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Nature Sep 2023The prevalence of highly repetitive sequences within the human Y chromosome has prevented its complete assembly to date and led to its systematic omission from genomic...
The prevalence of highly repetitive sequences within the human Y chromosome has prevented its complete assembly to date and led to its systematic omission from genomic analyses. Here we present de novo assemblies of 43 Y chromosomes spanning 182,900 years of human evolution and report considerable diversity in size and structure. Half of the male-specific euchromatic region is subject to large inversions with a greater than twofold higher recurrence rate compared with all other chromosomes. Ampliconic sequences associated with these inversions show differing mutation rates that are sequence context dependent, and some ampliconic genes exhibit evidence for concerted evolution with the acquisition and purging of lineage-specific pseudogenes. The largest heterochromatic region in the human genome, Yq12, is composed of alternating repeat arrays that show extensive variation in the number, size and distribution, but retain a 1:1 copy-number ratio. Finally, our data suggest that the boundary between the recombining pseudoautosomal region 1 and the non-recombining portions of the X and Y chromosomes lies 500 kb away from the currently established boundary. The availability of fully sequence-resolved Y chromosomes from multiple individuals provides a unique opportunity for identifying new associations of traits with specific Y-chromosomal variants and garnering insights into the evolution and function of complex regions of the human genome.
Topics: Humans; Male; Chromosomes, Human, Y; Genome, Human; Genomics; Mutation Rate; Phenotype; Evolution, Molecular; Euchromatin; Pseudogenes; Genetic Variation; Chromosomes, Human, X; Pseudoautosomal Regions
PubMed: 37612510
DOI: 10.1038/s41586-023-06425-6 -
Cell Reports Aug 2023Meiotic crossovers are required for the faithful segregation of homologous chromosomes and to promote genetic diversity. However, it is unclear how crossover formation...
Meiotic crossovers are required for the faithful segregation of homologous chromosomes and to promote genetic diversity. However, it is unclear how crossover formation is regulated, especially on the XY chromosomes, which show a homolog only at the tiny pseudoautosomal region. Here, we show that ATF7IP2 is a meiosis-specific ortholog of ATF7IP and a partner of SETDB1. In the absence of ATF7IP2, autosomes show increased axis length and more crossovers; however, many XY chromosomes lose the obligatory crossover, although the overall XY axis length is also increased. Additionally, meiotic DNA double-strand break formation/repair may also be affected by altered histone modifications. Ultimately, spermatogenesis is blocked, and male mice are infertile. These findings suggest that ATF7IP2 constraints autosomal axis length and crossovers on autosomes; meanwhile, it also modulates XY chromosomes to establish meiotic sex chromosome inactivation for cell-cycle progression and to ensure XY crossover formation during spermatogenesis.
Topics: Animals; Male; Mice; Chromosome Segregation; Histone-Lysine N-Methyltransferase; Meiosis; Sex Chromosomes; Spermatogenesis; Transcription Factors
PubMed: 37542719
DOI: 10.1016/j.celrep.2023.112953 -
Proceedings of the National Academy of... Nov 2023Meiotic DNA double-strand breaks (DSBs) initiate homologous recombination and are crucial for ensuring proper chromosome segregation. In mice, ANKRD31 recently emerged...
Meiotic DNA double-strand breaks (DSBs) initiate homologous recombination and are crucial for ensuring proper chromosome segregation. In mice, ANKRD31 recently emerged as a regulator of DSB timing, number, and location, with a particularly important role in targeting DSBs to the pseudoautosomal regions (PARs) of sex chromosomes. ANKRD31 interacts with multiple proteins, including the conserved and essential DSB-promoting factor REC114, so it was hypothesized to be a modular scaffold that "anchors" other proteins together and to meiotic chromosomes. To determine whether and why the REC114 interaction is important for ANKRD31 function, we generated mice with mutations that either reduced (missense mutation) or eliminated (C-terminal truncation) the ANKRD31-REC114 interaction without diminishing contacts with other known partners. A complete lack of the ANKRD31-REC114 interaction mimicked an null, with delayed DSB formation and recombination, defects in DSB repair, and altered DSB locations including failure to target DSBs to the PARs. In contrast, when the ANKRD31-REC114 interaction was substantially but not completely disrupted, spermatocytes again showed delayed DSB formation globally, but recombination and repair were hardly affected and DSB locations were similar to control mice. The missense allele showed a dosage effect, wherein combining it with the null or C-terminal truncation allele resulted in intermediate phenotypes for DSB formation, recombination, and DSB locations. Our results show that ANKRD31 function is critically dependent on its interaction with REC114 and that defects in ANKRD31 activity correlate with the severity of the disruption of the interaction.
Topics: Animals; Male; Mice; Chromosomes; Homologous Recombination; Meiosis; Mutation; Spermatogenesis
PubMed: 37976262
DOI: 10.1073/pnas.2310951120 -
PloS One 2023Many forces influence genetic variation across the genome including mutation, recombination, selection, and demography. Increased mutation and recombination both lead to...
Many forces influence genetic variation across the genome including mutation, recombination, selection, and demography. Increased mutation and recombination both lead to increases in genetic diversity in a region-specific manner, while complex demographic patterns shape patterns of diversity on a more global scale. While these processes act across the entire genome, the X chromosome is particularly interesting because it contains several distinct regions that are subject to different combinations and strengths of these forces: the pseudoautosomal regions (PARs) and the X-transposed region (XTR). The X chromosome thus can serve as a unique model for studying how genetic and demographic forces act in different contexts to shape patterns of observed variation. We therefore sought to explore diversity, divergence, and linkage disequilibrium in each region of the X chromosome using genomic data from 26 human populations. Across populations, we find that both diversity and substitution rate are consistently elevated in PAR1 and the XTR compared to the rest of the X chromosome. In contrast, linkage disequilibrium is lowest in PAR1, consistent with the high recombination rate in this region, and highest in the region of the X chromosome that does not recombine in males. However, linkage disequilibrium in the XTR is intermediate between PAR1 and the autosomes, and much lower than the non-recombining X. Finally, in addition to these global patterns, we also observed variation in ratios of X versus autosomal diversity consistent with population-specific evolutionary history as well. While our results were generally consistent with previous work, two unexpected observations emerged. First, our results suggest that the XTR does not behave like the rest of the recombining X and may need to be evaluated separately in future studies. Second, the different regions of the X chromosome appear to exhibit unique patterns of linked selection across different human populations. Together, our results highlight profound regional differences across the X chromosome, simultaneously making it an ideal system for exploring the action of evolutionary forces as well as necessitating its careful consideration and treatment in genomic analyses.
Topics: Male; Humans; Chromosomes, Human, X; Receptor, PAR-1; Selection, Genetic; X Chromosome; Mutation; Genomics; Demography; Genetic Variation
PubMed: 37910456
DOI: 10.1371/journal.pone.0287609 -
Environmental Health Perspectives Dec 2023Glyphosate is the most commonly used herbicide worldwide and has been implicated in the development of certain hematologic cancers. Although mechanistic studies in human...
BACKGROUND
Glyphosate is the most commonly used herbicide worldwide and has been implicated in the development of certain hematologic cancers. Although mechanistic studies in human cells and animals support the genotoxic effects of glyphosate, evidence in human populations is scarce.
OBJECTIVES
We evaluated the association between lifetime occupational glyphosate use and mosaic loss of chromosome Y (mLOY) as a marker of genotoxicity among male farmers.
METHODS
We analyzed blood-derived DNA from 1,606 farmers years of age in the Biomarkers of Exposure and Effect in Agriculture study, a subcohort of the Agricultural Health Study. mLOY was detected using genotyping array intensity data in the pseudoautosomal region of the sex chromosomes. Cumulative lifetime glyphosate use was assessed using self-reported pesticide exposure histories. Using multivariable logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between glyphosate use and any detectable mLOY (overall mLOY) or mLOY affecting of cells (expanded mLOY).
RESULTS
Overall, mLOY was detected in 21.4% of farmers, and 9.8% of all farmers had expanded mLOY. Increasing total lifetime days of glyphosate use was associated with expanded mLOY [highest vs. lowest quartile; (95% CI: 1.00, 3.07), ] but not with overall mLOY; the associations with expanded mLOY were most apparent among older ( years of age) men [ (95% CI: 1.13, 4.67), ], never smokers [ (95% CI: 1.04, 5.21), ], and nonobese men [ (95% CI: 0.99, 4.19), ]. Similar patterns of associations were observed for intensity-weighted lifetime days of glyphosate use.
DISCUSSION
High lifetime glyphosate use could be associated with mLOY affecting a larger fraction of cells, suggesting glyphosate could confer genotoxic or selective effects relevant for clonal expansion. As the first study to investigate this association, our findings contribute novel evidence regarding the carcinogenic potential of glyphosate and require replication in future studies. https://doi.org/10.1289/EHP12834.
Topics: Animals; Humans; Male; Chromosomes, Human, Y; Farmers; Mosaicism; Agriculture; Glyphosate
PubMed: 38055050
DOI: 10.1289/EHP12834 -
Cellular and Molecular Life Sciences :... Sep 2023XY chromosome missegregation is relatively common in humans and can lead to sterility or the generation of aneuploid spermatozoa. A leading cause of XY missegregation in...
XY chromosome missegregation is relatively common in humans and can lead to sterility or the generation of aneuploid spermatozoa. A leading cause of XY missegregation in mammals is the lack of formation of double-strand breaks (DSBs) in the pseudoautosomal region (PAR), a defect that may occur in mice due to faulty expression of Spo11 splice isoforms. Using a knock-in (ki) mouse that expresses only the single Spo11β splice isoform, here we demonstrate that by varying the genetic background of mice, the length of chromatin loops extending from the PAR axis and the XY recombination proficiency varies. In spermatocytes of C57 mice, in which loops are relatively short, recombination/synapsis between XY is fairly normal. In contrast, in cells of C57/129 males where PAR loops are relatively long, formation of DSBs in the PAR (more frequently the Y-PAR) and XY synapsis fails at a high rate, and mice produce sperm with sex-chromosomal aneuploidy. However, if the entire set of Spo11 splicing isoforms is expressed by a wild type allele in the C57/129 background, XY recombination and synapsis is recovered. By generating a Spo11αki mouse model, we prove that concomitant expression of SPO11β and SPO11α isoforms, boosts DSB formation in the PAR. Based on these findings, we propose that SPO11 splice isoforms cooperate functionally in promoting recombination in the PAR, constraining XY asynapsis defects that may arise due to differences in the conformation of the PAR between mouse strains.
Topics: Animals; Humans; Male; Mice; Alleles; Protein Isoforms; Pseudoautosomal Regions; Recombination, Genetic; Semen; Endodeoxyribonucleases
PubMed: 37682311
DOI: 10.1007/s00018-023-04912-7 -
BioRxiv : the Preprint Server For... Jul 2023Meiotic DNA double-strand breaks (DSBs) initiate homologous recombination and are crucial for ensuring proper chromosome segregation. In mice, ANKRD31 recently emerged...
Meiotic DNA double-strand breaks (DSBs) initiate homologous recombination and are crucial for ensuring proper chromosome segregation. In mice, ANKRD31 recently emerged as a regulator of DSB timing, number, and location, with a particularly important role in targeting DSBs to the pseudoautosomal regions (PARs) of sex chromosomes. ANKRD31 interacts with multiple proteins, including the conserved and essential DSB-promoting factor REC114, so it was hypothesized to be a modular scaffold that "anchors" other proteins together and to meiotic chromosomes. To determine if and why the REC114 interaction is important for ANKRD31 function, we generated mice with mutations that either reduced (missense mutation) or eliminated (C-terminal truncation) the ANKRD31-REC114 interaction without diminishing contacts with other known partners. A complete lack of the ANKRD31-REC114 interaction mimicked an null, with delayed DSB formation and recombination, defects in DSB repair, and altered DSB locations including failure to target DSBs to the PARs. In contrast, when the ANKRD31-REC114 interaction was substantially but not completely disrupted, spermatocytes again showed delayed DSB formation globally, but recombination and repair were hardly affected and DSB locations were similar to control mice. The missense allele showed a dosage effect, wherein combining it with the null or C-terminal truncation allele resulted in intermediate phenotypes for DSB formation, recombination, and DSB locations. Our results show that ANKRD31 function is critically dependent on its interaction with REC114, and that defects in ANKRD31 activity correlate with the severity of the disruption of the interaction.
PubMed: 37162821
DOI: 10.1101/2023.04.27.538541 -
Nature Communications Mar 2024We have previously identified a network of higher-order brain regions particularly vulnerable to the ageing process, schizophrenia and Alzheimer's disease. However, it...
We have previously identified a network of higher-order brain regions particularly vulnerable to the ageing process, schizophrenia and Alzheimer's disease. However, it remains unknown what the genetic influences on this fragile brain network are, and whether it can be altered by the most common modifiable risk factors for dementia. Here, in ~40,000 UK Biobank participants, we first show significant genome-wide associations between this brain network and seven genetic clusters implicated in cardiovascular deaths, schizophrenia, Alzheimer's and Parkinson's disease, and with the two antigens of the XG blood group located in the pseudoautosomal region of the sex chromosomes. We further reveal that the most deleterious modifiable risk factors for this vulnerable brain network are diabetes, nitrogen dioxide - a proxy for traffic-related air pollution - and alcohol intake frequency. The extent of these associations was uncovered by examining these modifiable risk factors in a single model to assess the unique contribution of each on the vulnerable brain network, above and beyond the dominating effects of age and sex. These results provide a comprehensive picture of the role played by genetic and modifiable risk factors on these fragile parts of the brain.
Topics: Humans; Brain; Aging; Alzheimer Disease; Risk Factors; Nitrogen Dioxide
PubMed: 38538590
DOI: 10.1038/s41467-024-46344-2 -
Cell May 2024Dolichol is a lipid critical for N-glycosylation as a carrier for activated sugars and nascent oligosaccharides. It is commonly thought to be directly produced from...
Dolichol is a lipid critical for N-glycosylation as a carrier for activated sugars and nascent oligosaccharides. It is commonly thought to be directly produced from polyprenol by the enzyme SRD5A3. Instead, we found that dolichol synthesis requires a three-step detour involving additional metabolites, where SRD5A3 catalyzes only the second reaction. The first and third steps are performed by DHRSX, whose gene resides on the pseudoautosomal regions of the X and Y chromosomes. Accordingly, we report a pseudoautosomal-recessive disease presenting as a congenital disorder of glycosylation in patients with missense variants in DHRSX (DHRSX-CDG). Of note, DHRSX has a unique dual substrate and cofactor specificity, allowing it to act as a NAD-dependent dehydrogenase and as a NADPH-dependent reductase in two non-consecutive steps. Thus, our work reveals unexpected complexity in the terminal steps of dolichol biosynthesis. Furthermore, we provide insights into the mechanism by which dolichol metabolism defects contribute to disease.
PubMed: 38821050
DOI: 10.1016/j.cell.2024.04.041