- Genesky Diagnostics (Suzhou) Inc, Suzhou, Peoples Republic of China.
| | - Juan Geng
- Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, Peoples Republic of China.
| | - Sun Chen
- Department of Pediatric Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, Peoples Republic of China.
| | - Zhengwen Jiang
- Genesky Diagnostics (Suzhou) Inc, Suzhou, Peoples Republic of China.
| | - Qihua Fu
- Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, Peoples Republic of China.
| | - Kun Sun
- Department of Pediatric Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, Peoples Republic of China.
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Zhang D, Li Z, Wang H, Yang M, Liang L, Fu J, Wang C, Ling J, Zhang Y, Zhang S, Xu Y, Zhu Y, Lai M. Interactions between obesity-related copy number variants and dietary behaviors in childhood obesity. Nutrients 2015; 7:3054-66. [PMID: 25912042 PMCID: PMC4425189 DOI: 10.3390/nu7043054] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Revised: 04/03/2015] [Accepted: 04/14/2015] [Indexed: 01/10/2023] Open
Abstract
Copy number variants (CNVs) have been implicated as an important genetic marker of obesity, and gene-environment interaction has been found to modulate risk of obesity. To evaluate the associations between CNVs and childhood obesity, as well as the interactions between CNVs and dietary behaviors, we recruited 534 obese children and 508 controls from six cities in China and six candidate CNVs were screened through published genome-wide studies (GWAS) on childhood obesity. We found three loci (10q11.22, 4q25 and 11q11) to be significantly associated with obesity after false discovery rate (FDR) correction (all the p ≤ 0.05). Cumulative effect of the three positive loci was measured by the genetic risk score (GRS), showing a significant relationship with the risk of obesity (Ptrend < 0.001). The OR of obesity increased to 21.38 (95% CI = 21.19-21.55) among the 10q11.22 deletion carriers who had meat-based diets, indicating prominent multiplicative interaction (MI) between deletions of 10q11.22 and preference for a meat-based diet. Simultaneous deletions of 5q13.2 and duplications of 6q14.1 had significant MI with a preference for salty foods. Our results suggested that CNVs may contribute to the genetic susceptibility of childhood obesity, and the CNV-diet interactions modulate the risk of obesity.
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Affiliation(s)
- Dandan Zhang
- Department of Pathology, Zhejiang University School of Medicine, 866 Yu-hang-tang Road, Hangzhou 310058, Zhejiang, China.
- Key Laboratory of Disease Proteomics of Zhejiang Province, 866 Yu-hang-tang Road, Hangzhou 310058, Zhejiang, China.
| | - Zhenli Li
- Department of Pathology, Zhejiang University School of Medicine, 866 Yu-hang-tang Road, Hangzhou 310058, Zhejiang, China.
- Key Laboratory of Disease Proteomics of Zhejiang Province, 866 Yu-hang-tang Road, Hangzhou 310058, Zhejiang, China.
| | - Hao Wang
- Department of Pathology, Zhejiang University School of Medicine, 866 Yu-hang-tang Road, Hangzhou 310058, Zhejiang, China.
- Key Laboratory of Disease Proteomics of Zhejiang Province, 866 Yu-hang-tang Road, Hangzhou 310058, Zhejiang, China.
| | - Min Yang
- Department of Nutrition, Zhejiang University School of Public Health, 866 Yu-hang-tang Road, Hangzhou 310058, Zhejiang, China.
| | - Li Liang
- Department of Pediatrics, the First Affiliated Hospital of College of Medicine, Zhejiang University, 79 Qing-chun Road, Hangzhou 310003, Zhejiang, China.
| | - Junfen Fu
- Department of Endocrinology, Children's Hospital of College of Medicine, Zhejiang University, 25 Guang-fu Road, Hangzhou 310003, Zhejiang, China.
| | - Chunling Wang
- Department of Pediatrics, the First Affiliated Hospital of College of Medicine, Zhejiang University, 79 Qing-chun Road, Hangzhou 310003, Zhejiang, China.
| | - Jie Ling
- Department of Epidemiology & Biostatistics, Zhejiang University School of Public Health, 866 Yu-hang-tang Road, Hangzhou 310058, Zhejiang, China.
| | - Yan Zhang
- Department of Epidemiology & Biostatistics, Zhejiang University School of Public Health, 866 Yu-hang-tang Road, Hangzhou 310058, Zhejiang, China.
| | - Shuai Zhang
- Department of Pathology, Zhejiang University School of Medicine, 866 Yu-hang-tang Road, Hangzhou 310058, Zhejiang, China.
- Key Laboratory of Disease Proteomics of Zhejiang Province, 866 Yu-hang-tang Road, Hangzhou 310058, Zhejiang, China.
| | - Yuyang Xu
- Department of Epidemiology & Biostatistics, Zhejiang University School of Public Health, 866 Yu-hang-tang Road, Hangzhou 310058, Zhejiang, China.
| | - Yimin Zhu
- Department of Epidemiology & Biostatistics, Zhejiang University School of Public Health, 866 Yu-hang-tang Road, Hangzhou 310058, Zhejiang, China.
| | - Maode Lai
- Department of Pathology, Zhejiang University School of Medicine, 866 Yu-hang-tang Road, Hangzhou 310058, Zhejiang, China.
- Key Laboratory of Disease Proteomics of Zhejiang Province, 866 Yu-hang-tang Road, Hangzhou 310058, Zhejiang, China.
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Hou S, Liao D, Zhang J, Fang J, Chen L, Qi J, Zhang Q, Liu Y, Bai L, Zhou Y, Kijlstra A, Yang P. Genetic Variations of IL17F and IL23A Show Associations with Behçet’s Disease and Vogt-Koyanagi-Harada Syndrome. Ophthalmology 2015; 122:518-23. [DOI: 10.1016/j.ophtha.2014.09.025] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2014] [Revised: 09/16/2014] [Accepted: 09/16/2014] [Indexed: 11/28/2022] Open
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Hu L, Wu Y, Tan D, Meng H, Wang K, Bai Y, Yang K. Up-regulation of long noncoding RNA MALAT1 contributes to proliferation and metastasis in esophageal squamous cell carcinoma. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2015; 34:7. [PMID: 25613496 PMCID: PMC4322446 DOI: 10.1186/s13046-015-0123-z] [Citation(s) in RCA: 195] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/02/2014] [Accepted: 01/04/2015] [Indexed: 01/26/2023]
Abstract
BACKGROUND Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1) has been demonstrated to be an important player in various human malignancies; it is thought to promote tumor growth by cell cycle regulating. However, the roles of MALAT1 in esophageal squamous cell carcinoma(ESCC), and the mechanisms involved in cell cycle regulation remain poorly understood. Moreover, the factors contributing to its up-regulation in tumor tissues are still largely unclear. METHODS Expression of MALAT1 was determined from cell lines and clinical samples by qRT-PCR. The effects of MALAT1 knockdown on cell proliferation, cell cycle, apoptosis, migration, and invasion were evaluated by in vitro and in vivo assays. The potential protein expression changes were investigated by Western-blotting. The methylation status of the CpG island in the MALAT1 promoter was explored by bisulfite sequencing, while the copy numbers in tumor tissues and blood samples were detected by a well-established AccuCopy(TM) method. RESULTS MALAT1 was over-expressed in 46.3% of ESCC tissues, mostly in the high-stage tumor samples. Enhanced MALAT1 expression levels were positively correlated with clinical stages, primary tumor size, and lymph node metastasis. Inhibition of MALAT1 suppressed tumor proliferation in vitro and in vivo, as well as the migratory and invasive capacity. MALAT1 depletion also induced G2/M phase arrest and increased the percentage of apoptotic cells. Western-blotting results implicated that the ATM-CHK2 pathway which is associated with G2/M arrest was phosphorylated by MALAT1 knockdown. No effects of CpG island methylation status on MALAT1 expression were found, whereas amplification of MALAT1 was found in 22.2% of tumor tissues, which correlated significantly with its over-expression. However, neither association between tissue copy number amplification and germline copy number variation, nor correlation between germline copy number variation and ESCC risk were identified in the case-control study. CONCLUSIONS Our data suggest that MALAT1 serves as an oncogene in ESCC, and it regulates ESCC growth by modifying the ATM-CHK2 pathway. Moreover, amplification of MALAT1 in tumor tissues may play an important role for its up-regulation, and it seems that the gene amplification in tumor tissues emerges during ESCC progression, but is not derived from germline origins.
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Affiliation(s)
- Liwen Hu
- Department of Cardiothoracic Surgery, Southwest Hospital, Third Military Medical University, Gaotanyan St., Shapingba District, Chongqing, People's Republic of China.
| | - Yuanyuan Wu
- Department of Medical Genetics, College of Basic Medical Science, Third Military Medical University, Gaotanyan St., Shapingba District, Chongqing, People's Republic of China.
| | - Deli Tan
- Department of Cardiothoracic Surgery, Southwest Hospital, Third Military Medical University, Gaotanyan St., Shapingba District, Chongqing, People's Republic of China.
| | - Hui Meng
- Department of Medical Genetics, College of Basic Medical Science, Third Military Medical University, Gaotanyan St., Shapingba District, Chongqing, People's Republic of China.
| | - Kai Wang
- Department of Medical Genetics, College of Basic Medical Science, Third Military Medical University, Gaotanyan St., Shapingba District, Chongqing, People's Republic of China.
| | - Yun Bai
- Department of Medical Genetics, College of Basic Medical Science, Third Military Medical University, Gaotanyan St., Shapingba District, Chongqing, People's Republic of China.
| | - Kang Yang
- Department of Cardiothoracic Surgery, Southwest Hospital, Third Military Medical University, Gaotanyan St., Shapingba District, Chongqing, People's Republic of China.
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Abstract
We constructed a 400K WG tiling oligoarray for the horse and applied it for the discovery of copy number variations (CNVs) in 38 normal horses of 16 diverse breeds, and the Przewalski horse. Probes on the array represented 18,763 autosomal and X-linked genes, and intergenic, sub-telomeric and chrY sequences. We identified 258 CNV regions (CNVRs) across all autosomes, chrX and chrUn, but not in chrY. CNVs comprised 1.3% of the horse genome with chr12 being most enriched. American Miniature horses had the highest and American Quarter Horses the lowest number of CNVs in relation to Thoroughbred reference. The Przewalski horse was similar to native ponies and draft breeds. The majority of CNVRs involved genes, while 20% were located in intergenic regions. Similar to previous studies in horses and other mammals, molecular functions of CNV-associated genes were predominantly in sensory perception, immunity and reproduction. The findings were integrated with previous studies to generate a composite genome-wide dataset of 1476 CNVRs. Of these, 301 CNVRs were shared between studies, while 1174 were novel and require further validation. Integrated data revealed that to date, 41 out of over 400 breeds of the domestic horse have been analyzed for CNVs, of which 11 new breeds were added in this study. Finally, the composite CNV dataset was applied in a pilot study for the discovery of CNVs in 6 horses with XY disorders of sexual development. A homozygous deletion involving AKR1C gene cluster in chr29 in two affected horses was considered possibly causative because of the known role of AKR1C genes in testicular androgen synthesis and sexual development. While the findings improve and integrate the knowledge of CNVs in horses, they also show that for effective discovery of variants of biomedical importance, more breeds and individuals need to be analyzed using comparable methodological approaches. Genomes of individuals in a species vary in many ways, one of which is DNA copy number variation (CNV). This includes deletions, duplications, and complex rearrangements typically larger than 50 base-pairs. CNVs are part of normal genetic variation contributing to phenotypic diversity but can also be pathogenic and associated with diseases and disorders. In order to distinguish between the two, detailed knowledge about CNVs in the species of interest is needed. Here we studied the genomes of 38 normal horses of 16 diverse breeds, and identified 258 CNV regions. We integrated our findings with previously published horse CNVs and generated a composite dataset of ∼1400 CNVRs. Despite this large number, our analysis shows that CNV research in horses needs further improvement because the current data are based on 10% of horse breeds and that most CNVRs are study-specific and require validation. Finally, we analyzed CNVs in horses with disorders of sexual development and found in two male pseudo-hermaphrodites a large deletion disrupting a group of genes involved in sex hormone metabolism and sexual differentiation. The findings underline the possible role of CNVs in complex disorders such as development and reproduction.
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Lu C, Jiang J, Zhang R, Wang Y, Xu M, Qin Y, Lin Y, Guo X, Ni B, Zhao Y, Diao N, Chen F, Shen H, Sha J, Xia Y, Hu Z, Wang X. Gene copy number alterations in the azoospermia-associated AZFc region and their effect on spermatogenic impairment. Mol Hum Reprod 2014; 20:836-843. [PMID: 24935076 DOI: 10.1093/molehr/gau043] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
The azoospermia factor c (AZFc) region in the long arm of human Y chromosome is characterized by massive palindromes. It harbors eight multi-copy gene families that are expressed exclusively or predominantly in testis. To assess systematically the role of the AZFc region and these eight gene families in spermatogenesis, we conducted a comprehensive molecular analysis (including Y chromosome haplogrouping, AZFc deletion typing and gene copy quantification) in 654 idiopathic infertile men and 781 healthy controls in a Han Chinese population. The b2/b3 partial deletion (including both deletion-only and deletion-duplication) was consistently associated with spermatogenic impairment. In the subjects without partial AZFc deletions, a notable finding was that the frequency of DAZ and/or BPY2 copy number alterations in the infertile group was significantly higher than in the controls. Combined patterns of DAZ and/or BPY2 copy number abnormality were associated with spermatogenic impairment when compared with the pattern of all AZFc genes with common level copies. In addition, in Y chromosome haplogroup O1 (Y-hg O1), the frequency of copy number alterations of all eight gene families was significantly higher in the case group than that in the control group. Our findings indicate that the DAZ, BPY2 genes may be prominent players in spermatogenesis, and genomic rearrangements may be enriched in individuals belonging to Y-hg O1. Our findings emphasize the necessity of routine molecular analysis of AZFc structural variation during the workup of azoospermia and/or oligozoospermia, which may diminish the genetic risk of assisted reproduction.
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Affiliation(s)
- Chuncheng Lu
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, China
| | - Jie Jiang
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, China Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Ruyang Zhang
- Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, China Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Ying Wang
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, China
| | - Miaofei Xu
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, China
| | - Yufeng Qin
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, China
| | - Yuan Lin
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, China Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Xuejiang Guo
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China
| | - Bixian Ni
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, China Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Yang Zhao
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Nancy Diao
- Department of Environmental Health, Harvard School of Public Health, Harvard University, Boston, MA, USA
| | - Feng Chen
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Hongbing Shen
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, China Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Jiahao Sha
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China
| | - Yankai Xia
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, China
| | - Zhibin Hu
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, China Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Xinru Wang
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, China
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Zhang X, Du R, Li S, Zhang F, Jin L, Wang H. Evaluation of copy number variation detection for a SNP array platform. BMC Bioinformatics 2014; 15:50. [PMID: 24555668 PMCID: PMC4015297 DOI: 10.1186/1471-2105-15-50] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2013] [Accepted: 02/06/2014] [Indexed: 11/26/2022] Open
Abstract
Background Copy Number Variations (CNVs) are usually inferred from Single Nucleotide Polymorphism (SNP) arrays by use of some software packages based on given algorithms. However, there is no clear understanding of the performance of these software packages; it is therefore difficult to select one or several software packages for CNV detection based on the SNP array platform. We selected four publicly available software packages designed for CNV calling from an Affymetrix SNP array, including Birdsuite, dChip, Genotyping Console (GTC) and PennCNV. The publicly available dataset generated by Array-based Comparative Genomic Hybridization (CGH), with a resolution of 24 million probes per sample, was considered to be the “gold standard”. Compared with the CGH-based dataset, the success rate, average stability rate, sensitivity, consistence and reproducibility of these four software packages were assessed compared with the “gold standard”. Specially, we also compared the efficiency of detecting CNVs simultaneously by two, three and all of the software packages with that by a single software package. Results Simply from the quantity of the detected CNVs, Birdsuite detected the most while GTC detected the least. We found that Birdsuite and dChip had obvious detecting bias. And GTC seemed to be inferior because of the least amount of CNVs it detected. Thereafter we investigated the detection consistency produced by one certain software package and the rest three software suits. We found that the consistency of dChip was the lowest while GTC was the highest. Compared with the CNVs detecting result of CGH, in the matching group, GTC called the most matching CNVs, PennCNV-Affy ranked second. In the non-overlapping group, GTC called the least CNVs. With regards to the reproducibility of CNV calling, larger CNVs were usually replicated better. PennCNV-Affy shows the best consistency while Birdsuite shows the poorest. Conclusion We found that PennCNV outperformed the other three packages in the sensitivity and specificity of CNV calling. Obviously, each calling method had its own limitations and advantages for different data analysis. Therefore, the optimized calling methods might be identified using multiple algorithms to evaluate the concordance and discordance of SNP array-based CNV calling.
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Affiliation(s)
| | | | | | | | | | - Hongyan Wang
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, 220 Handan Road, Shanghai 200433, China.
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