|
1
|
Doyle S, Winrow D, Buckley F, Pernevik E, Johnson M, Thompson K, Howard L, Coleman CM. Optimization of 3D Extrusion-Printed Particle-Containing Hydrogels for Osteogenic Differentiation. ACS OMEGA 2025; 10:15036-15051. [PMID: 40290951 PMCID: PMC12019730 DOI: 10.1021/acsomega.4c10515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 01/31/2025] [Accepted: 03/26/2025] [Indexed: 04/30/2025]
Abstract
There is a continued increase in demand for novel bone grafting substitutes to reduce reliance on and address challenges associated with allograft and autograft bone grafts. Current synthetic bone grafting substitutes exhibit low mechanical strength and bioactivity, which has inspired the development of novel grafting materials. Accelerating the translation of new bone graft substitutes requires workflows for high-throughput fabrication and analysis of particle-containing models. This study utilized 3D sacrificial printing for the fabrication of reproducible, cellular scaffolds containing tricalcium phosphate (TCP), hydroxyapatite (HA), or natural coral particles. High-throughput analysis of the cellular scaffolds included quantifying cell metabolism, viability, and calcium consumption, as well as nondestructive analysis of collagen accumulation and destructive methods for assessing cell number and morphological changes. Both particle- and non-particle-containing inks sustained cell metabolism with low and decreasing cell death for 7 days post-printing. Collagen staining, scanning electron microscopy imaging, and calcium and collagen quantification suggested that, under osteogenic induction conditions, cells migrated to the surface of the scaffolds and formed a sheet of cells and a collagen-containing extracellular matrix, thereby indicating osteogenic differentiation. The workflow described herein enables the creation of in vitro models to study the osteogenic nature of new bone grafting substitute materials. High-throughput printing combined with non-destructive screening techniques resulted in reduced time, resources, and associated costs and could be applicable to a broader range of cell types.
Collapse
Affiliation(s)
- Stephanie
E. Doyle
- College
of Medicine, Nursing and Health Science, School of Medicine, Regenerative
Medicine Institute (REMEDI), University
of Galway, County Galway, Galway H91 W2TY, Ireland
| | - Deirdre Winrow
- College
of Medicine, Nursing and Health Science, School of Medicine, Regenerative
Medicine Institute (REMEDI), University
of Galway, County Galway, Galway H91 W2TY, Ireland
| | - Fiona Buckley
- College
of Medicine, Nursing and Health Science, School of Medicine, Regenerative
Medicine Institute (REMEDI), University
of Galway, County Galway, Galway H91 W2TY, Ireland
| | - Elin Pernevik
- CELLINK
Bioprinting AB, Långfilsgatan
7, Gothenburg 412 76, Sweden
| | - Martin Johnson
- Zoan
Nuáil Teoranta T/A Zoan BioMed, The Hatchery Building, Cloonacarton,
Recess, Galway H91 VW58, Ireland
| | - Kerry Thompson
- College
of Medicine, Nursing and Health Science, School of Medicine, Anatomy
Imaging and Microscopy, University of Galway, Galway H91 W5P7, Ireland
| | - Linda Howard
- College
of Medicine, Nursing and Health Science, School of Medicine, Regenerative
Medicine Institute (REMEDI), University
of Galway, County Galway, Galway H91 W2TY, Ireland
| | - Cynthia M. Coleman
- College
of Medicine, Nursing and Health Science, School of Medicine, Regenerative
Medicine Institute (REMEDI), University
of Galway, County Galway, Galway H91 W2TY, Ireland
| |
Collapse
|
|
2
|
Casten LG, Koomar T, Thomas TR, Koh JY, Hofamman D, Thenuwara S, Momany A, O'Brien M, Murra JC, Bruce Tomblin J, Michaelson JJ. Rapidly evolved genomic regions shape individual language abilities in present-day humans. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.07.641231. [PMID: 40161630 PMCID: PMC11952349 DOI: 10.1101/2025.03.07.641231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
1Minor genetic changes have produced profound differences in cognitive abilities between humans and our closest relatives, particularly in language. Despite decades of research, ranging from single-gene studies to broader evolutionary analyses[1, 2, 3, 4, 5], key questions about the genomic foundations of human language have persisted, including which sequences are involved, how they evolved, and whether similar changes occur in other vocal learning species. Here we provide the first evidence directly linking rapidly evolved genomic regions to language abilities in contemporary humans. Through extensive analysis of 65 million years of evolutionary events in over 30,000 individuals, we demonstrate that Human Ancestor Quickly Evolved Regions (HAQERs)[5] - sequences that rapidly accumulated mutations after the human-chimpanzee split - specifically influence language but not general cognition. These regions evolved to shape language development by altering binding of Forkhead domain transcription factors, including FOXP2. Strikingly, language-associated HAQER variants show higher prevalence in Neanderthals than modern humans, have been stable throughout recent human history, and show evidence of convergent evolution across other mammalian vocal learners. An unexpected pattern of balancing selection acting on these apparently beneficial alleles is explained by their pleiotropic effects on prenatal brain development contributing to birth complications, reflecting an evolutionary trade-off between language capability and reproductive fitness. By developing the Evolution Stratified-Polygenic Score analysis, we show that language capabilities likely emerged before the human-Neanderthal split - far earlier than previously thought[3, 6, 7]. Our findings establish the first direct link between ancient genomic divergence and present-day variation in language abilities, while revealing how evolutionary constraints continue to shape human cognitive development.
Collapse
Affiliation(s)
| | | | | | - Jin-Young Koh
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland
| | | | | | - Allison Momany
- Stead Family Department of Pediatrics, University of Iowa
| | - Marlea O'Brien
- Department of Communication Science and Disorders, University of Iowa
| | | | - J Bruce Tomblin
- Department of Communication Science and Disorders, University of Iowa
| | - Jacob J Michaelson
- Department of Psychiatry, University of Iowa
- Department of Communication Science and Disorders, University of Iowa
| |
Collapse
|
|
3
|
Ren J, Liu K, Hu L, Yang R, Liu Y, Wang S, Chen X, Zhao S, Jing L, Liu T, Hu B, Zhang X, Wang H, Li H. An Efficient Probe-Based Quantitative PCR Assay Targeting Human-Specific DNA in ST6GALNAC3 for the Quantification of Human Cells in Preclinical Animal Models. Mol Biotechnol 2025; 67:1156-1164. [PMID: 38456963 DOI: 10.1007/s12033-024-01115-8] [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: 03/05/2023] [Accepted: 02/04/2024] [Indexed: 03/09/2024]
Abstract
Precise quantification of human cells in preclinical animal models by a sensitive and specific approach is warranted. The probe-based quantitative PCR (qPCR) assay as a sensitive and swift approach is suitable for the quantification of human cells by targeting human-specific DNA sequences. In this study, we developed an efficient qPCR assay targeting human-specific DNA in ST6GALNAC3 (termed ST6GAL-qPCR) for the quantification of human cells in preclinical animal models. ST6GAL-qPCR probe was synthesized with FAM and non-fluorescent quencher-minor groove binder conjugated to the 5' and 3' end of the probe, respectively. Genomic DNA from human, rhesus monkeys, cynomolgus monkeys, New Zealand White rabbits, SD rats, C57BL/6, and BALB/c mice were utilized for analyzing the specificity and sensitivity of the ST6GAL-qPCR assay. The ST6GAL-qPCR assay targeted human-specific DNA was cloned to pUCM-T vector and released by EcoR I/Hind III digestion for generating a calibration curve. Cell mixing experiment was performed to validate the ST6GAL-qPCR assay by analysis of 0.1%, 0.01%, and 0.001% of human leukocytes mixed with murine thymocytes. The ST6GAL-qPCR assay detected human DNA rather than DNA from the tested animal species. The amplification efficiency of the ST6GAL-qPCR assay was 93% and the linearity of calibration curve was R2 = 0.999. The ST6GAL-qPCR assay detected as low as 5 copies of human-specific DNA and is efficient to specially amplify as low as 30-pg human DNA in the presence of 1 μg of DNA from the tested species, respectively. The ST6GAL-qPCR assay was able to quantify as low as 0.01% of human leukocytes within murine thymocytes. This ST6GAL-qPCR assay can be used as an efficient approach for the quantification of human cells in preclinical animal models.
Collapse
Affiliation(s)
- Jinfeng Ren
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
- National Experimental Demonstration Center for Basic Medicine Education, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Ke Liu
- Department of Gastroenterology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, Jiangsu, China
| | - Lang Hu
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
- National Experimental Demonstration Center for Basic Medicine Education, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Ruoning Yang
- Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Yuting Liu
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
- National Experimental Demonstration Center for Basic Medicine Education, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Siyu Wang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
- National Experimental Demonstration Center for Basic Medicine Education, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Xinzhu Chen
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
- National Experimental Demonstration Center for Basic Medicine Education, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Shuli Zhao
- General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Luyao Jing
- Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Tiantian Liu
- Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Bin Hu
- Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Xuefeng Zhang
- Jiangsu Tripod Preclinical Research Laboratories Inc, Nanjing, China
| | - Hui Wang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China.
- National Experimental Demonstration Center for Basic Medicine Education, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China.
| | - Hui Li
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China.
- National Experimental Demonstration Center for Basic Medicine Education, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China.
- Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China.
- Department of Pathogenic Biology and Immunology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, China.
| |
Collapse
|
|
4
|
Lalanne C, Silar P. FungANI, a BLAST-based program for analyzing average nucleotide identity (ANI) between two fungal genomes, enables easy fungal species delimitation. Fungal Genet Biol 2025; 177:103969. [PMID: 39894199 DOI: 10.1016/j.fgb.2025.103969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 12/18/2024] [Accepted: 01/25/2025] [Indexed: 02/04/2025]
Abstract
Fungal species delimitation and phylogeny will likely rely in the future upon whole genome sequence comparison, as the costs of such sequences are rapidly decreasing. Average Nucleotide Identity (ANI) between genomes is a convenient metric that can be rapidly calculated for species delimitation. However, there is presently no easy-to-use program calculating the ANI between two fungal genomes and providing easy-to interpret results that can be help mycologists having limited access to bioinformatic facilities. Here, we present FungANI, a customizable BLAST-based program that calculate ANI between genomes. The program primarily targets Linux workstations or servers but it can be run on the latest Windows, macOS and Linux 64-Bit operating systems as a standalone desktop application. It was tested with various publicly-available genomes from species belonging to the Sordariales order. It proved efficient to differentiate closely related species and retrace their possible phylogenetic relationships. However, FungANI did not perform well for phylogenetic reconstruction on a broader evolutionary scale such as inferring relationships between distant genera. The program is freely available at https://github.com/podo-gec/fungani.
Collapse
Affiliation(s)
- Christophe Lalanne
- Univ Paris Paris Cité, Laboratoire Interdisciplinaire des Energies de Demain, 75205 Paris Cité CEDEX 13, France
| | - Philippe Silar
- Univ Paris Paris Cité, Laboratoire Interdisciplinaire des Energies de Demain, 75205 Paris Cité CEDEX 13, France.
| |
Collapse
|
|
5
|
Hannon Bozorgmehr J. The De Novo Emergence of Two Brain Genes in the Human Lineage Appears to be Unsupported. J Mol Evol 2025; 93:3-10. [PMID: 39725692 DOI: 10.1007/s00239-024-10227-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Accepted: 12/10/2024] [Indexed: 12/28/2024]
Abstract
Recently, certain studies have claimed that cognitive features and pathologies unique to humans can be traced to certain changes in the nervous system. These are caused by genes that have likely evolved "from scratch," not having any coding precursors. The translated proteins would not appear outside of the human lineage and any orthologs in other species should be non-coding. This contrasts with research that has identified a decisive role for duplication, and modifications to regulatory sequences, for such phenotypic traits. Closer examination, however, reveals that the inferred lineage-specific emergence of at least two of these genes is likely a misinterpretation owing to a lack of peptide verification, experimental oversights, and insufficient species comparisons. A possible pseudogenic origin is proposed for one of them. The implications of these claims for the study of molecular evolution are discussed.
Collapse
|
|
6
|
Hayakawa T, Kishida T, Go Y, Inoue E, Kawaguchi E, Aizu T, Ishizaki H, Toyoda A, Fujiyama A, Matsuzawa T, Hashimoto C, Furuichi T, Agata K. Genome-scale evolution in local populations of wild chimpanzees. Sci Rep 2025; 15:548. [PMID: 39747985 PMCID: PMC11696052 DOI: 10.1038/s41598-024-84163-z] [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: 07/25/2024] [Accepted: 12/20/2024] [Indexed: 01/04/2025] Open
Abstract
Analysis of genome-scale evolution has been difficult in large, endangered animals because opportunities to collect high-quality genetic samples are limited. There is a need for novel field-friendly, cost-effective genetic techniques. This study conducted an exome-wide analysis of a total of 42 chimpanzees (Pan troglodytes) across six African regions, providing insights into population discrimination techniques. Wild chimpanzee DNA was extracted noninvasively from collected fecal samples using the lysis-buffer storage method. To target genome-scale regions of host DNA, exome-capture sequencing was performed using cost-effective baits originally designed for humans (closely related to chimpanzees). Multivariate analysis effectively discriminated differences in local populations, aiding in the identification of samples' geographical origins. Exome-wide heterozygosity was negatively correlated significantly with genome-wide nonsynonymous-synonymous substitution ratios, suggesting that mutation loads exist at the local population level. Exome sequences revealed functional diversity and protein-coding gene divergence. Segregating pseudogenes were comprehensively annotated, with many being population-specific and others shared among populations. Focusing on multicopy chemosensory receptor genes, the segregating pseudogenes OR7D4 (an olfactory receptor) and TAS2R42 (a bitter taste receptor) were shared among western and eastern chimpanzees. Overall, our analytical framework offers ecological insights into chimpanzees and may be applicable to other organisms.
Collapse
Grants
- 12J04270, 25257409, 16K18630, 19K16241, 21H04919, 22770240, 24113511, 25711027, 25304019 Japan Society for the Promotion of Science
- 12J04270, 25257409, 16K18630, 19K16241, 21H04919, 22770240, 24113511, 25711027, 25304019 Japan Society for the Promotion of Science
- 12J04270, 25257409, 16K18630, 19K16241, 21H04919, 22770240, 24113511, 25711027, 25304019 Japan Society for the Promotion of Science
Collapse
Affiliation(s)
- Takashi Hayakawa
- Faculty of Environmental Earth Science, Hokkaido University, Sapporo, Hokkaido, Japan.
| | - Takushi Kishida
- College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa, Japan
- Wildlife Research Center, Kyoto University, Kyoto, Japan
| | - Yasuhiro Go
- Graduate School of Information Science, University of Hyogo, Kobe, Hyogo, Japan
- Department of System Neuroscience, Division of Behavioral Development, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Aichi, Japan
- Cognitive Genomics Research Group, Exploratory Research Center on Life and Living Systems (ExCELLS), National Institutes of Natural Sciences, Okazaki, Aichi, Japan
| | - Eiji Inoue
- Faculty of Science, Toho University, Funabashi, Chiba, Japan
| | - Eri Kawaguchi
- Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
| | - Tomoyuki Aizu
- Department of Genomics and Evolutionary Biology, National Institute of Genetics, Mishima, Shizuoka, Japan
- Advanced Genomics Center, National Institute of Genetics, Mishima, Shizuoka, Japan
| | - Hinako Ishizaki
- Department of Genomics and Evolutionary Biology, National Institute of Genetics, Mishima, Shizuoka, Japan
- Advanced Genomics Center, National Institute of Genetics, Mishima, Shizuoka, Japan
| | - Atsushi Toyoda
- Department of Genomics and Evolutionary Biology, National Institute of Genetics, Mishima, Shizuoka, Japan
- Advanced Genomics Center, National Institute of Genetics, Mishima, Shizuoka, Japan
| | - Asao Fujiyama
- Advanced Genomics Center, National Institute of Genetics, Mishima, Shizuoka, Japan
| | - Tetsuro Matsuzawa
- Department of Pedagogy, Chubu Gakuin University, Gifu, Japan
- College of Life Sciences, Northwest University, Xi'an, China
| | - Chie Hashimoto
- Wildlife Research Center, Kyoto University, Kyoto, Japan
| | | | - Kiyokazu Agata
- Laboratory for Regenerative Biology, National Institute for Basic Biology, Okazaki, Aichi, Japan
| |
Collapse
|
|
7
|
Wall LL, Brown D. Personhood Begins at Birth: The Rational Foundation for Abortion Policy in a Secular State. JOURNAL OF BIOETHICAL INQUIRY 2024; 21:751-769. [PMID: 39172346 DOI: 10.1007/s11673-024-10352-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 03/03/2024] [Indexed: 08/23/2024]
Abstract
The struggle over legal abortion access in the United States is a religious controversy, not a scientific debate. Religious activists who believe that meaningful individual life (i.e., "personhood") begins at a specific "moment-of-conception" are attempting to pass laws that force this view upon all pregnant persons, irrespective of their medical circumstances, individual preferences, or personal religious beliefs. This paper argues that such actions promote a constitutionally prohibited "establishment of religion." Abortion policy in a secular state must be based upon scientifically accurate biology, not unprovable theological presuppositions. The scientific facts regarding human pregnancy do not support the position that personhood begins with fertilization-at which point a pregnancy does not yet even exist. Abortion policy should regard the embryo/fetus as part of the pregnant individual's body until delivery. We argue that individual "personhood" only begins when the latent potentialities of the fetal nervous system are actualized in the newborn after delivery. The paper argues that instantiating non-scientific beliefs concerning embryonic/fetal "personhood" into the law as the basis for abortion policy establishes a state-sponsored religion. The protection of religious liberty requires that abortion be decriminalized. Abortion should be treated like any other medical procedure and regulated similarly. To protect both religious freedom and sound medical practice, individual legal personhood should be recognized as beginning only at birth.
Collapse
Affiliation(s)
- L Lewis Wall
- Departments of Obstetrics & Gynecology and Anthropology, Washington University in St. Louis, St. Louis, MO, United States.
| | - Douglas Brown
- Department of Surgery, Washington University in St. Louis, St. Louis, MO, United States
| |
Collapse
|
|
8
|
Moss ND, Lollis D, Silver DL. How our brains are built: emerging approaches to understand human-specific features. Curr Opin Genet Dev 2024; 89:102278. [PMID: 39549607 DOI: 10.1016/j.gde.2024.102278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 10/08/2024] [Accepted: 10/21/2024] [Indexed: 11/18/2024]
Abstract
Understanding what makes us uniquely human is a long-standing question permeating fields from genomics, neuroscience, and developmental biology to medicine. The discovery of human-specific genomic sequences has enabled a new understanding of the molecular features of human brain evolution. Advances in sequencing, computational, and in vitro screening approaches collectively reveal new roles of uniquely human sequences in regulating gene expression. Here, we review the landscape of human-specific loci and describe how emerging technologies are being used to understand their molecular functions and impact on brain development. We describe current challenges in the field and the potential of integrating new hypotheses and approaches to propel our understanding of the human brain.
Collapse
Affiliation(s)
- Nicole D Moss
- Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA
| | - Davoneshia Lollis
- Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA. https://twitter.com/@_mlollis
| | - Debra L Silver
- Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA; Department of Cell Biology and Neurobiology, Duke University Medical Center, Durham, NC 27710, USA; Duke Institute for Brain Sciences and Duke Regeneration Center, Duke University Medical Center, Durham, NC 27710, USA.
| |
Collapse
|
|
9
|
Tada Y, Shimizu A. Vascular bundle cell-specific expression of a phosphate transporter improves phosphate use efficiency of transgenic Arabidopsis without detrimental effects. Sci Rep 2024; 14:26713. [PMID: 39496723 PMCID: PMC11535314 DOI: 10.1038/s41598-024-78500-5] [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: 07/25/2024] [Accepted: 10/31/2024] [Indexed: 11/06/2024] Open
Abstract
Constitutive overexpression of phosphate (Pi) transporter family 1 often results in the accumulation of toxic levels of Pi, which causes growth retardation in plants. In contrast, we had previously reported that root epidermis-specific overexpression of the phosphate transporter TaPT2 in Arabidopsis leads to improved growth and Pi use efficiency. In the present study, we used promoters AtHKT1;1 and SKOR, which are predominantly expressed in the vascular bundle tissues, to overexpress TaPT2. Transgenic lines exhibited increased shoot growth compared to wild type plants under normal- and low-Pi conditions, along with elevated root Pi and total P content, and higher xylem sap Pi concentration, specifically under low-Pi conditions. This was attributed to moderate Pi accumulation in the xylem parenchyma cells, enhancing the Pi uploading capacity to the xylem. SKOR-TaPT2, however, did not complement pho1 mutant, which was defective in uploading Pi to the xylem. The transcriptional levels of VPT1 and VPT3, which are responsible for transporting excess Pi into a vacuole, were upregulated in SKOR promoter lines under normal-Pi conditions. Our results suggested that root vascular bundle-specific expression of TaPT2 is another promising strategy for increasing biomass production, Pi uptake, and Pi use efficiency while preventing growth retardation in transgenic plants.
Collapse
Affiliation(s)
- Yuichi Tada
- School of Bioscience and Biotechnology, Tokyo University of Technology, 1404-1 Katakura, Hachioji, Tokyo, 192-0982, Japan.
- Center for the Future of Food and Agriculture, Tokyo University of Technology, 1404-1 Katakura, Hachioji, Tokyo, 192-0982, Japan.
| | - Aoi Shimizu
- Graduate School of Bionics, Tokyo University of Technology, 1404-1 Katakura, Hachioji, Tokyo, 192-0982, Japan
| |
Collapse
|
|
10
|
Alsaab HO, Alzahrani MS, F Alaqile A, Waggas DS, Almutairy B. Long non-coding RNAs; potential contributors in cancer chemoresistance through modulating diverse molecular mechanisms and signaling pathways. Pathol Res Pract 2024; 260:155455. [PMID: 39043005 DOI: 10.1016/j.prp.2024.155455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Revised: 06/29/2024] [Accepted: 07/05/2024] [Indexed: 07/25/2024]
Abstract
One of the mainstays of cancer treatment is chemotherapy. Drug resistance, however, continues to be the primary factor behind clinical treatment failure. Gene expression is regulated by long non-coding RNAs (lncRNAs) in several ways, including chromatin remodeling, translation, epigenetic, and transcriptional levels. Cancer hallmarks such as DNA damage, metastasis, immunological evasion, cell stemness, drug resistance, metabolic reprogramming, and angiogenesis are all influenced by LncRNAs. Numerous studies have been conducted on LncRNA-driven mechanisms of resistance to different antineoplastic drugs. Diverse medication kinds elicit diverse resistance mechanisms, and each mechanism may have multiple contributing factors. As a result, several lncRNAs have been identified as new biomarkers and therapeutic targets for identifying and managing cancers. This compels us to thoroughly outline the crucial roles that lncRNAs play in drug resistance. In this regard, this article provides an in-depth analysis of the recently discovered functions of lncRNAs in the pathogenesis and chemoresistance of cancer. As a result, the current research might offer a substantial foundation for future drug resistance-conquering strategies that target lncRNAs in cancer therapies.
Collapse
Affiliation(s)
- Hashem O Alsaab
- Department of Pharmaceutics and Pharmaceutical Technology, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.
| | - Mohammad S Alzahrani
- Department of Clinical Pharmacy, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Atheer F Alaqile
- College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Dania S Waggas
- Department of Pathological Sciences, Fakeeh College for Medical Sciences, Jeddah, Saudi Arabia
| | - Bandar Almutairy
- Department of Pharmacology, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia.
| |
Collapse
|
|
11
|
Nehme R, Pietiläinen O, Barrett LE. Genomic, molecular, and cellular divergence of the human brain. Trends Neurosci 2024; 47:491-505. [PMID: 38897852 PMCID: PMC11956863 DOI: 10.1016/j.tins.2024.05.009] [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: 02/29/2024] [Revised: 04/29/2024] [Accepted: 05/21/2024] [Indexed: 06/21/2024]
Abstract
While many core biological processes are conserved across species, the human brain has evolved with unique capacities. Current understanding of the neurobiological mechanisms that endow human traits as well as associated vulnerabilities remains limited. However, emerging data have illuminated species divergence in DNA elements and genome organization, in molecular, morphological, and functional features of conserved neural cell types, as well as temporal differences in brain development. Here, we summarize recent data on unique features of the human brain and their complex implications for the study and treatment of brain diseases. We also consider key outstanding questions in the field and discuss the technologies and foundational knowledge that will be required to accelerate understanding of human neurobiology.
Collapse
Affiliation(s)
- Ralda Nehme
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
| | - Olli Pietiläinen
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Neuroscience Center, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
| | - Lindy E Barrett
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
| |
Collapse
|
|
12
|
Lindhout FW, Krienen FM, Pollard KS, Lancaster MA. A molecular and cellular perspective on human brain evolution and tempo. Nature 2024; 630:596-608. [PMID: 38898293 DOI: 10.1038/s41586-024-07521-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 04/29/2024] [Indexed: 06/21/2024]
Abstract
The evolution of the modern human brain was accompanied by distinct molecular and cellular specializations, which underpin our diverse cognitive abilities but also increase our susceptibility to neurological diseases. These features, some specific to humans and others shared with related species, manifest during different stages of brain development. In this multi-stage process, neural stem cells proliferate to produce a large and diverse progenitor pool, giving rise to excitatory or inhibitory neurons that integrate into circuits during further maturation. This process unfolds over varying time scales across species and has progressively become slower in the human lineage, with differences in tempo correlating with differences in brain size, cell number and diversity, and connectivity. Here we introduce the terms 'bradychrony' and 'tachycrony' to describe slowed and accelerated developmental tempos, respectively. We review how recent technical advances across disciplines, including advanced engineering of in vitro models, functional comparative genetics and high-throughput single-cell profiling, are leading to a deeper understanding of how specializations of the human brain arise during bradychronic neurodevelopment. Emerging insights point to a central role for genetics, gene-regulatory networks, cellular innovations and developmental tempo, which together contribute to the establishment of human specializations during various stages of neurodevelopment and at different points in evolution.
Collapse
Affiliation(s)
- Feline W Lindhout
- MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, UK.
| | - Fenna M Krienen
- Princeton Neuroscience Institute, Princeton University, Princeton, NJ, USA
| | - Katherine S Pollard
- Gladstone Institutes, San Francisco, CA, USA
- Chan Zuckerberg Biohub, San Francisco, CA, USA
- Department of Epidemiology & Biostatistics, Institute for Computational Health Sciences, and Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
| | - Madeline A Lancaster
- MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, UK.
| |
Collapse
|
|
13
|
Redl M, Shayegan A, Rollinger JM. Application of 3Rs in Caenorhabditis elegans Research for the Identification of Health-Promoting Natural Products. PLANTA MEDICA 2024; 90:576-587. [PMID: 38843797 DOI: 10.1055/a-2254-0131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2024]
Abstract
The average age of the population is increasing worldwide, which has a profound impact on our society. This leads to an increasing demand for medicines and requires the development of new strategies to promote health during the additional years. In the search for resources and therapeutics for improved health during an extended life span, attention has to be paid to environmental exposure and ecosystem burdens that inevitably emerge with the extended consumption of medicines and drug development, even in the preclinical stage. The hereby introduced sustainable strategy for drug discovery is built on 3Rs, "R: obustness, R: eliability, and saving R: esources", inspired by both the 3Rs used in animal experiments and environmental protection, and centers on the usefulness and the variety of the small model organism Caenorhabditis elegans for detecting health-promoting natural products. A workflow encompassing a multilevel screening approach is presented to maximize the amount of information on health-promoting samples, while considering the 3Rs. A detailed, methodology- and praxis-oriented compilation and discussion of proposed C. elegans health span assays and more disease-specific assays are presented to offer guidance for scientists intending to work with C. elegans, thus facilitating the initial steps towards the integration of C. elegans assays in their laboratories.
Collapse
Affiliation(s)
- Martina Redl
- Division of Pharmacognosy, Department of Pharmaceutical Sciences, University of Vienna, Vienna, Austria
- Vienna Doctoral School of Pharmaceutical, Nutritional, and Sport Sciences, University of Vienna, Vienna, Austria
| | - Anusha Shayegan
- Division of Pharmacognosy, Department of Pharmaceutical Sciences, University of Vienna, Vienna, Austria
| | - Judith M Rollinger
- Division of Pharmacognosy, Department of Pharmaceutical Sciences, University of Vienna, Vienna, Austria
| |
Collapse
|
|
14
|
Shorbaji A, Pushparaj PN, Bakhashab S, Al-Ghafari AB, Al-Rasheed RR, Siraj Mira L, Basabrain MA, Alsulami M, Abu Zeid IM, Naseer MI, Rasool M. Current genetic models for studying congenital heart diseases: Advantages and disadvantages. Bioinformation 2024; 20:415-429. [PMID: 39132229 PMCID: PMC11309114 DOI: 10.6026/973206300200415] [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: 05/01/2024] [Revised: 05/31/2024] [Accepted: 05/31/2024] [Indexed: 08/13/2024] Open
Abstract
Congenital heart disease (CHD) encompasses a diverse range of structural and functional anomalies that affect the heart and the major blood vessels. Epidemiological studies have documented a global increase in CHD prevalence, which can be attributed to advancements in diagnostic technologies. Extensive research has identified a plethora of CHD-related genes, providing insights into the biochemical pathways and molecular mechanisms underlying this pathological state. In this review, we discuss the advantages and challenges of various In vitro and in vivo CHD models, including primates, canines, Xenopus frogs, rabbits, chicks, mice, Drosophila, zebrafish, and induced pluripotent stem cells (iPSCs). Primates are closely related to humans but are rare and expensive. Canine models are costly but structurally comparable to humans. Xenopus frogs are advantageous because of their generation of many embryos, ease of genetic modification, and cardiac similarity. Rabbits mimic human physiology but are challenging to genetically control. Chicks are inexpensive and simple to handle; however, cardiac events can vary among humans. Mice differ physiologically, while being evolutionarily close and well-resourced. Drosophila has genes similar to those of humans but different heart structures. Zebrafish have several advantages, including high gene conservation in humans and physiological cardiac similarities but limitations in cross-reactivity with mammalian antibodies, gene duplication, and limited embryonic stem cells for reverse genetic methods. iPSCs have the potential for gene editing, but face challenges in terms of 2D structure and genomic stability. CRISPR-Cas9 allows for genetic correction but requires high technical skills and resources. These models have provided valuable knowledge regarding cardiac development, disease simulation, and the verification of genetic factors. This review highlights the distinct features of various models with respect to their biological characteristics, vulnerability to developing specific heart diseases, approaches employed to induce particular conditions, and the comparability of these species to humans. Therefore, the selection of appropriate models is based on research objectives, ultimately leading to an enhanced comprehension of disease pathology and therapy.
Collapse
Affiliation(s)
- Ayat Shorbaji
- Biochemistry Department, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Peter Natesan Pushparaj
- Center of Excellence in Genomic Medicine Research, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Sherin Bakhashab
- Biochemistry Department, King Abdulaziz University, Jeddah, Saudi Arabia
- Center of Excellence in Genomic Medicine Research, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Ayat B Al-Ghafari
- Biochemistry Department, King Abdulaziz University, Jeddah, Saudi Arabia
- Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Rana R Al-Rasheed
- Experimental Biochemistry Unit, King Fahad research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Loubna Siraj Mira
- Center of Excellence in Genomic Medicine Research, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mohammad Abdullah Basabrain
- Center of Excellence in Genomic Medicine Research, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Majed Alsulami
- Center of Excellence in Genomic Medicine Research, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Isam M Abu Zeid
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Muhammad Imran Naseer
- Center of Excellence in Genomic Medicine Research, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mahmood Rasool
- Center of Excellence in Genomic Medicine Research, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| |
Collapse
|
|
15
|
Drobyshev A, Modestov A, Suntsova M, Poddubskaya E, Seryakov A, Moisseev A, Sorokin M, Tkachev V, Zakharova G, Simonov A, Zolotovskaia MA, Buzdin A. Pan-cancer experimental characteristic of human transcriptional patterns connected with telomerase reverse transcriptase ( TERT) gene expression status. Front Genet 2024; 15:1401100. [PMID: 38859942 PMCID: PMC11163056 DOI: 10.3389/fgene.2024.1401100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 05/08/2024] [Indexed: 06/12/2024] Open
Abstract
The TERT gene encodes the reverse transcriptase subunit of telomerase and is normally transcriptionally suppressed in differentiated human cells but reactivated in cancers where its expression is frequently associated with poor survival prognosis. Here we experimentally assessed the RNA sequencing expression patterns associated with TERT transcription in 1039 human cancer samples of 27 tumor types. We observed a bimodal distribution of TERT expression where ∼27% of cancer samples did not express TERT and the rest showed a bell-shaped distribution. Expression of TERT strongly correlated with 1443 human genes including 103 encoding transcriptional factor proteins. Comparison of TERT- positive and negative cancers showed the differential activation of 496 genes and 1975 molecular pathways. Therein, 32/38 (84%) of DNA repair pathways were hyperactivated in TERT+ cancers which was also connected with accelerated replication, transcription, translation, and cell cycle progression. In contrast, the level of 40 positive cell cycle regulator proteins and a set of epithelial-to-mesenchymal transition pathways was specific for the TERT- group suggesting different proliferation strategies for both groups of cancer. Our pilot study showed that the TERT+ group had ∼13% of cancers with C228T or C250T mutated TERT promoter. However, the presence of promoter mutations was not associated with greater TERT expression compared with other TERT+ cancers, suggesting parallel mechanisms of its transcriptional activation in cancers. In addition, we detected a decreased expression of L1 retrotransposons in the TERT+ group, and further decreased L1 expression in promoter mutated TERT+ cancers. TERT expression was correlated with 17 genes encoding molecular targets of cancer therapeutics and may relate to differential survival patterns of TERT- positive and negative cancers.
Collapse
Affiliation(s)
- Aleksey Drobyshev
- Endocrinology Research Center, Moscow, Russia
- Institute of Personalized Oncology, I. M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Alexander Modestov
- Institute of Personalized Oncology, I. M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Maria Suntsova
- Endocrinology Research Center, Moscow, Russia
- Institute of Personalized Oncology, I. M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Elena Poddubskaya
- Institute of Personalized Oncology, I. M. Sechenov First Moscow State Medical University, Moscow, Russia
- Clinical Center Vitamed, Moscow, Russia
| | | | - Aleksey Moisseev
- Institute of Personalized Oncology, I. M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Maksim Sorokin
- Endocrinology Research Center, Moscow, Russia
- Institute of Personalized Oncology, I. M. Sechenov First Moscow State Medical University, Moscow, Russia
| | | | - Galina Zakharova
- Institute of Personalized Oncology, I. M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Aleksander Simonov
- Institute of Personalized Oncology, I. M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Marianna A. Zolotovskaia
- Endocrinology Research Center, Moscow, Russia
- Institute of Personalized Oncology, I. M. Sechenov First Moscow State Medical University, Moscow, Russia
- Moscow Center for Advanced Studies 20, Moscow, Russia
| | - Anton Buzdin
- Endocrinology Research Center, Moscow, Russia
- Institute of Personalized Oncology, I. M. Sechenov First Moscow State Medical University, Moscow, Russia
- Moscow Center for Advanced Studies 20, Moscow, Russia
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia
| |
Collapse
|
|
16
|
Takahi M, Hamazaki Y, Ohnuma K, Imamura M. Cardiac differentiation of chimpanzee induced pluripotent stem cell lines with different subspecies backgrounds. In Vitro Cell Dev Biol Anim 2024; 60:555-562. [PMID: 38753247 DOI: 10.1007/s11626-024-00914-2] [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: 11/30/2023] [Accepted: 04/23/2024] [Indexed: 05/26/2024]
Abstract
The comparative analysis between humans and non-human primates is an instrumental approach for elucidating the evolutional traits and disease propensity of humans. However, in primates, cross-species analyses of their developmental events have encountered constraints because of the ethical and technical limitations in available sample collection, sequential monitoring, and manipulations. In an endeavor to surmount these challenges, in recent years, induced pluripotent stem cells (iPSCs) have garnered escalating interest as an in vitro tool for cross-species analyses between humans and non-human primates. Meanwhile, compared to humans, there is less information on in vitro differentiation of non-human primate iPSCs, and their genetic diversity including subspecies may cause different eligibility to in vitro differentiation methods. Therefore, antecedent to embarking on a comparative analysis to humans, it is a prerequisite to develop the efficacious methodologies for in vitro differentiation regardless of the intraspecies genetic background in non-human primates. In this study, we executed the in vitro differentiation of cardiomyocytes from four chimpanzee iPSC lines with different subspecies and individual backgrounds. To induce cardiomyocytes from chimpanzee iPSCs, we evaluated our methodology for in vitro cardiac differentiation of human iPSCs. Eventually, with minor alterations, our cardiac differentiation method was applicable to all chimpanzee iPSC lines tested as assessed by the expression of cardiac marker genes and the beating ability. Hence, our in vitro differentiation method will advance iPSC-based research of chimpanzee cardiac development and also hold possible utility to cross-species analyses among primate species.
Collapse
Affiliation(s)
- Mika Takahi
- Department of Science of Technology Innovation, Nagaoka University of Technology, 1603-1 Kamitomioka, Nagaoka, Niigata, 940-2188, Japan.
| | - Yusuke Hamazaki
- Molecular Biology Section, Center for the Evolutionary Origins of Human Behavior, Kyoto University, Inuyama, Aichi, 484-8506, Japan
| | - Kiyoshi Ohnuma
- Department of Science of Technology Innovation, Nagaoka University of Technology, 1603-1 Kamitomioka, Nagaoka, Niigata, 940-2188, Japan
| | - Masanori Imamura
- Molecular Biology Section, Center for the Evolutionary Origins of Human Behavior, Kyoto University, Inuyama, Aichi, 484-8506, Japan
| |
Collapse
|
|
17
|
Walter NG. Are non-protein coding RNAs junk or treasure?: An attempt to explain and reconcile opposing viewpoints of whether the human genome is mostly transcribed into non-functional or functional RNAs. Bioessays 2024; 46:e2300201. [PMID: 38351661 DOI: 10.1002/bies.202300201] [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: 10/18/2023] [Revised: 01/18/2024] [Accepted: 01/19/2024] [Indexed: 03/28/2024]
Abstract
The human genome project's lasting legacies are the emerging insights into human physiology and disease, and the ascendance of biology as the dominant science of the 21st century. Sequencing revealed that >90% of the human genome is not coding for proteins, as originally thought, but rather is overwhelmingly transcribed into non-protein coding, or non-coding, RNAs (ncRNAs). This discovery initially led to the hypothesis that most genomic DNA is "junk", a term still championed by some geneticists and evolutionary biologists. In contrast, molecular biologists and biochemists studying the vast number of transcripts produced from most of this genome "junk" often surmise that these ncRNAs have biological significance. What gives? This essay contrasts the two opposing, extant viewpoints, aiming to explain their bases, which arise from distinct reference frames of the underlying scientific disciplines. Finally, it aims to reconcile these divergent mindsets in hopes of stimulating synergy between scientific fields.
Collapse
Affiliation(s)
- Nils G Walter
- Center for RNA Biomedicine, Single Molecule Analysis Group, Department of Chemistry, University of Michigan, Ann Arbor, Michigan, USA
| |
Collapse
|
|
18
|
Bacher J, Lali N, Steiner F, Jungbauer A. Cytokines as fast indicator of infectious virus titer during process development. J Biotechnol 2024; 383:55-63. [PMID: 38325657 DOI: 10.1016/j.jbiotec.2024.01.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 01/29/2024] [Accepted: 01/29/2024] [Indexed: 02/09/2024]
Abstract
Measuring infectious titer is the most time-consuming method during the production and process development of live viruses. Conventionally, it is done by measuring the tissue culture infectious dose (TCID50) or plaque forming units (pfu) in cell-based assays. Such assays require a time span of more than a week to the readout and significantly slow down process development. In this study, we utilized the pro-inflammatory cytokine response of a Vero production cell line to a recombinant measles vaccine virus (MVV) as model system for rapidly determining infectious virus titer within several hours after infection instead of one week. Cytokines are immunostimulatory proteins contributing to the first line of defence against virus infection. The probed cytokines in this study were MCP-1 and RANTES, which are secreted in a virus dose as well as time dependent manner and correlate to TCID50 over a concentration range of several logarithmic levels with R2 = 0.86 and R2 = 0.83, respectively. Furthermore, the pro-inflammatory cytokine response of the cells was specific for infectious virus particles and not evoked with filtered virus seed. We also discovered that individual cytokine candidates may be more suitable for off- or at-line analysis, depending on the secretion profile as well as their sensitivity towards changing process conditions. Furthermore, the method can be applied to follow a purification procedure and is therefore suited for process development and control.
Collapse
Affiliation(s)
- Johanna Bacher
- acib - Austrian Centre of Industrial Biotechnology, Krenngasse 37, Graz A-8010, Austria; Department of Biotechnology, Institute of Bioprocess Science and Engineering, University of Natural Resources and Life Sciences Vienna, Vienna, Austria
| | - Narges Lali
- acib - Austrian Centre of Industrial Biotechnology, Krenngasse 37, Graz A-8010, Austria; Department of Biotechnology, Institute of Bioprocess Science and Engineering, University of Natural Resources and Life Sciences Vienna, Vienna, Austria
| | - Florian Steiner
- acib - Austrian Centre of Industrial Biotechnology, Krenngasse 37, Graz A-8010, Austria
| | - Alois Jungbauer
- acib - Austrian Centre of Industrial Biotechnology, Krenngasse 37, Graz A-8010, Austria; Department of Biotechnology, Institute of Bioprocess Science and Engineering, University of Natural Resources and Life Sciences Vienna, Vienna, Austria.
| |
Collapse
|
|
19
|
Fukuda K. The role of transposable elements in human evolution and methods for their functional analysis: current status and future perspectives. Genes Genet Syst 2024; 98:289-304. [PMID: 37866889 DOI: 10.1266/ggs.23-00140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2023] Open
Abstract
Transposable elements (TEs) are mobile DNA sequences that can insert themselves into various locations within the genome, causing mutations that may provide advantages or disadvantages to individuals and species. The insertion of TEs can result in genetic variation that may affect a wide range of human traits including genetic disorders. Understanding the role of TEs in human biology is crucial for both evolutionary and medical research. This review discusses the involvement of TEs in human traits and disease susceptibility, as well as methods for functional analysis of TEs.
Collapse
Affiliation(s)
- Kei Fukuda
- Integrative Genomics Unit, The University of Melbourne
| |
Collapse
|
|
20
|
Kuderna LFK, Ulirsch JC, Rashid S, Ameen M, Sundaram L, Hickey G, Cox AJ, Gao H, Kumar A, Aguet F, Christmas MJ, Clawson H, Haeussler M, Janiak MC, Kuhlwilm M, Orkin JD, Bataillon T, Manu S, Valenzuela A, Bergman J, Rouselle M, Silva FE, Agueda L, Blanc J, Gut M, de Vries D, Goodhead I, Harris RA, Raveendran M, Jensen A, Chuma IS, Horvath JE, Hvilsom C, Juan D, Frandsen P, Schraiber JG, de Melo FR, Bertuol F, Byrne H, Sampaio I, Farias I, Valsecchi J, Messias M, da Silva MNF, Trivedi M, Rossi R, Hrbek T, Andriaholinirina N, Rabarivola CJ, Zaramody A, Jolly CJ, Phillips-Conroy J, Wilkerson G, Abee C, Simmons JH, Fernandez-Duque E, Kanthaswamy S, Shiferaw F, Wu D, Zhou L, Shao Y, Zhang G, Keyyu JD, Knauf S, Le MD, Lizano E, Merker S, Navarro A, Nadler T, Khor CC, Lee J, Tan P, Lim WK, Kitchener AC, Zinner D, Gut I, Melin AD, Guschanski K, Schierup MH, Beck RMD, Karakikes I, Wang KC, Umapathy G, Roos C, Boubli JP, Siepel A, Kundaje A, Paten B, Lindblad-Toh K, Rogers J, Marques Bonet T, Farh KKH. Identification of constrained sequence elements across 239 primate genomes. Nature 2024; 625:735-742. [PMID: 38030727 PMCID: PMC10808062 DOI: 10.1038/s41586-023-06798-8] [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: 02/09/2023] [Accepted: 10/30/2023] [Indexed: 12/01/2023]
Abstract
Noncoding DNA is central to our understanding of human gene regulation and complex diseases1,2, and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome3-9. Identifying the genomic elements that have become constrained specifically in primates has been hampered by the faster evolution of noncoding DNA compared to protein-coding DNA10, the relatively short timescales separating primate species11, and the previously limited availability of whole-genome sequences12. Here we construct a whole-genome alignment of 239 species, representing nearly half of all extant species in the primate order. Using this resource, we identified human regulatory elements that are under selective constraint across primates and other mammals at a 5% false discovery rate. We detected 111,318 DNase I hypersensitivity sites and 267,410 transcription factor binding sites that are constrained specifically in primates but not across other placental mammals and validate their cis-regulatory effects on gene expression. These regulatory elements are enriched for human genetic variants that affect gene expression and complex traits and diseases. Our results highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals.
Collapse
Affiliation(s)
- Lukas F K Kuderna
- Illumina Artificial Intelligence Laboratory, Illumina, San Diego, CA, USA
| | - Jacob C Ulirsch
- Illumina Artificial Intelligence Laboratory, Illumina, San Diego, CA, USA
| | - Sabrina Rashid
- Illumina Artificial Intelligence Laboratory, Illumina, San Diego, CA, USA
| | - Mohamed Ameen
- Illumina Artificial Intelligence Laboratory, Illumina, San Diego, CA, USA
| | - Laksshman Sundaram
- Illumina Artificial Intelligence Laboratory, Illumina, San Diego, CA, USA
| | - Glenn Hickey
- UC Santa Cruz Genomics Institute, University of California, Santa Cruz, CA, USA
| | - Anthony J Cox
- Illumina Artificial Intelligence Laboratory, Illumina, San Diego, CA, USA
| | - Hong Gao
- Illumina Artificial Intelligence Laboratory, Illumina, San Diego, CA, USA
| | - Arvind Kumar
- Illumina Artificial Intelligence Laboratory, Illumina, San Diego, CA, USA
| | - Francois Aguet
- Illumina Artificial Intelligence Laboratory, Illumina, San Diego, CA, USA
| | - Matthew J Christmas
- Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
| | - Hiram Clawson
- UC Santa Cruz Genomics Institute, University of California, Santa Cruz, CA, USA
| | | | - Mareike C Janiak
- School of Science, Engineering and Environment, University of Salford, Salford, UK
| | - Martin Kuhlwilm
- Department of Evolutionary Anthropology, University of Vienna, Vienna, Austria
- Human Evolution and Archaeological Sciences (HEAS), University of Vienna, Vienna, Austria
| | - Joseph D Orkin
- Département d'Anthropologie, Université de Montréal, Montréal, Quebec, Canada
| | - Thomas Bataillon
- Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark
| | - Shivakumara Manu
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
- Laboratory for the Conservation of Endangered Species, CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India
| | - Alejandro Valenzuela
- IBE, Institute of Evolutionary Biology (UPF-CSIC), Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain
| | - Juraj Bergman
- Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark
- Section for Ecoinformatics and Biodiversity, Department of Biology, Aarhus University, Aarhus, Denmark
| | | | - Felipe Ennes Silva
- Research Group on Primate Biology and Conservation, Mamirauá Institute for Sustainable Development, Tefé, Brazil
- Evolutionary Biology and Ecology (EBE), Département de Biologie des Organismes, Université libre de Bruxelles (ULB), Brussels, Belgium
| | - Lidia Agueda
- Centro Nacional de Analisis Genomico (CNAG), Barcelona, Spain
| | - Julie Blanc
- Centro Nacional de Analisis Genomico (CNAG), Barcelona, Spain
| | - Marta Gut
- Centro Nacional de Analisis Genomico (CNAG), Barcelona, Spain
| | - Dorien de Vries
- School of Science, Engineering and Environment, University of Salford, Salford, UK
| | - Ian Goodhead
- School of Science, Engineering and Environment, University of Salford, Salford, UK
| | - R Alan Harris
- Human Genome Sequencing Center and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Muthuswamy Raveendran
- Human Genome Sequencing Center and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Axel Jensen
- Department of Ecology and Genetics, Animal Ecology, Uppsala University, Uppsala, Sweden
| | | | - Julie E Horvath
- North Carolina Museum of Natural Sciences, Raleigh, NC, USA
- Department of Biological and Biomedical Sciences, North Carolina Central University, Durham, NC, USA
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA
- Department of Evolutionary Anthropology, Duke University, Durham, NC, USA
- Renaissance Computing Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | | | - David Juan
- IBE, Institute of Evolutionary Biology (UPF-CSIC), Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain
| | | | - Joshua G Schraiber
- Illumina Artificial Intelligence Laboratory, Illumina, San Diego, CA, USA
| | | | - Fabrício Bertuol
- Universidade Federal do Amazonas, Departamento de Genética, Laboratório de Evolução e Genética Animal (LEGAL), Manaus, Brazil
| | - Hazel Byrne
- Department of Anthropology, University of Utah, Salt Lake City, UT, USA
| | | | - Izeni Farias
- Universidade Federal do Amazonas, Departamento de Genética, Laboratório de Evolução e Genética Animal (LEGAL), Manaus, Brazil
| | - João Valsecchi
- Research Group on Terrestrial Vertebrate Ecology, Mamirauá Institute for Sustainable Development, Tefé, Brazil
- Rede de Pesquisa em Diversidade, Conservação e Uso da Fauna da Amazônia - RedeFauna, Manaus, Brazil
- Comunidad de Manejo de Fauna Silvestre en la Amazonía y en Latinoamérica-ComFauna, Iquitos, Peru
| | - Malu Messias
- Universidade Federal de Rondônia, Porto Velho, Brazil
| | | | - Mihir Trivedi
- Laboratory for the Conservation of Endangered Species, CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India
| | - Rogerio Rossi
- Instituto de Biociências, Universidade Federal do Mato Grosso, Cuiabá, Brazil
| | - Tomas Hrbek
- Universidade Federal do Amazonas, Departamento de Genética, Laboratório de Evolução e Genética Animal (LEGAL), Manaus, Brazil
- Department of Biology, Trinity University, San Antonio, TX, USA
| | - Nicole Andriaholinirina
- Life Sciences and Environment, Technology and Environment of Mahajanga, University of Mahajanga, Mahajanga, Madagascar
| | - Clément J Rabarivola
- Life Sciences and Environment, Technology and Environment of Mahajanga, University of Mahajanga, Mahajanga, Madagascar
| | - Alphonse Zaramody
- Life Sciences and Environment, Technology and Environment of Mahajanga, University of Mahajanga, Mahajanga, Madagascar
| | - Clifford J Jolly
- Department of Anthropology, New York University, New York, NY, USA
| | - Jane Phillips-Conroy
- Department of Neuroscience, Washington University School of Medicine in St Louis, St Louis, MO, USA
| | - Gregory Wilkerson
- Keeling Center for Comparative Medicine and Research, MD Anderson Cancer Center, Bastrop, TX, USA
| | - Christian Abee
- Keeling Center for Comparative Medicine and Research, MD Anderson Cancer Center, Bastrop, TX, USA
| | - Joe H Simmons
- Keeling Center for Comparative Medicine and Research, MD Anderson Cancer Center, Bastrop, TX, USA
| | | | - Sree Kanthaswamy
- School of Interdisciplinary Forensics, Arizona State University, Phoenix, AZ, USA
- California National Primate Research Center, University of California, Davis, CA, USA
| | - Fekadu Shiferaw
- Guinea Worm Eradication Program, The Carter Center Ethiopia, Addis Ababa, Ethiopia
| | - Dongdong Wu
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Long Zhou
- Center for Evolutionary and Organismal Biology, Zhejiang University School of Medicine, Hangzhou, China
| | - Yong Shao
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Guojie Zhang
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
- Center for Evolutionary and Organismal Biology, Zhejiang University School of Medicine, Hangzhou, China
- Villum Centre for Biodiversity Genomics, Section for Ecology and Evolution, Department of Biology, University of Copenhagen, Copenhagen, Denmark
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Julius D Keyyu
- Tanzania Wildlife Research Institute (TAWIRI), Arusha, Tanzania
| | - Sascha Knauf
- Institute of International Animal Health/One Health, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Germany
- Professorship for International Animal Health/One Health, Faculty of Veterinary Medicine, Justus Liebig University, Giessen, Germany
| | - Minh D Le
- Department of Environmental Ecology, Faculty of Environmental Sciences, University of Science and Central Institute for Natural Resources and Environmental Studies, Vietnam National University, Hanoi, Vietnam
| | - Esther Lizano
- IBE, Institute of Evolutionary Biology (UPF-CSIC), Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain
- Institut Català de Paleontologia Miquel Crusafont, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Stefan Merker
- Department of Zoology, State Museum of Natural History Stuttgart, Stuttgart, Germany
| | - Arcadi Navarro
- IBE, Institute of Evolutionary Biology (UPF-CSIC), Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain
- Universitat Pompeu Fabra, Barcelona, Spain
| | - Tilo Nadler
- Cuc Phuong Commune, Nho Quan District, Vietnam
| | - Chiea Chuen Khor
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
| | | | - Patrick Tan
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
- SingHealth Duke-NUS Institute of Precision Medicine (PRISM), Singapore, Singapore
- Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, Singapore
| | - Weng Khong Lim
- SingHealth Duke-NUS Institute of Precision Medicine (PRISM), Singapore, Singapore
- Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, Singapore
- SingHealth Duke-NUS Genomic Medicine Centre, Singapore, Singapore
| | - Andrew C Kitchener
- Department of Natural Sciences, National Museums Scotland, Edinburgh, UK
- School of Geosciences, Edinburgh, UK
| | - Dietmar Zinner
- Cognitive Ethology Laboratory, Germany Primate Center, Leibniz Institute for Primate Research, Göttingen, Germany
- Department of Primate Cognition, Georg-August-Universität Göttingen, Göttingen, Germany
- Leibniz ScienceCampus Primate Cognition, Göttingen, Germany
| | - Ivo Gut
- Centro Nacional de Analisis Genomico (CNAG), Barcelona, Spain
| | - Amanda D Melin
- Department of Anthropology and Archaeology, University of Calgary, Calgary, Alberta, Canada
- Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada
- Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
| | - Katerina Guschanski
- Department of Ecology and Genetics, Animal Ecology, Uppsala University, Uppsala, Sweden
- Institute of Ecology and Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh, UK
| | | | - Robin M D Beck
- School of Science, Engineering and Environment, University of Salford, Salford, UK
| | - Ioannis Karakikes
- Cardiovascular Institute, Stanford University, Stanford, CA, USA
- Department of Cardiothoracic Surgery, Stanford University, Stanford, CA, USA
| | - Kevin C Wang
- Department of Cancer Biology, Stanford University, Stanford, CA, USA
- Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA
- Veterans Affairs Palo Alto Healthcare System, Palo Alto, CA, USA
| | - Govindhaswamy Umapathy
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
- Laboratory for the Conservation of Endangered Species, CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India
| | - Christian Roos
- Gene Bank of Primates and Primate Genetics Laboratory, German Primate Center, Leibniz Institute for Primate Research, Göttingen, Germany
| | - Jean P Boubli
- School of Science, Engineering and Environment, University of Salford, Salford, UK
| | - Adam Siepel
- Simons Center for Quantitative Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
| | - Anshul Kundaje
- Department of Computer Science, Stanford University, Stanford, CA, USA
- Department of Genetics, Stanford University, Stanford, CA, USA
| | - Benedict Paten
- UC Santa Cruz Genomics Institute, University of California, Santa Cruz, CA, USA
| | - Kerstin Lindblad-Toh
- Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Jeffrey Rogers
- Human Genome Sequencing Center and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
| | - Tomas Marques Bonet
- IBE, Institute of Evolutionary Biology (UPF-CSIC), Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
- Centro Nacional de Analisis Genomico (CNAG), Barcelona, Spain.
- Institut Català de Paleontologia Miquel Crusafont, Universitat Autònoma de Barcelona, Barcelona, Spain.
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
- Universitat Pompeu Fabra, Barcelona, Spain.
| | - Kyle Kai-How Farh
- Illumina Artificial Intelligence Laboratory, Illumina, San Diego, CA, USA.
| |
Collapse
|
|
21
|
Lyu K, Xiao J, Lyu S, Liu R. Comparative Analysis of Transposable Elements in Strawberry Genomes of Different Ploidy Levels. Int J Mol Sci 2023; 24:16935. [PMID: 38069258 PMCID: PMC10706760 DOI: 10.3390/ijms242316935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 11/25/2023] [Accepted: 11/27/2023] [Indexed: 12/18/2023] Open
Abstract
Transposable elements (TEs) make up a large portion of plant genomes and play a vital role in genome structure, function, and evolution. Cultivated strawberry (Fragaria x ananassa) is one of the most important fruit crops, and its octoploid genome was formed through several rounds of genome duplications from diploid ancestors. Here, we built a pan-genome TE library for the Fragaria genus using ten published strawberry genomes at different ploidy levels, including seven diploids, one tetraploid, and two octoploids, and performed comparative analysis of TE content in these genomes. The TEs comprise 51.83% (F. viridis) to 60.07% (F. nilgerrensis) of the genomes. Long terminal repeat retrotransposons (LTR-RTs) are the predominant TE type in the Fragaria genomes (20.16% to 34.94%), particularly in F. iinumae (34.94%). Estimating TE content and LTR-RT insertion times revealed that species-specific TEs have shaped each strawberry genome. Additionally, the copy number of different LTR-RT families inserted in the last one million years reflects the genetic distance between Fragaria species. Comparing cultivated strawberry subgenomes to extant diploid ancestors showed that F. vesca and F. iinumae are likely the diploid ancestors of the cultivated strawberry, but not F. viridis. These findings provide new insights into the TE variations in the strawberry genomes and their roles in strawberry genome evolution.
Collapse
Affiliation(s)
- Keliang Lyu
- College of Horticulture, Fujian Agriculture and Forestry University, Fuzhou 350002, China; (K.L.); (S.L.)
- Haixia Institute of Science and Technology, Fujian Agriculture and Forestry University, Fuzhou 350002, China;
| | - Jiajing Xiao
- Haixia Institute of Science and Technology, Fujian Agriculture and Forestry University, Fuzhou 350002, China;
| | - Shiheng Lyu
- College of Horticulture, Fujian Agriculture and Forestry University, Fuzhou 350002, China; (K.L.); (S.L.)
| | - Renyi Liu
- Haixia Institute of Science and Technology, Fujian Agriculture and Forestry University, Fuzhou 350002, China;
| |
Collapse
|
|
22
|
Liu K, Hu L, Wang S, Chen X, Liu Y, Zhao S, Wang H, Li L, Li H. An efficient qPCR assay for the quantification of human cells in preclinical animal models by targeting human specific DNA in the intron of BRCA1. Mol Biol Rep 2023; 50:9229-9237. [PMID: 37805662 DOI: 10.1007/s11033-023-08853-z] [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: 04/06/2023] [Accepted: 09/26/2023] [Indexed: 10/09/2023]
Abstract
BACKGROUND Precise quantification of grafted human cells in preclinical animal models such as non-human primates, rodents and rabbits is needed for the evaluations of the safety and efficacy of cell therapy. Quantitative PCR (qPCR) as a swift, sensitive and powerful assay is suitable for human cell quantification. However, it is a formidable challenge due to that the genome of non-human primates share more than 95% of similarity as human. METHODS In the present study, we developed a probe-based quantitative PCR (qPCR) assay for the quantification of human cells in preclinical animal models via targeting human specific DNA in the intron of BRCA1 (termed BRCA1-qPCR). The 5' and 3' end of BRCA1-qPCR probe was conjugated with FAM and non-fluorescent quencher-minor groove binder (NFQ-MGB), respectively. 1 µg of genomic DNA from human and preclinical animal models including rhesus monkeys, cynomolgus monkeys, New Zealand white rabbits, SD rats, C57BL/6 and BALB/c mice were used for determining the specificity and sensitivity of the BRCA1-qPCR assay. A calibration curve was generated by BRCA1-qPCR analysis of linearized plasmid containing targeted human specific DNA in BRCA1. The BRCA1-qPCR assay was validated by analysis of 0.003%, 0.03% and 0.3% of human leukocytes mixed within murine leukocytes. RESULTS The BRCA1-qPCR assay detected human DNA rather than DNA from tested species. The amplification efficiency of the BRCA1-qPCR assay was 95.4% and the linearity of the calibration curve was R2 = 0.9997. The BRCA1-qPCR assay detected as low as 5 copies of human specific DNA and is efficient to specially amplify 30 pg human DNA in the presence of 1 µg of genomic DNA from tested species, respectively. The BRCA1-qPCR assay was able to quantify as low as 0.003% of human cells within murine leukocytes. CONCLUSION The BRCA1-qPCR assay is efficient for the quantification of human cells in preclinical animal models.
Collapse
Affiliation(s)
- Ke Liu
- Department of Gastroenterology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, Jiangsu, China
| | - Lang Hu
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
- National Experimental Demonstration Center for Basic Medicine Education, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Siyu Wang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
- National Experimental Demonstration Center for Basic Medicine Education, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Xinzhu Chen
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
- National Experimental Demonstration Center for Basic Medicine Education, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Yuting Liu
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
- National Experimental Demonstration Center for Basic Medicine Education, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Shuli Zhao
- General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Hui Wang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
- National Experimental Demonstration Center for Basic Medicine Education, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Li Li
- Department of Gastroenterology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, Jiangsu, China.
| | - Hui Li
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China.
- National Experimental Demonstration Center for Basic Medicine Education, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China.
- Department of Biotechnology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China.
| |
Collapse
|
|
23
|
Park EG, Lee YJ, Huh JW, Park SJ, Imai H, Kim WR, Lee DH, Kim JM, Shin HJ, Kim HS. Identification of microRNAs Derived from Transposable Elements in the Macaca mulatta (Rhesus Monkey) Genome. Genes (Basel) 2023; 14:1984. [PMID: 38002927 PMCID: PMC10671384 DOI: 10.3390/genes14111984] [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: 09/15/2023] [Revised: 10/20/2023] [Accepted: 10/23/2023] [Indexed: 11/26/2023] Open
Abstract
Transposable elements (TEs) are mobile DNA entities that can move within the host genome. Over long periods of evolutionary time, TEs are typically silenced via the accumulation of mutations in the genome, ultimately resulting in their immobilization. However, they still play an important role in the host genome by acting as regulatory elements. They influence host transcription in various ways, one of which as the origin of the generation of microRNAs (miRNAs), which are so-called miRNAs derived from TEs (MDTEs). miRNAs are small non-coding RNAs that are involved in many biological processes by regulating gene expression at the post-transcriptional level. Here, we identified MDTEs in the Macaca mulatta (rhesus monkey) genome, which is phylogenetically close species to humans, based on the genome coordinates of miRNAs and TEs. The expression of 5 out of 17 MDTEs that were exclusively registered in M. mulatta from the miRBase database (v22) was examined via quantitative polymerase chain reaction (qPCR). Moreover, Gene Ontology analysis was performed to examine the functional implications of the putative target genes of the five MDTEs.
Collapse
Affiliation(s)
- Eun Gyung Park
- Department of Integrated Biological Sciences, Pusan National University, Busan 46241, Republic of Korea; (E.G.P.); (Y.J.L.); (W.R.K.); (D.H.L.); (J.-m.K.)
- Institute of Systems Biology, Pusan National University, Busan 46241, Republic of Korea
| | - Yun Ju Lee
- Department of Integrated Biological Sciences, Pusan National University, Busan 46241, Republic of Korea; (E.G.P.); (Y.J.L.); (W.R.K.); (D.H.L.); (J.-m.K.)
- Institute of Systems Biology, Pusan National University, Busan 46241, Republic of Korea
| | - Jae-Won Huh
- National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Republic of Korea; (J.-W.H.); (S.-J.P.)
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon 34113, Republic of Korea
| | - Sang-Je Park
- National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Republic of Korea; (J.-W.H.); (S.-J.P.)
| | - Hiroo Imai
- Molecular Biology Section, Center for the Evolutionary Origins of Human Behavior, Kyoto University, Inuyama, Aichi 484-8506, Japan;
| | - Woo Ryung Kim
- Department of Integrated Biological Sciences, Pusan National University, Busan 46241, Republic of Korea; (E.G.P.); (Y.J.L.); (W.R.K.); (D.H.L.); (J.-m.K.)
- Institute of Systems Biology, Pusan National University, Busan 46241, Republic of Korea
| | - Du Hyeong Lee
- Department of Integrated Biological Sciences, Pusan National University, Busan 46241, Republic of Korea; (E.G.P.); (Y.J.L.); (W.R.K.); (D.H.L.); (J.-m.K.)
- Institute of Systems Biology, Pusan National University, Busan 46241, Republic of Korea
| | - Jung-min Kim
- Department of Integrated Biological Sciences, Pusan National University, Busan 46241, Republic of Korea; (E.G.P.); (Y.J.L.); (W.R.K.); (D.H.L.); (J.-m.K.)
- Institute of Systems Biology, Pusan National University, Busan 46241, Republic of Korea
| | - Hae Jin Shin
- Department of Integrated Biological Sciences, Pusan National University, Busan 46241, Republic of Korea; (E.G.P.); (Y.J.L.); (W.R.K.); (D.H.L.); (J.-m.K.)
- Institute of Systems Biology, Pusan National University, Busan 46241, Republic of Korea
| | - Heui-Soo Kim
- Institute of Systems Biology, Pusan National University, Busan 46241, Republic of Korea
- Department of Biological Sciences, College of Natural Sciences, Pusan National University, Busan 46241, Republic of Korea
| |
Collapse
|
|
24
|
Yadav S, Kalwan G, Meena S, Gill SS, Yadava YK, Gaikwad K, Jain PK. Unravelling the due importance of pseudogenes and their resurrection in plants. PLANT PHYSIOLOGY AND BIOCHEMISTRY : PPB 2023; 203:108062. [PMID: 37778114 DOI: 10.1016/j.plaphy.2023.108062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 09/22/2023] [Accepted: 09/26/2023] [Indexed: 10/03/2023]
Abstract
The complexities of a genome are underpinned to the vast expanses of the intergenic region, which constitutes ∼97-98% of the genome. This region is essentially composed of what is colloquially referred to as the "junk DNA" and is composed of various elements like transposons, repeats, pseudogenes, etc. The latter have long been considered as dead elements merely contributing to transcriptional noise in the genome. Many studies now describe the previously unknown regulatory functions of these genes. Recent advances in the Next-generation sequencing (NGS) technologies have allowed unprecedented access to these regions. With the availability of whole genome sequences of more than 788 different plant species in past 20 years, genome annotation has become feasible like never before. Different bioinformatic pipelines are available for the identification of pseudogenes. However, still little is known about their biological functions. The functional validation of these genes remains challenging and research in this area is still in infancy, particularly in plants. CRISPR/Cas-based genome editing could provide solutions to understand the biological roles of these genes by allowing creation of precise edits within these genes. The possibility of pseudogene reactivation or resurrection as has been demonstrated in a few studies might open new avenues of genetic manipulation to yield a desirable phenotype. This review aims at comprehensively summarizing the progress made with regards to the identification of pseudogenes and understanding their biological functions in plants.
Collapse
Affiliation(s)
- Sheel Yadav
- ICAR-National Institute for Plant Biotechnology, New Delhi, 110012, India; PG School, ICAR-Indian Agricultural Research Institute, New Delhi, 110012, India; Division of Genomic Resources, ICAR-National Bureau of Plant Genetic Resources, New Delhi, 110012, India
| | - Gopal Kalwan
- ICAR-National Institute for Plant Biotechnology, New Delhi, 110012, India; PG School, ICAR-Indian Agricultural Research Institute, New Delhi, 110012, India
| | - Shashi Meena
- PG School, ICAR-Indian Agricultural Research Institute, New Delhi, 110012, India; Division of Plant Physiology, ICAR-Indian Agricultural Research Institute, New Delhi, 110012, India
| | - Sarvajeet Singh Gill
- Stress Physiology & Molecular Biology Lab, Centre for Biotechnology, Maharshi Dayanand University, Rohtak, 124 001, Haryana, India
| | - Yashwant K Yadava
- ICAR-National Institute for Plant Biotechnology, New Delhi, 110012, India
| | - Kishor Gaikwad
- ICAR-National Institute for Plant Biotechnology, New Delhi, 110012, India
| | - P K Jain
- ICAR-National Institute for Plant Biotechnology, New Delhi, 110012, India.
| |
Collapse
|
|
25
|
Erdem M, Cicek M, Erson-Bensan AE. Versatile RNA: overlooked gems of the transcriptome. FEBS J 2023; 290:4843-4851. [PMID: 36719259 DOI: 10.1111/febs.16742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 01/16/2023] [Accepted: 01/30/2023] [Indexed: 02/01/2023]
Abstract
The critical role of RNA, its use and targetability concerning different aspects of human health are gaining more attention because our understanding of the versatility of RNA has dramatically evolved over the last decades. We now appreciate that RNA is far more critical than a messenger molecule and possesses many complicated functions. As a multifunctional molecule with its sequence, flexible structures and enzymatic abilities, RNA is genuinely powerful. Mammalian transcriptomes consist of a dynamically regulated plethora of coding and noncoding RNA types. However, some aspects of RNA metabolism remain to be explored. In this Viewpoint, we focus on the transcriptome's unconventional and possibly overlooked aspects to emphasize the importance of RNA in mammalian systems.
Collapse
Affiliation(s)
- Murat Erdem
- Department of Biological Sciences, Middle East Technical University, Ankara, Turkey
| | - Mustafa Cicek
- Department of Biology, Kamil Ozdag Faculty of Science, Karamanoglu Mehmetbey University, Karaman, Turkey
| | | |
Collapse
|
|
26
|
Pollen AA, Kilik U, Lowe CB, Camp JG. Human-specific genetics: new tools to explore the molecular and cellular basis of human evolution. Nat Rev Genet 2023; 24:687-711. [PMID: 36737647 PMCID: PMC9897628 DOI: 10.1038/s41576-022-00568-4] [Citation(s) in RCA: 48] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/08/2022] [Indexed: 02/05/2023]
Abstract
Our ancestors acquired morphological, cognitive and metabolic modifications that enabled humans to colonize diverse habitats, develop extraordinary technologies and reshape the biosphere. Understanding the genetic, developmental and molecular bases for these changes will provide insights into how we became human. Connecting human-specific genetic changes to species differences has been challenging owing to an abundance of low-effect size genetic changes, limited descriptions of phenotypic differences across development at the level of cell types and lack of experimental models. Emerging approaches for single-cell sequencing, genetic manipulation and stem cell culture now support descriptive and functional studies in defined cell types with a human or ape genetic background. In this Review, we describe how the sequencing of genomes from modern and archaic hominins, great apes and other primates is revealing human-specific genetic changes and how new molecular and cellular approaches - including cell atlases and organoids - are enabling exploration of the candidate causal factors that underlie human-specific traits.
Collapse
Affiliation(s)
- 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.
| | - Umut Kilik
- Institute of Human Biology (IHB), Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
- University of Basel, Basel, Switzerland
| | - Craig B Lowe
- Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA.
| | - J Gray Camp
- Institute of Human Biology (IHB), Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.
- University of Basel, Basel, Switzerland.
| |
Collapse
|
|
27
|
Zhou B, He Y, Chen Y, Su B. Comparative Genomic Analysis Identifies Great-Ape-Specific Structural Variants and Their Evolutionary Relevance. Mol Biol Evol 2023; 40:msad184. [PMID: 37565562 PMCID: PMC10461412 DOI: 10.1093/molbev/msad184] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 08/01/2023] [Accepted: 08/10/2023] [Indexed: 08/12/2023] Open
Abstract
During the origin of great apes about 14 million years ago, a series of phenotypic innovations emerged, such as the increased body size, the enlarged brain volume, the improved cognitive skill, and the diversified diet. Yet, the genomic basis of these evolutionary changes remains unclear. Utilizing the high-quality genome assemblies of great apes (including human), gibbon, and macaque, we conducted comparative genome analyses and identified 15,885 great ape-specific structural variants (GSSVs), including eight coding GSSVs resulting in the creation of novel proteins (e.g., ACAN and CMYA5). Functional annotations of the GSSV-related genes revealed the enrichment of genes involved in development and morphogenesis, especially neurogenesis and neural network formation, suggesting the potential role of GSSVs in shaping the great ape-shared traits. Further dissection of the brain-related GSSVs shows great ape-specific changes of enhancer activities and gene expression in the brain, involving a group of GSSV-regulated genes (such as NOL3) that potentially contribute to the altered brain development and function in great apes. The presented data highlight the evolutionary role of structural variants in the phenotypic innovations during the origin of the great ape lineage.
Collapse
Affiliation(s)
- Bin Zhou
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China
- National Resource Center for Non-Human Primates, Kunming Primate Research Center, and National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China
- Kunming College of Life Science, University of Chinese Academy of Sciences, Beijing, China
| | - Yaoxi He
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China
- National Resource Center for Non-Human Primates, Kunming Primate Research Center, and National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China
| | - Yongjie Chen
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China
- National Resource Center for Non-Human Primates, Kunming Primate Research Center, and National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China
- Kunming College of Life Science, University of Chinese Academy of Sciences, Beijing, China
| | - Bing Su
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China
- National Resource Center for Non-Human Primates, Kunming Primate Research Center, and National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China
- Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, Yunnan, China
| |
Collapse
|
|
28
|
Vaill M, Kawanishi K, Varki N, Gagneux P, Varki A. Comparative physiological anthropogeny: exploring molecular underpinnings of distinctly human phenotypes. Physiol Rev 2023; 103:2171-2229. [PMID: 36603157 PMCID: PMC10151058 DOI: 10.1152/physrev.00040.2021] [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: 11/05/2021] [Revised: 12/26/2022] [Accepted: 12/28/2022] [Indexed: 01/06/2023] Open
Abstract
Anthropogeny is a classic term encompassing transdisciplinary investigations of the origins of the human species. Comparative anthropogeny is a systematic comparison of humans and other living nonhuman hominids (so-called "great apes"), aiming to identify distinctly human features in health and disease, with the overall goal of explaining human origins. We begin with a historical perspective, briefly describing how the field progressed from the earliest evolutionary insights to the current emphasis on in-depth molecular and genomic investigations of "human-specific" biology and an increased appreciation for cultural impacts on human biology. While many such genetic differences between humans and other hominids have been revealed over the last two decades, this information remains insufficient to explain the most distinctive phenotypic traits distinguishing humans from other living hominids. Here we undertake a complementary approach of "comparative physiological anthropogeny," along the lines of the preclinical medical curriculum, i.e., beginning with anatomy and considering each physiological system and in each case considering genetic and molecular components that are relevant. What is ultimately needed is a systematic comparative approach at all levels from molecular to physiological to sociocultural, building networks of related information, drawing inferences, and generating testable hypotheses. The concluding section will touch on distinctive considerations in the study of human evolution, including the importance of gene-culture interactions.
Collapse
Affiliation(s)
- Michael Vaill
- Center for Academic Research and Training in Anthropogeny, University of California, San Diego, La Jolla, California
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California
- Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California
| | - Kunio Kawanishi
- Center for Academic Research and Training in Anthropogeny, University of California, San Diego, La Jolla, California
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California
- Department of Experimental Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Nissi Varki
- Center for Academic Research and Training in Anthropogeny, University of California, San Diego, La Jolla, California
- Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California
- Department of Pathology, University of California, San Diego, La Jolla, California
| | - Pascal Gagneux
- Center for Academic Research and Training in Anthropogeny, University of California, San Diego, La Jolla, California
- Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California
- Department of Pathology, University of California, San Diego, La Jolla, California
| | - Ajit Varki
- Center for Academic Research and Training in Anthropogeny, University of California, San Diego, La Jolla, California
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California
- Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California
| |
Collapse
|
|
29
|
Chen F, Yalcin I, Zhao M, Chen C, Blankenfeldt W, Pessler F, Büssow K. Amino acid positions near the active site determine the reduced activity of human ACOD1 compared to murine ACOD1. Sci Rep 2023; 13:10360. [PMID: 37365251 DOI: 10.1038/s41598-023-37373-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 06/20/2023] [Indexed: 06/28/2023] Open
Abstract
cis-Aconitate decarboxylase (ACOD1, IRG1) converts cis-aconitate to the immunomodulatory and antibacterial metabolite itaconate. Although the active site residues of human and mouse ACOD1 are identical, the mouse enzyme is about fivefold more active. Aiming to identify the cause of this difference, we mutated positions near the active site in human ACOD1 to the corresponding residues of mouse ACOD1 and measured resulting activities in vitro and in transfected cells. Interestingly, Homo sapiens is the only species with methionine instead of isoleucine at residue 154 and introduction of isoleucine at this position increased the activity of human ACOD1 1.5-fold in transfected cells and 3.5-fold in vitro. Enzyme activity of gorilla ACOD1, which is almost identical to the human enzyme but has isoleucine at residue 154, was similar to the mouse enzyme in vitro. Met154 in human ACOD1 forms a sulfur-π bond to Phe381, which is positioned to impede access of the substrate to the active site. It appears that the ACOD1 sequence has changed at position 154 during human evolution, resulting in a pronounced decrease in activity. This change might have offered a selective advantage in diseases such as cancer.
Collapse
Affiliation(s)
- Fangfang Chen
- Department of Structure and Function of Proteins, Helmholtz Centre for Infection Research, Braunschweig, Germany
- Research Group Biomarkers for Infectious Diseases, TWINCORE Centre for Experimental and Clinical Infection Research, a Joint Venture Between Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany
| | - Israfil Yalcin
- Department of Structure and Function of Proteins, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Mingming Zhao
- Department of Structure and Function of Proteins, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Chutao Chen
- Research Group Biomarkers for Infectious Diseases, TWINCORE Centre for Experimental and Clinical Infection Research, a Joint Venture Between Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany
| | - Wulf Blankenfeldt
- Department of Structure and Function of Proteins, Helmholtz Centre for Infection Research, Braunschweig, Germany
- Institute for Biochemistry, Biotechnology and Bioinformatics, Technische Universität Braunschweig, 38106, Braunschweig, Germany
| | - Frank Pessler
- Research Group Biomarkers for Infectious Diseases, TWINCORE Centre for Experimental and Clinical Infection Research, a Joint Venture Between Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany
- Centre for Individualised Infection Medicine, Hannover, Germany
| | - Konrad Büssow
- Department of Structure and Function of Proteins, Helmholtz Centre for Infection Research, Braunschweig, Germany.
| |
Collapse
|
|
30
|
Zakharova G, Modestov A, Pugacheva P, Mekic R, Savina E, Guryanova A, Rachkova A, Yakushov S, Alimov A, Kulaeva E, Fedoseeva E, Kleyman A, Vasin K, Tkachev V, Garazha A, Sekacheva M, Suntsova M, Sorokin M, Buzdin A, Zolotovskaia MA. Distinct Traits of Structural and Regulatory Evolutional Conservation of Human Genes with Specific Focus on Major Cancer Molecular Pathways. Cells 2023; 12:cells12091299. [PMID: 37174700 PMCID: PMC10177184 DOI: 10.3390/cells12091299] [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: 02/06/2023] [Revised: 04/24/2023] [Accepted: 04/24/2023] [Indexed: 05/15/2023] Open
Abstract
The evolution of protein-coding genes has both structural and regulatory components. The first can be assessed by measuring the ratio of non-synonymous to synonymous nucleotide substitutions. The second component can be measured as the normalized proportion of transposable elements that are used as regulatory elements. For the first time, we characterized in parallel the regulatory and structural evolutionary profiles for 10,890 human genes and 2972 molecular pathways. We observed a ~0.1 correlation between the structural and regulatory metrics at the gene level, which appeared much higher (~0.4) at the pathway level. We deposited the data in the publicly available database RetroSpect. We also analyzed the evolutionary dynamics of six cancer pathways of two major axes: Notch/WNT/Hedgehog and AKT/mTOR/EGFR. The Hedgehog pathway had both components slower, whereas the Akt pathway had clearly accelerated structural evolution. In particular, the major hub nodes Akt and beta-catenin showed both components strongly decreased, whereas two major regulators of Akt TCL1 and CTMP had outstandingly high evolutionary rates. We also noticed structural conservation of serine/threonine kinases and the genes related to guanosine metabolism in cancer signaling: GPCRs, G proteins, and small regulatory GTPases (Src, Rac, Ras); however, this was compensated by the accelerated regulatory evolution.
Collapse
Affiliation(s)
- Galina Zakharova
- World-Class Research Center "Digital Biodesign and Personalized Healthcare", Sechenov First Moscow State Medical University, Moscow 119991, Russia
| | - Alexander Modestov
- Laboratory of Clinical and Genomic Bioinformatics, I.M. Sechenov First Moscow State Medical University, Moscow 119991, Russia
| | - Polina Pugacheva
- Laboratory of Clinical and Genomic Bioinformatics, I.M. Sechenov First Moscow State Medical University, Moscow 119991, Russia
- Laboratory for Translational Genomic Bioinformatics, Moscow Institute of Physics and Technology, Dolgoprudny 141701, Russia
| | - Rijalda Mekic
- Laboratory for Translational Genomic Bioinformatics, Moscow Institute of Physics and Technology, Dolgoprudny 141701, Russia
| | - Ekaterina Savina
- Laboratory of Clinical and Genomic Bioinformatics, I.M. Sechenov First Moscow State Medical University, Moscow 119991, Russia
| | - Anastasia Guryanova
- Laboratory for Translational Genomic Bioinformatics, Moscow Institute of Physics and Technology, Dolgoprudny 141701, Russia
| | - Anastasia Rachkova
- Laboratory of Clinical and Genomic Bioinformatics, I.M. Sechenov First Moscow State Medical University, Moscow 119991, Russia
| | - Semyon Yakushov
- Laboratory of Clinical and Genomic Bioinformatics, I.M. Sechenov First Moscow State Medical University, Moscow 119991, Russia
| | - Andrei Alimov
- Laboratory of Clinical and Genomic Bioinformatics, I.M. Sechenov First Moscow State Medical University, Moscow 119991, Russia
| | - Elizaveta Kulaeva
- Laboratory of Clinical and Genomic Bioinformatics, I.M. Sechenov First Moscow State Medical University, Moscow 119991, Russia
| | - Elena Fedoseeva
- Laboratory of Clinical and Genomic Bioinformatics, I.M. Sechenov First Moscow State Medical University, Moscow 119991, Russia
| | - Artem Kleyman
- Laboratory of Clinical and Genomic Bioinformatics, I.M. Sechenov First Moscow State Medical University, Moscow 119991, Russia
| | - Kirill Vasin
- Laboratory of Clinical and Genomic Bioinformatics, I.M. Sechenov First Moscow State Medical University, Moscow 119991, Russia
| | | | | | - Marina Sekacheva
- World-Class Research Center "Digital Biodesign and Personalized Healthcare", Sechenov First Moscow State Medical University, Moscow 119991, Russia
| | - Maria Suntsova
- World-Class Research Center "Digital Biodesign and Personalized Healthcare", Sechenov First Moscow State Medical University, Moscow 119991, Russia
| | - Maksim Sorokin
- Laboratory of Clinical and Genomic Bioinformatics, I.M. Sechenov First Moscow State Medical University, Moscow 119991, Russia
- Laboratory for Translational Genomic Bioinformatics, Moscow Institute of Physics and Technology, Dolgoprudny 141701, Russia
- Laboratory of Systems Biology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia
| | - Anton Buzdin
- World-Class Research Center "Digital Biodesign and Personalized Healthcare", Sechenov First Moscow State Medical University, Moscow 119991, Russia
- Laboratory for Translational Genomic Bioinformatics, Moscow Institute of Physics and Technology, Dolgoprudny 141701, Russia
- Laboratory of Systems Biology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia
- PathoBiology Group, European Organization for Research and Treatment of Cancer (EORTC), 1200 Brussels, Belgium
| | - Marianna A Zolotovskaia
- Laboratory of Clinical and Genomic Bioinformatics, I.M. Sechenov First Moscow State Medical University, Moscow 119991, Russia
- Laboratory for Translational Genomic Bioinformatics, Moscow Institute of Physics and Technology, Dolgoprudny 141701, Russia
| |
Collapse
|
|
31
|
Evolution and implications of de novo genes in humans. Nat Ecol Evol 2023:10.1038/s41559-023-02014-y. [PMID: 36928843 DOI: 10.1038/s41559-023-02014-y] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Accepted: 02/06/2023] [Indexed: 03/18/2023]
Abstract
Genes and translated open reading frames (ORFs) that emerged de novo from previously non-coding sequences provide species with opportunities for adaptation. When aberrantly activated, some human-specific de novo genes and ORFs have disease-promoting properties-for instance, driving tumour growth. Thousands of putative de novo coding sequences have been described in humans, but we still do not know what fraction of those ORFs has readily acquired a function. Here, we discuss the challenges and controversies surrounding the detection, mechanisms of origin, annotation, validation and characterization of de novo genes and ORFs. Through manual curation of literature and databases, we provide a thorough table with most de novo genes reported for humans to date. We re-evaluate each locus by tracing the enabling mutations and list proposed disease associations, protein characteristics and supporting evidence for translation and protein detection. This work will support future explorations of de novo genes and ORFs in humans.
Collapse
|
|
32
|
Bracci AN, Dallmann A, Ding Q, Hubisz MJ, Caballero M, Koren A. The evolution of the human DNA replication timing program. Proc Natl Acad Sci U S A 2023; 120:e2213896120. [PMID: 36848554 PMCID: PMC10013799 DOI: 10.1073/pnas.2213896120] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 01/23/2023] [Indexed: 03/01/2023] Open
Abstract
DNA is replicated according to a defined spatiotemporal program that is linked to both gene regulation and genome stability. The evolutionary forces that have shaped replication timing programs in eukaryotic species are largely unknown. Here, we studied the molecular causes and consequences of replication timing evolution across 94 humans, 95 chimpanzees, and 23 rhesus macaques. Replication timing differences recapitulated the species' phylogenetic tree, suggesting continuous evolution of the DNA replication timing program in primates. Hundreds of genomic regions had significant replication timing variation between humans and chimpanzees, of which 66 showed advances in replication origin firing in humans, while 57 were delayed. Genes overlapping these regions displayed correlated changes in expression levels and chromatin structure. Many human-chimpanzee variants also exhibited interindividual replication timing variation, pointing to ongoing evolution of replication timing at these loci. Association of replication timing variation with genetic variation revealed that DNA sequence evolution can explain replication timing variation between species. Taken together, DNA replication timing shows substantial and ongoing evolution in the human lineage that is driven by sequence alterations and could impact regulatory evolution at specific genomic sites.
Collapse
Affiliation(s)
- Alexa N. Bracci
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY14853
| | - Anissa Dallmann
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY14853
| | - Qiliang Ding
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY14853
| | - Melissa J. Hubisz
- Bioinformatics Facility, Institute of Biotechnology, Cornell University, Ithaca, NY14853
| | - Madison Caballero
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY14853
| | - Amnon Koren
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY14853
| |
Collapse
|
|
33
|
King SB, Singh M. Primate protein-ligand interfaces exhibit significant conservation and unveil human-specific evolutionary drivers. PLoS Comput Biol 2023; 19:e1010966. [PMID: 36952575 PMCID: PMC10035887 DOI: 10.1371/journal.pcbi.1010966] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 02/22/2023] [Indexed: 03/25/2023] Open
Abstract
Despite the vast phenotypic differences observed across primates, their protein products are largely similar to each other at the sequence level. We hypothesized that, since proteins accomplish all their functions via interactions with other molecules, alterations in the sites that participate in these interactions may be of critical importance. To uncover the extent to which these sites evolve across primates, we built a structurally-derived dataset of ~4,200 one-to-one orthologous sequence groups across 18 primate species, consisting of ~68,000 ligand-binding sites that interact with DNA, RNA, small molecules, ions, or peptides. Using this dataset, we identify functionally important patterns of conservation and variation within the amino acid residues that facilitate protein-ligand interactions across the primate phylogeny. We uncover that interaction sites are significantly more conserved than other sites, and that sites binding DNA and RNA further exhibit the lowest levels of variation. We also show that the subset of ligand-binding sites that do vary are enriched in components of gene regulatory pathways and uncover several instances of human-specific ligand-binding site changes within transcription factors. Altogether, our results suggest that ligand-binding sites have experienced selective pressure in primates and propose that variation in these sites may have an outsized effect on phenotypic variation in primates through pleiotropic effects on gene regulation.
Collapse
Affiliation(s)
- Sean B. King
- Department of Molecular Biology, Princeton University, Princeton, New Jersey, United States of America
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, United States of America
| | - Mona Singh
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, United States of America
- Department of Computer Science, Princeton University, Princeton, New Jersey, United States of America
| |
Collapse
|
|
34
|
Caselli M, Russo E, Guéry JP, Demuru E, Norscia I. More Than Just Kibbles: Keeper Familiarity and Food Can Affect Bonobo Behavior. Animals (Basel) 2023; 13:ani13030410. [PMID: 36766299 PMCID: PMC9913499 DOI: 10.3390/ani13030410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Revised: 01/10/2023] [Accepted: 01/23/2023] [Indexed: 01/27/2023] Open
Abstract
The welfare of captive animals relies on numerous factors. Keepers can affect animals' welfare and this could especially apply to emotionally and cognitively complex species, such as great apes. We collected video data over three months on 17 bonobos (La Vallée des Singes, France) and extracted five behaviours (play, aggression, anxiety, gestures, sociosexual interactions) -during two-minute slots-under three conditions: keeper-present/food-unavailable; keeper-present/food-available; keeper-absent/food-unavailable. We ran generalized linear models to investigate whether behavioral frequencies were affected by food presence/quality and keeper familiarity. Anxiety-related behaviors increased when the keeper was present and in absence of food, due to food expectation. Sociosexual interactions increased in presence of more familiar keepers and in absence of food, maybe to decrease the tension around food. Gestures increased in presence of more familiar keepers and with low-quality food, which was provided in large 'catchable' pieces. Aggression levels increased with high-quality food with no effect of keeper. Play behavior was not affected by any variable. Hence, bonobos were affected not just by food but also by keeper features. Considering multiple variables in the 'welfare equation' can improve captive management and increase the well-being of bonobos, a species that is much closer to humans than to other non-human animals.
Collapse
Affiliation(s)
- Marta Caselli
- Department of Life Science and System Biology, University of Torino, Via Accademia Albertina 13, 10123 Torino, Italy
| | - Emilio Russo
- Department of Life Science and System Biology, University of Torino, Via Accademia Albertina 13, 10123 Torino, Italy
| | | | - Elisa Demuru
- Laboratoire Dynamique du Langage, CNRS-UMR 5596, Université de Lyon, 14 Avenue Berthelot, 69363 Lyon, France
- ENES Bioacoustics Research Lab, CRNL, CNRS-UMR 5292, InsermUMR_S1028, Université de Saint-Etienne, 21, rue du Dr. Paul Michelon, 42100 Saint-Etienne, France
- Correspondence: (E.D.); (I.N.); Tel.: +33-0472-726546 (E.D.); +39-011-670-4547 (I.N.)
| | - Ivan Norscia
- Department of Life Science and System Biology, University of Torino, Via Accademia Albertina 13, 10123 Torino, Italy
- Correspondence: (E.D.); (I.N.); Tel.: +33-0472-726546 (E.D.); +39-011-670-4547 (I.N.)
| |
Collapse
|
|
35
|
Ruggieri AA, Livraghi L, Lewis JJ, Evans E, Cicconardi F, Hebberecht L, Ortiz-Ruiz Y, Montgomery SH, Ghezzi A, Rodriguez-Martinez JA, Jiggins CD, McMillan WO, Counterman BA, Papa R, Van Belleghem SM. A butterfly pan-genome reveals that a large amount of structural variation underlies the evolution of chromatin accessibility. Genome Res 2022; 32:1862-1875. [PMID: 36109150 PMCID: PMC9712634 DOI: 10.1101/gr.276839.122] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Accepted: 09/13/2022] [Indexed: 01/16/2023]
Abstract
Despite insertions and deletions being the most common structural variants (SVs) found across genomes, not much is known about how much these SVs vary within populations and between closely related species, nor their significance in evolution. To address these questions, we characterized the evolution of indel SVs using genome assemblies of three closely related Heliconius butterfly species. Over the relatively short evolutionary timescales investigated, up to 18.0% of the genome was composed of indels between two haplotypes of an individual Heliconius charithonia butterfly and up to 62.7% included lineage-specific SVs between the genomes of the most distant species (11 Mya). Lineage-specific sequences were mostly characterized as transposable elements (TEs) inserted at random throughout the genome and their overall distribution was similarly affected by linked selection as single nucleotide substitutions. Using chromatin accessibility profiles (i.e., ATAC-seq) of head tissue in caterpillars to identify sequences with potential cis-regulatory function, we found that out of the 31,066 identified differences in chromatin accessibility between species, 30.4% were within lineage-specific SVs and 9.4% were characterized as TE insertions. These TE insertions were localized closer to gene transcription start sites than expected at random and were enriched for sites with significant resemblance to several transcription factor binding sites with known function in neuron development in Drosophila We also identified 24 TE insertions with head-specific chromatin accessibility. Our results show high rates of structural genome evolution that were previously overlooked in comparative genomic studies and suggest a high potential for structural variation to serve as raw material for adaptive evolution.
Collapse
Affiliation(s)
- Angelo A Ruggieri
- Department of Biology, University of Puerto Rico-Rio Piedras, San Juan PR 00931, Puerto Rico
| | - Luca Livraghi
- Department of Biological Sciences, The George Washington University, Washington, DC 20052, USA
- Smithsonian Tropical Research Institute, Apartado 0843-03092 Panamá, Panama
| | - James J Lewis
- Department of Zoology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada
| | - Elizabeth Evans
- Department of Biology, University of Puerto Rico-Rio Piedras, San Juan PR 00931, Puerto Rico
| | - Francesco Cicconardi
- School of Biological Sciences, Bristol University, Bristol BS8 1QU, United Kingdom
| | - Laura Hebberecht
- School of Biological Sciences, Bristol University, Bristol BS8 1QU, United Kingdom
| | - Yadira Ortiz-Ruiz
- Department of Biology, University of Puerto Rico-Rio Piedras, San Juan PR 00931, Puerto Rico
- Molecular Sciences and Research Center, University of Puerto Rico, San Juan 00926, Puerto Rico
| | - Stephen H Montgomery
- School of Biological Sciences, Bristol University, Bristol BS8 1QU, United Kingdom
| | - Alfredo Ghezzi
- Department of Biology, University of Puerto Rico-Rio Piedras, San Juan PR 00931, Puerto Rico
| | | | - Chris D Jiggins
- Department of Zoology, University of Cambridge, Cambridge CB2 3EJ, United Kingdom
| | - W Owen McMillan
- Smithsonian Tropical Research Institute, Apartado 0843-03092 Panamá, Panama
| | - Brian A Counterman
- Department of Biological Sciences, Auburn University, Auburn, Alabama 36849, USA
| | - Riccardo Papa
- Department of Biology, University of Puerto Rico-Rio Piedras, San Juan PR 00931, Puerto Rico
- Molecular Sciences and Research Center, University of Puerto Rico, San Juan 00926, Puerto Rico
| | - Steven M Van Belleghem
- Department of Biology, University of Puerto Rico-Rio Piedras, San Juan PR 00931, Puerto Rico
- Ecology, Evolution and Conservation Biology, Biology Department, KU Leuven, 3000 Leuven, Belgium
| |
Collapse
|
|
36
|
Douglas J, Bouckaert R. Quantitatively defining species boundaries with more efficiency and more biological realism. Commun Biol 2022; 5:755. [PMID: 35902726 PMCID: PMC9334598 DOI: 10.1038/s42003-022-03723-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 07/12/2022] [Indexed: 11/09/2022] Open
Abstract
We introduce a widely applicable species delimitation method based on the multispecies coalescent model that is more efficient and more biologically realistic than existing methods. We extend a threshold-based method to allow the ancestral speciation rate to vary through time as a smooth piecewise function. Furthermore, we introduce the cutting-edge proposal kernels of StarBeast3 to this model, thus enabling rapid species delimitation on large molecular datasets and allowing the use of relaxed molecular clock models. We validate these methods with genomic sequence data and SNP data, and show they are more efficient than existing methods at achieving parameter convergence during Bayesian MCMC. Lastly, we apply these methods to two datasets (Hemidactylus and Galagidae) and find inconsistencies with the published literature. Our methods are powerful for rapid quantitative testing of species boundaries in large multilocus datasets and are implemented as an open source BEAST 2 package called SPEEDEMON. Introducing SPEEDEMON, a package for BEAST 2 that better defines species boundaries based on molecular data demonstrated on gecko and loris datasets.
Collapse
Affiliation(s)
- Jordan Douglas
- School of Computer Science, The University of Auckland, Auckland, New Zealand.
| | - Remco Bouckaert
- School of Computer Science, The University of Auckland, Auckland, New Zealand
| |
Collapse
|
|
37
|
Wexler BE. Returning to basic principles to develop more effective treatments for central nervous system disorders. Exp Biol Med (Maywood) 2022; 247:856-867. [PMID: 35172621 PMCID: PMC9158240 DOI: 10.1177/15353702221078291] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Development of new treatments for diseases of the central nervous system (CNS) is
stalled. Of candidate drugs developed through costly preclinical research, 93%
fail clinical trials. Hoped-for improvements in diagnosis or treatment from
decades of positron emission tomography (PET) and functional magnetic resonance
imaging (fMRI) imaging have yet to materialize. To understand what we are doing
wrong, I begin with recognition that all aspects of life, including the brain
and mind, are physical phenomena consistent with processes described by
physicists. Two processes, emergence and entropy, are of particular relevance in
complex arrangements of matter that constitute life in general and the brain in
particular. The human brain functions through dynamically reconfiguring and
hierarchically organized neural functional systems with emergent properties of
cognition, emotion, and conscious experience. These systems are shaped and
maintained by negentropic environmental input transformed by sensory receptors
into neural signals that trigger epigenetic neuroplastic processes. CNS diseases
produce clinical disorders by disrupting these systems. As researchers seek
appropriate levels of system organization at which to characterize and treat
illness, focus has been on medications that impact processes at lower levels or
transcranial electric or magnetic stimulation that impact broad contiguous
swaths of tissue. Neither align with the brain’s neurosystem organization and
therefore lack specificity necessary to be effective and to limit side effects.
Digital neurotherapies (DNTs), in contrast, align with neurosystem organization
and achieve the needed specificity using the same input pathways and
neuroplastic processes that created the neural systems organization to repair
it. The omission of DNTs from major systems-based initiatives represents
powerful residua of dualist thinking. Interventions based on perceptual and
cognitive processes are not thought of as being as physical as drugs or electric
or magnetic stimulation through the skull. In fact, they are examples of the
most basic processes that create and support life itself.
Collapse
|
|
38
|
Pattan V, Kashyap R, Bansal V, Candula N, Koritala T, Surani S. Genomics in medicine: A new era in medicine. World J Methodol 2021; 11:231-242. [PMID: 34631481 PMCID: PMC8472545 DOI: 10.5662/wjm.v11.i5.231] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 06/18/2021] [Accepted: 07/19/2021] [Indexed: 02/06/2023] Open
Abstract
The sequencing of complete human genome revolutionized the genomic medicine. However, the complex interplay of gene-environment-lifestyle and influence of non-coding genomic regions on human health remain largely unexplored. Genomic medicine has great potential for diagnoses or disease prediction, disease prevention and, targeted treatment. However, many of the promising tools of genomic medicine are still in their infancy and their application may be limited because of the limited knowledge we have that precludes its use in many clinical settings. In this review article, we have reviewed the evolution of genomic methodologies/tools, their limitations, and scope, for current and future clinical application.
Collapse
Affiliation(s)
- Vishwanath Pattan
- Division of Endocrinology, Wyoming Medical Center, Casper, WY 82601, United States
| | - Rahul Kashyap
- Department of Anesthesiology and Peri-operative Medicine, Mayo Clinic, Rochester, MN 55905, United States
| | - Vikas Bansal
- Department of Anesthesiology and Peri-operative Medicine, Mayo Clinic, Rochester, MN 55905, United States
| | - Narsimha Candula
- Hospital Medicine, University Florida Health, Jacksonville, FL 32209, United States
| | - Thoyaja Koritala
- Hospital Medicine, Mayo Clinic Health System, Mankato, MN 56001, United States
| | - Salim Surani
- Department of Internal Medicine, Texas A&M University, Corpus Christi, TX 78405, United States
| |
Collapse
|
|
39
|
Using proteomic and transcriptomic data to assess activation of intracellular molecular pathways. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2021; 127:1-53. [PMID: 34340765 DOI: 10.1016/bs.apcsb.2021.02.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Analysis of molecular pathway activation is the recent instrument that helps to quantize activities of various intracellular signaling, structural, DNA synthesis and repair, and biochemical processes. This may have a deep impact in fundamental research, bioindustry, and medicine. Unlike gene ontology analyses and numerous qualitative methods that can establish whether a pathway is affected in principle, the quantitative approach has the advantage of exactly measuring the extent of a pathway up/downregulation. This results in emergence of a new generation of molecular biomarkers-pathway activation levels, which reflect concentration changes of all measurable pathway components. The input data can be the high-throughput proteomic or transcriptomic profiles, and the output numbers take both positive and negative values and positively reflect overall pathway activation. Due to their nature, the pathway activation levels are more robust biomarkers compared to the individual gene products/protein levels. Here, we review the current knowledge of the quantitative gene expression interrogation methods and their applications for the molecular pathway quantization. We consider enclosed bioinformatic algorithms and their applications for solving real-world problems. Besides a plethora of applications in basic life sciences, the quantitative pathway analysis can improve molecular design and clinical investigations in pharmaceutical industry, can help finding new active biotechnological components and can significantly contribute to the progressive evolution of personalized medicine. In addition to the theoretical principles and concepts, we also propose publicly available software for the use of large-scale protein/RNA expression data to assess the human pathway activation levels.
Collapse
|
|
40
|
Tatarinova TV, Baranova AV, Anashkina AA, Orlov YL. Genomics and Systems Biology at the "Century of Human Population Genetics" conference. BMC Genomics 2020; 21:592. [PMID: 32912158 PMCID: PMC7487983 DOI: 10.1186/s12864-020-06993-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Affiliation(s)
- Tatiana V Tatarinova
- La Verne University, La Verne, CA, 91750, USA
- Department of Fundamental Biology and Biotechnology, Siberian Federal University, 660074, Krasnoyarsk, Russia
- George Mason University, Fairfax, VA, 22030, USA
| | - Ancha V Baranova
- George Mason University, Fairfax, VA, 22030, USA
- Research Centre for Medical Genetics, 115522, Moscow, Russia
| | | | - Yuriy L Orlov
- The Digital Health Institute, I.M.Sechenov First Moscow State Medical University (Sechenov University), 119991, Moscow, Russia.
- Institute of Cytology and Genetics SB RAS, 630090, Novosibirsk, Russia.
- Novosibirsk State University, 630090, Novosibirsk, Russia.
| |
Collapse
|