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Journal of Neuroscience Research Jan 2017The X chromosome has played a critical role in the development of sexually selected characteristics for over 300 million years, and during that time it has accumulated a... (Review)
Review
The X chromosome has played a critical role in the development of sexually selected characteristics for over 300 million years, and during that time it has accumulated a disproportionate number of genes concerned with mental functions. There are relatively specific effects of X-linked genes on social cognition, language, emotional regulation, visuospatial, and numerical skills. Many human X-linked genes outside the X-Y pairing pseudoautosomal regions escape X-inactivation. Dosage differences in the expression of such genes (which constitute at least 15% of the total) are likely to play an important role in male-female neural differentiation, and in cognitive deficits and behavioral characteristics, particularly in the realm of social communication, that are associated with sex chromosome aneuploidies. © 2016 Wiley Periodicals, Inc.
Topics: Aneuploidy; Animals; Brain; Cognition; Humans; Mental Disorders; Sex Characteristics; Sex Chromosomes; Sex Differentiation; Social Behavior
PubMed: 27870409
DOI: 10.1002/jnr.23951 -
PLoS Genetics Apr 2021Recombination between the X and Y human sex chromosomes is limited to the two pseudoautosomal regions (PARs) that present quite distinct evolutionary origins. Despite...
Recombination between the X and Y human sex chromosomes is limited to the two pseudoautosomal regions (PARs) that present quite distinct evolutionary origins. Despite the crucial importance for male meiosis, genetic diversity patterns and evolutionary dynamics of these regions are poorly understood. In the present study, we analyzed and compared the genetic diversity of the PAR regions using publicly available genomic sequences encompassing both PAR1 and PAR2. Comparisons were performed through allele diversities, linkage disequilibrium status and recombination frequencies within and between X and Y chromosomes. In agreement with previous studies, we confirmed the role of PAR1 as a male-specific recombination hotspot, but also observed similar characteristic patterns of diversity in both regions although male recombination occurs at PAR2 to a much lower extent (at least one recombination event at PAR1 and in ≈1% in normal male meioses at PAR2). Furthermore, we demonstrate that both PARs harbor significantly different allele frequencies between X and Y chromosomes, which could support that recombination is not sufficient to homogenize the pseudoautosomal gene pool or is counterbalanced by other evolutionary forces. Nevertheless, the observed patterns of diversity are not entirely explainable by sexually antagonistic selection. A better understanding of such processes requires new data from intergenerational transmission studies of PARs, which would be decisive on the elucidation of PARs evolution and their role in male-driven heterosomal aneuploidies.
Topics: Chromosome Mapping; Chromosomes, Human, X; Chromosomes, Human, Y; Crossing Over, Genetic; Female; Gene Frequency; Genetic Linkage; Humans; Linkage Disequilibrium; Male; Meiosis; Pseudoautosomal Regions; Recombination, Genetic
PubMed: 33872316
DOI: 10.1371/journal.pgen.1009532 -
Genome Biology and Evolution Nov 2021Birds in the clade Palaeognathae, excluding Tinamiformes, have morphologically conserved karyotypes and less differentiated ZW sex chromosomes compared with those of...
Birds in the clade Palaeognathae, excluding Tinamiformes, have morphologically conserved karyotypes and less differentiated ZW sex chromosomes compared with those of other birds. In particular, the sex chromosomes of the ostrich and emu have exceptionally large recombining pseudoautosomal regions (PARs), whereas non-PARs are classified into two strata according to the date of their origins: stratum 0 and stratum 1 (S1). However, the construction and analysis of the genome sequences in these regions in the clade Palaeognathae can be challenging because assembling the S1 region is difficult owing to low sequence diversity between gametologs (Z-linked and W-linked sequences). We addressed this issue by applying the Platanus-allee assembler and successfully constructed the haplotype-resolved (phased) assembly for female emu, cassowary, and ostrich using only sequence read data derived from the Illumina platform. Comparative genomic and phylogenetic analyses based on assembled Z-linked and W-linked sequences confirmed that the S1 region of emu and cassowary formed in their common ancestor. Moreover, the interspersed repetitive sequence landscapes in the S1 regions of female emu showed an expansion of younger repetitive elements in the W-linked S1 region, suggesting an interruption in homologous recombination in the S1 region. These results provide novel insights into the trajectory of sex chromosome evolution in the clade Palaeognathae and suggest that the Illumina-based phased assembly method is an effective approach for elucidating the evolutionary process underlying the transition from homomorphic to differentiated sex chromosomes.
Topics: Animals; Evolution, Molecular; Female; Karyotyping; Palaeognathae; Phylogeny; Sex Chromosomes; Struthioniformes
PubMed: 34718546
DOI: 10.1093/gbe/evab242 -
GigaScience Dec 2022The swamp buffalo (Bubalus bubalis carabanesis) is an economically important livestock supplying milk, meat, leather, and draft power. Several female buffalo genomes...
BACKGROUND
The swamp buffalo (Bubalus bubalis carabanesis) is an economically important livestock supplying milk, meat, leather, and draft power. Several female buffalo genomes have been available, but the lack of high-quality male genomes hinders studies on chromosome evolution, especially Y, as well as meiotic recombination.
RESULTS
Here, a chromosome-level genome with a contig N50 of 72.2 Mb and a fine-scale recombination map of male buffalo were reported. We found that transposable elements (TEs) and structural variants (SVs) may contribute to buffalo evolution by influencing adjacent gene expression. We further found that the pseudoautosomal region (PAR) of the Y chromosome is subject to stronger purification selection. The meiotic recombination map showed that there were 2 obvious recombination hotspots on chromosome 8, and the genes around them were mainly related to tooth development, which may have helped to enhance the adaption of buffalo to inferior feed. Among several genomic features, TE density has the strongest correlation with recombination rates. Moreover, the TE subfamily, SINE/tRNA, is likely to play a role in driving recombination into SVs.
CONCLUSIONS
The male genome and sperm sequencing will facilitate the understanding of the buffalo genomic evolution and functional research.
Topics: Male; Female; Animals; Semen; Bison; Genomics; Buffaloes; Chromosomes
PubMed: 37589307
DOI: 10.1093/gigascience/giad063 -
Human Genetics Jan 2023Pathogenic variants on the X-chromosome can have more severe consequences for hemizygous males, while heterozygote females can avoid severe consequences due to diploidy...
Pathogenic variants on the X-chromosome can have more severe consequences for hemizygous males, while heterozygote females can avoid severe consequences due to diploidy and the capacity for nonrandom expression. Thus, when an allele is more common in females this could indicate that it increases the probability of early death in the male hemizygous state, which can be considered a measure of pathogenicity. Importantly, large-scale genomic data now makes it possible to compare allele proportions between the sexes. To discover pathogenic variants on the X-chromosome, we analyzed exome data from 125,748 ancestrally diverse participants in the Genome Aggregation Database (gnomAD). After filtering out duplicates and extremely rare variants, 44,606 of the original 348,221 remained for analysis. We divided the proportion of variant alleles in females by the proportion in males for all variant sites, and then placed each variant into one of three a priori categories: (1) Reference (Primarily synonymous and intronic), (2) Unlikely-to-be-tolerated (Primarily missense), and (3) Least-likely-to-be-tolerated (Primarily frameshift). To assess the impact of ploidy, we compared the distribution of these ratios between pseudoautosomal and non-pseudoautosomal regions. In the non-pseudoautosomal regions, mean female-to-male ratios were lowest among Reference (2.40), greater for Unlikely-to-be-tolerated (2.77) and highest for Least-likely-to-be-tolerated (3.28) variants. Corresponding ratios were lower in the pseudoautosomal regions (1.52, 1.57, and 1.68, respectively), with the most extreme ratio being just below 11. Because pathogenic effects in the pseudoautosomal regions should not drive ratio increases, this maximum ratio provides an upper bound for baseline noise. In the non-pseudoautosomal regions, 319 variants had a ratio over 11. In sum, we identified a measure with a dataset specific threshold for identifying pathogenicity in non-pseudoautosomal X-chromosome variants: the female-to-male allele proportion ratio.
Topics: Female; Humans; Male; Chromosomes; Exome; Heterozygote; Virulence; X Chromosome
PubMed: 35994124
DOI: 10.1007/s00439-022-02478-1 -
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 -
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 -
Genes Jan 2021The unique evolutionary dynamics and complex structure make the Y chromosome the most diverse and least understood region in the mammalian genome, despite its...
The unique evolutionary dynamics and complex structure make the Y chromosome the most diverse and least understood region in the mammalian genome, despite its undisputable role in sex determination, development, and male fertility. Here we present the first contig-level annotated draft assembly for the alpaca () Y chromosome based on hybrid assembly of short- and long-read sequence data of flow-sorted Y. The latter was also used for cDNA selection providing Y-enriched testis transcriptome for annotation. The final assembly of 8.22 Mb comprised 4.5 Mb of male specific Y (MSY) and 3.7 Mb of the pseudoautosomal region. In MSY, we annotated 15 X-degenerate genes and two novel transcripts, but no transposed sequences. Two MSY genes, and are multicopy. The pseudoautosomal boundary is located between and Comparative analysis shows that the small and cytogenetically distinct alpaca Y shares most of MSY sequences with the larger dromedary and Bactrian camel Y chromosomes. Most of alpaca X-degenerate genes are also shared with other mammalian MSYs, though is Y-specific only in alpaca/camels and the horse. The partial alpaca Y assembly is a starting point for further expansion and will have applications in the study of camelid populations and male biology.
Topics: Animals; Camelids, New World; Male; Y Chromosome
PubMed: 33467186
DOI: 10.3390/genes12010105 -
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 -
Frontiers in Genetics 2020The unique structure of the X chromosome shaped by evolution has led to the present gender-specific genetic differences, which are not shared by its counterpart, the Y... (Review)
Review
The unique structure of the X chromosome shaped by evolution has led to the present gender-specific genetic differences, which are not shared by its counterpart, the Y chromosome, and neither by the autosomes. In males, recombination between the X and Y chromosomes is limited to the pseudoautosomal regions, PAR1 and PAR2; therefore, in males, the X chromosome is (almost) entirely transmitted to female offspring. On the other hand, the X chromosome is present in females with two copies that recombine along the whole chromosome during female meiosis and that is transmitted to both female and male descendants. These transmission characteristics, besides the obvious clinical impact (sex chromosome aneuploidies are extremely frequent), make the X chromosome an irreplaceable genetic tool for population genetic-based studies as well as for kinship and forensic investigations. In the early 2000s, the number of publications using X-chromosomal polymorphisms in forensic and population genetic applications increased steadily. However, nearly 20 years later, we observe a conspicuous decrease in the rate of these publications. In light of this observation, the main aim of this article is to provide a comprehensive review of the advances and applications of X-chromosomal markers in population and forensic genetics over the last two decades. The foremost relevant topics are addressed as: (i) developments concerning the number and types of markers available, with special emphasis on short tandem repeat (STR) polymorphisms (STR nomenclatures and practical concerns); (ii) overview of worldwide population (frequency) data; (iii) the use of X-chromosomal markers in (complex) kinship testing and the forensic statistical evaluation of evidence; (iv) segregation and mutation studies; and (v) current weaknesses and future prospects.
PubMed: 33093840
DOI: 10.3389/fgene.2020.00926