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Nature Sep 2023The human Y chromosome has been notoriously difficult to sequence and assemble because of its complex repeat structure that includes long palindromes, tandem repeats and...
The human Y chromosome has been notoriously difficult to sequence and assemble because of its complex repeat structure that includes long palindromes, tandem repeats and segmental duplications. As a result, more than half of the Y chromosome is missing from the GRCh38 reference sequence and it remains the last human chromosome to be finished. Here, the Telomere-to-Telomere (T2T) consortium presents the complete 62,460,029-base-pair sequence of a human Y chromosome from the HG002 genome (T2T-Y) that corrects multiple errors in GRCh38-Y and adds over 30 million base pairs of sequence to the reference, showing the complete ampliconic structures of gene families TSPY, DAZ and RBMY; 41 additional protein-coding genes, mostly from the TSPY family; and an alternating pattern of human satellite 1 and 3 blocks in the heterochromatic Yq12 region. We have combined T2T-Y with a previous assembly of the CHM13 genome and mapped available population variation, clinical variants and functional genomics data to produce a complete and comprehensive reference sequence for all 24 human chromosomes.
Topics: Humans; Base Sequence; Chromosomes, Human, Y; DNA, Satellite; Genetic Variation; Genetics, Population; Genomics; Heterochromatin; Multigene Family; Reference Standards; Segmental Duplications, Genomic; Sequence Analysis, DNA; Tandem Repeat Sequences; Telomere
PubMed: 37612512
DOI: 10.1038/s41586-023-06457-y -
Cell Aug 2023Many regions in the human genome vary in length among individuals due to variable numbers of tandem repeats (VNTRs). To assess the phenotypic impact of VNTRs...
Many regions in the human genome vary in length among individuals due to variable numbers of tandem repeats (VNTRs). To assess the phenotypic impact of VNTRs genome-wide, we applied a statistical imputation approach to estimate the lengths of 9,561 autosomal VNTR loci in 418,136 unrelated UK Biobank participants and 838 GTEx participants. Association and statistical fine-mapping analyses identified 58 VNTRs that appeared to influence a complex trait in UK Biobank, 18 of which also appeared to modulate expression or splicing of a nearby gene. Non-coding VNTRs at TMCO1 and EIF3H appeared to generate the largest known contributions of common human genetic variation to risk of glaucoma and colorectal cancer, respectively. Each of these two VNTRs associated with a >2-fold range of risk across individuals. These results reveal a substantial and previously unappreciated role of non-coding VNTRs in human health and gene regulation.
Topics: Humans; Calcium Channels; Colorectal Neoplasms; Genome, Human; Glaucoma; Minisatellite Repeats; Polymorphism, Genetic; Eukaryotic Initiation Factor-3
PubMed: 37527660
DOI: 10.1016/j.cell.2023.07.002 -
Genes Jan 2024New phylogenetic tools and population genetics methods have been developed and vastly advanced over the last decade [...].
New phylogenetic tools and population genetics methods have been developed and vastly advanced over the last decade [...].
Topics: Animals; Phylogeny; Primates
PubMed: 38254958
DOI: 10.3390/genes15010068 -
Nature Sep 2023Humans display substantial interindividual clinical variability after SARS-CoV-2 infection, the genetic and immunological basis of which has begun to be deciphered....
Humans display substantial interindividual clinical variability after SARS-CoV-2 infection, the genetic and immunological basis of which has begun to be deciphered. However, the extent and drivers of population differences in immune responses to SARS-CoV-2 remain unclear. Here we report single-cell RNA-sequencing data for peripheral blood mononuclear cells-from 222 healthy donors of diverse ancestries-that were stimulated with SARS-CoV-2 or influenza A virus. We show that SARS-CoV-2 induces weaker, but more heterogeneous, interferon-stimulated gene activity compared with influenza A virus, and a unique pro-inflammatory signature in myeloid cells. Transcriptional responses to viruses display marked population differences, primarily driven by changes in cell abundance including increased lymphoid differentiation associated with latent cytomegalovirus infection. Expression quantitative trait loci and mediation analyses reveal a broad effect of cell composition on population disparities in immune responses, with genetic variants exerting a strong effect on specific loci. Furthermore, we show that natural selection has increased population differences in immune responses, particularly for variants associated with SARS-CoV-2 response in East Asians, and document the cellular and molecular mechanisms by which Neanderthal introgression has altered immune functions, such as the response of myeloid cells to viruses. Finally, colocalization and transcriptome-wide association analyses reveal an overlap between the genetic basis of immune responses to SARS-CoV-2 and COVID-19 severity, providing insights into the factors contributing to current disparities in COVID-19 risk.
Topics: Animals; Humans; Cell Differentiation; COVID-19; Cytomegalovirus; East Asian People; Genetic Introgression; Genetics, Population; Influenza A virus; Interferons; Leukocytes, Mononuclear; Myeloid Cells; Neanderthals; SARS-CoV-2; Selection, Genetic; Single-Cell Gene Expression Analysis; Virus Latency
PubMed: 37558883
DOI: 10.1038/s41586-023-06422-9 -
Molecular Biology and Evolution May 2024This perspective article offers a meditation on FST and other quantities developed by Sewall Wright to describe the population structure, defined as any departure from...
This perspective article offers a meditation on FST and other quantities developed by Sewall Wright to describe the population structure, defined as any departure from reproduction through random union of gametes. Concepts related to the F-statistics draw from studies of the partitioning of variation, identity coefficients, and diversity measures. Relationships between the first two approaches have recently been clarified and unified. This essay addresses the third pillar of the discussion: Nei's GST and related measures. A hierarchy of probabilities of identity-by-state provides a description of the relationships among levels of a structured population with respect to genetic diversity. Explicit expressions for the identity-by-state probabilities are determined for models of structured populations undergoing regular inbreeding and recurrent mutation. Levels of genetic diversity within and between subpopulations reflect mutation as well as migration. Accordingly, indices of the population structure are inherently locus-specific, contrary to the intentions of Wright. Some implications of this locus-specificity are explored.
Topics: Models, Genetic; Genetic Variation; Genetics, Population; Mutation; Inbreeding
PubMed: 38696269
DOI: 10.1093/molbev/msae083 -
Frontiers in Genetics 2023Numerous associations of HLA variants with susceptibility to diseases, namely, those with an immunopathological component, have been described to date. The strongest HLA... (Review)
Review
Numerous associations of HLA variants with susceptibility to diseases, namely, those with an immunopathological component, have been described to date. The strongest HLA associations were incorporated into the standard algorithms for the diagnostics. Disease-associated HLA variants are routinely detected by various techniques including DNA-based assays. For the identification of HLA markers or their combinations with the highest diagnostic value and those with frequent clinical indications (e.g., HLA-B*27, -B*57:01, -DQ2/-DQ8, -DQB1*06:02), diagnostic tests that focus on a single or limited number of specific HLA antigens/alleles, have already been developed; the use of complete typing for particular HLA loci is a relevant alternative. Importantly, external proficiency testing (EPT) became an integral part of good laboratory practice for HLA disease associations in accredited laboratories and not only supports correct "technical" identification of the associated HLA variants, but also adequate interpretation of the results to the clinicians. In the present article selected aspects of EPT for HLA disease associations related to population genetics are reviewed and discussed with the emphasis on the optimal level of HLA typing resolution, population-based differences in disease associated HLA alleles within the allelic group, distribution and linkage disequilibrium of HLA alleles in particular populations and interpretation of the presence of less common HLA variants/haplotypes. In conclusion, the laboratories that perform and interpret the tests to the clinicians, producers of the certified diagnostics and EPT providers should consider, among others, the genetic characteristics of the populations in order to optimise the diagnostic value of the tests for disease-associated HLA variants.
PubMed: 37937194
DOI: 10.3389/fgene.2023.1268705 -
Frontiers in Genetics 2023
PubMed: 37799142
DOI: 10.3389/fgene.2023.1267719 -
Genes Apr 2024The dialogue between population genetics and evolutionary biology, which historically followed separate paths, has now developed into a complex and interdisciplinary...
The dialogue between population genetics and evolutionary biology, which historically followed separate paths, has now developed into a complex and interdisciplinary field of study [...].
Topics: Genetics, Population; Genomics; Humans; Evolution, Molecular; Population Dynamics; Genetic Variation; Animals; Biological Evolution
PubMed: 38674381
DOI: 10.3390/genes15040446 -
Frontiers in Genetics 2023
PubMed: 37811143
DOI: 10.3389/fgene.2023.1269792 -
Trends in Ecology & Evolution Oct 2023Our ability to assess the threat posed by the genetic load to small and declining populations has been greatly improved by advances in genome sequencing and... (Review)
Review
Our ability to assess the threat posed by the genetic load to small and declining populations has been greatly improved by advances in genome sequencing and computational approaches. Yet, considerable confusion remains around the definitions of the genetic load and its dynamics, and how they impact individual fitness and population viability. We illustrate how both selective purging and drift affect the distribution of deleterious mutations during population size decline and recovery. We show how this impacts the composition of the genetic load, and how this affects the extinction risk and recovery potential of populations. We propose a framework to examine load dynamics and advocate for the introduction of load estimates in the management of endangered populations.
Topics: Genetics, Population; Genetic Load; Population Density; Inbreeding; Genetic Variation
PubMed: 37344276
DOI: 10.1016/j.tree.2023.05.008