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Molecular Psychiatry Feb 2021Autosomal variants have successfully been associated with trait neuroticism in genome-wide analysis of adequately powered samples. But such studies have so far excluded...
Autosomal variants have successfully been associated with trait neuroticism in genome-wide analysis of adequately powered samples. But such studies have so far excluded the X chromosome from analysis. Here, we report genetic association analyses of X chromosome and XY pseudoautosomal single nucleotide polymorphisms (SNPs) and trait neuroticism using UK Biobank samples (N = 405,274). Significant association was found with neuroticism on the X chromosome for 204 markers found within three independent loci (a further 783 were suggestive). Most of the lead neuroticism-related X chromosome variants were located in intergenic regions (n = 397). Involvement of HS6ST2, which has been previously associated with sociability behaviour in the dog, was supported by single SNP and gene-based tests. We found that the amino acid and nucleotide sequences are highly conserved between dogs and humans. From the suggestive X chromosome variants, there were 19 nearby genes which could be linked to gene ontology information. Molecular function was primarily related to binding and catalytic activity; notable biological processes were cellular and metabolic, and nucleic acid binding and transcription factor protein classes were most commonly involved. X-variant heritability of neuroticism was estimated at 0.22% (SE = 0.05) from a full dosage compensation model. A polygenic X-variant score created in an independent sample (maximum N ≈ 7,300) did not predict significant variance in neuroticism, psychological distress, or depressive disorder. We conclude that the X chromosome harbours significant variants influencing neuroticism, and might prove important for other quantitative traits and complex disorders.
Topics: Animals; Dogs; Genetic Association Studies; Multifactorial Inheritance; Neuroticism; Phenotype; Polymorphism, Single Nucleotide; X Chromosome
PubMed: 30842574
DOI: 10.1038/s41380-019-0388-2 -
PLoS Genetics Jul 2014The pseudoautosomal region (PAR) is a short region of homology between the mammalian X and Y chromosomes, which has undergone rapid evolution. A crossover in the PAR is...
The pseudoautosomal region (PAR) is a short region of homology between the mammalian X and Y chromosomes, which has undergone rapid evolution. A crossover in the PAR is essential for the proper disjunction of X and Y chromosomes in male meiosis, and PAR deletion results in male sterility. This leads the human PAR with the obligatory crossover, PAR1, to having an exceptionally high male crossover rate, which is 17-fold higher than the genome-wide average. However, the mechanism by which this obligatory crossover occurs remains unknown, as does the fine-scale positioning of crossovers across this region. Recent research in mice has suggested that crossovers in PAR may be mediated independently of the protein PRDM9, which localises virtually all crossovers in the autosomes. To investigate recombination in this region, we construct the most fine-scale genetic map containing directly observed crossovers to date using African-American pedigrees. We leverage recombination rates inferred from the breakdown of linkage disequilibrium in human populations and investigate the signatures of DNA evolution due to recombination. Further, we identify direct PRDM9 binding sites using ChIP-seq in human cells. Using these independent lines of evidence, we show that, in contrast with mouse, PRDM9 does localise peaks of recombination in the human PAR1. We find that recombination is a far more rapid and intense driver of sequence evolution in PAR1 than it is on the autosomes. We also show that PAR1 hotspot activities differ significantly among human populations. Finally, we find evidence that PAR1 hotspot positions have changed between human and chimpanzee, with no evidence of sharing among the hottest hotspots. We anticipate that the genetic maps built and validated in this work will aid research on this vital and fascinating region of the genome.
Topics: Chromosomes, Human, X; Chromosomes, Human, Y; Crossing Over, Genetic; Female; Genetics, Population; HapMap Project; Histone-Lysine N-Methyltransferase; Humans; Infertility, Male; Linkage Disequilibrium; Male; Meiosis; Recombination, Genetic
PubMed: 25033397
DOI: 10.1371/journal.pgen.1004503 -
Biology of Sex Differences Jan 2020Sex bias in immune function has been contributed in part to a preponderance of immune system-related genes (ISRG) on the X-chromosome. We verified whether ISRG are more... (Comparative Study)
Comparative Study
BACKGROUND
Sex bias in immune function has been contributed in part to a preponderance of immune system-related genes (ISRG) on the X-chromosome. We verified whether ISRG are more abundant on the X chromosome as compared to autosomal chromosomes and reflected on the impact of our findings.
METHODS
Consulting freely accessible databases, we performed a comparative study consisting of three complementary strategies. First, among coding X/Y-linked genes, the abundance of ISRG was compared to the abundance of genes dedicated to other systems. Genes were assigned considering three criteria: disease, tissue expression, and function (DEF approach). In addition, we carried out two genome-wide approaches to compare the contribution of sex and autosomal chromosomes to immune genes defined by an elevated expression in lymphatic tissues (LTEEG approach) or annotation to an immune system process, GO:0002376 (GO approach).
RESULTS
The X chromosome had less immune genes than the median of the autosomal chromosomes. Among X-linked genes, ISRG ranked fourth after the reproductive and nervous systems and genes dedicated to development, proliferation and apoptosis. On the Y chromosome, ISRG ranked second, and at the pseudoautosomal region (PAR) first. According to studies on the expression of X-linked genes in a variety of (mostly non-lymphatic) tissues, almost two-thirds of ISRG are expressed without sex bias, and the remaining ISRG presented female and male bias with similar frequency. Various epigenetic controllers, X-linked MSL3 and Y-linked KDM5D and UTY, were preferentially expressed in leukocytes and deserve further attention for a possible role in sex biased expression or its neutralisation.
CONCLUSIONS
The X chromosome is not enriched for ISRG, though particular X-linked genes may be responsible for sex differences in certain immune responses. So far, there is insufficient information on sex-biased expression of X/Y-linked ISRG in leukocytes to draw general conclusions on the impact of X/Y-linked ISRG in immune function. More research on the regulation of the expression X-linked genes is required with attention to 1) female and male mechanisms that may either augment or diminish sex biased expression and 2) tissue-specific expression studies.
Topics: Chromosomes, Human, X; Chromosomes, Human, Y; Female; Gene Expression Profiling; Humans; Immune System; Male; Sex Characteristics
PubMed: 31937374
DOI: 10.1186/s13293-019-0278-y -
Philosophical Transactions of the Royal... May 2022The genus brings many opportunities for the study of various processes involved in the evolution of dioecy and young sex chromosomes. Here we focus on a dioecious clade...
The genus brings many opportunities for the study of various processes involved in the evolution of dioecy and young sex chromosomes. Here we focus on a dioecious clade in subgenus and closely related species. This study provides improved support for monophyly of this clade (based on inclusion of further dioecious species) and a new estimate of its age ( 2.3 million years). We observed a rise in adaptive evolution in the autosomal and pseudoautosomal parts of the genome on the branch where dioecy originated. This increase is not a result of the accumulation of sexually antagonistic genes in the pseudoautosomal region. It is also not caused by the coevolution of genes acting in mitochondria (despite the possibility that dioecy along this branch could have evolved from a nucleo-cytoplasmic male sterility-based system). After considering other possibilities, the most parsimonious explanation for the increase seen in the number of positively selected codons is the adaptive evolution of genes involved in the adaptation of the autosomal part of the genome to dioecy, as described in Charnov's sex-allocation theory. As the observed coincidence cannot prove causality, studies in other dioecious clades are necessary to allow the formation of general conclusions. This article is part of the theme issue 'Sex determination and sex chromosome evolution in land plants'.
Topics: Chromosomes, Plant; Evolution, Molecular; Magnoliopsida; Sex Chromosomes; Silene
PubMed: 35306886
DOI: 10.1098/rstb.2021.0228 -
Nature Sep 2020After two decades of improvements, the current human reference genome (GRCh38) is the most accurate and complete vertebrate genome ever produced. However, no single...
After two decades of improvements, the current human reference genome (GRCh38) is the most accurate and complete vertebrate genome ever produced. However, no single chromosome has been finished end to end, and hundreds of unresolved gaps persist. Here we present a human genome assembly that surpasses the continuity of GRCh38, along with a gapless, telomere-to-telomere assembly of a human chromosome. This was enabled by high-coverage, ultra-long-read nanopore sequencing of the complete hydatidiform mole CHM13 genome, combined with complementary technologies for quality improvement and validation. Focusing our efforts on the human X chromosome, we reconstructed the centromeric satellite DNA array (approximately 3.1 Mb) and closed the 29 remaining gaps in the current reference, including new sequences from the human pseudoautosomal regions and from cancer-testis ampliconic gene families (CT-X and GAGE). These sequences will be integrated into future human reference genome releases. In addition, the complete chromosome X, combined with the ultra-long nanopore data, allowed us to map methylation patterns across complex tandem repeats and satellite arrays. Our results demonstrate that finishing the entire human genome is now within reach, and the data presented here will facilitate ongoing efforts to complete the other human chromosomes.
Topics: Centromere; Chromosomes, Human, X; CpG Islands; DNA Methylation; DNA, Satellite; Female; Genome, Human; Humans; Hydatidiform Mole; Male; Pregnancy; Reproducibility of Results; Telomere; Testis
PubMed: 32663838
DOI: 10.1038/s41586-020-2547-7 -
Genes Jun 2018Three types of sex chromosome system exist in nature: diploid XY and ZW systems and haploid UV systems. For many years, research has focused exclusively on XY and ZW...
Three types of sex chromosome system exist in nature: diploid XY and ZW systems and haploid UV systems. For many years, research has focused exclusively on XY and ZW systems, leaving UV chromosomes and haploid sex determination largely neglected. Here, we perform a detailed analysis of DNA sequence neutral diversity levels across the U and V sex chromosomes of the model brown alga using a large population dataset. We show that the U and V non-recombining regions of the sex chromosomes (SDR) exhibit about half as much neutral diversity as the autosomes. This difference is consistent with the reduced effective population size of these regions compared with the rest of the genome, suggesting that the influence of additional factors such as background selection or selective sweeps is minimal. The pseudoautosomal region (PAR) of this UV system, in contrast, exhibited surprisingly high neutral diversity and there were several indications that genes in this region may be under balancing selection. The PAR of is known to exhibit unusual genomic features and our results lay the foundation for further work aimed at understanding whether, and to what extent, these structural features underlie the high level of genetic diversity. Overall, this study fills a gap between available information on genetic diversity in XY/ZW systems and UV systems and significantly contributes to advancing our knowledge of the evolution of UV sex chromosomes.
PubMed: 29882839
DOI: 10.3390/genes9060286 -
Nature Structural & Molecular Biology Aug 2017In mammals, homologous chromosomes rarely pair outside meiosis. One exception is the X chromosome, which transiently pairs during X-chromosome inactivation (XCI). How...
In mammals, homologous chromosomes rarely pair outside meiosis. One exception is the X chromosome, which transiently pairs during X-chromosome inactivation (XCI). How two chromosomes find each other in 3D space is not known. Here, we reveal a required interaction between the X-inactivation center (Xic) and the telomere in mouse embryonic stem (ES) cells. The subtelomeric, pseudoautosomal regions (PARs) of the two sex chromosomes (X and Y) also undergo pairing in both female and male cells. PARs transcribe a class of telomeric RNA, dubbed PAR-TERRA, which accounts for a vast majority of all TERRA transcripts. PAR-TERRA binds throughout the genome, including to the PAR and Xic. During X-chromosome pairing, PAR-TERRA anchors the Xic to the PAR, creating a 'tetrad' of pairwise homologous interactions (Xic-Xic, PAR-PAR, and Xic-PAR). Xic pairing occurs within the tetrad. Depleting PAR-TERRA abrogates pairing and blocks initiation of XCI, whereas autosomal PAR-TERRA induces ectopic pairing. We propose a 'constrained diffusion model' in which PAR-TERRA creates an interaction hub to guide Xic homology searching during XCI.
Topics: Animals; Chromosome Pairing; DNA-Binding Proteins; Mice; Pseudoautosomal Regions; Sex Chromosomes; Transcription Factors; Transcription, Genetic; X Chromosome Inactivation
PubMed: 28692038
DOI: 10.1038/nsmb.3432 -
BMC Genetics Jan 2013Sex chromosomes are subject to evolutionary pressures distinct from the remainder of the genome, shaping their structure and sequence content. We are interested in the...
BACKGROUND
Sex chromosomes are subject to evolutionary pressures distinct from the remainder of the genome, shaping their structure and sequence content. We are interested in the sex chromosomes of domestic pigs (Sus scrofa), how their structure and gene content compares and contrasts with other mammalian species, and the role of sex-linked genes in fertility. This requires an understanding of the XY-homologous sequence on these chromosomes.To this end, we performed microarray-based comparative genomic hybridisation (array-CGH) with male and female Duroc genomic DNA on a pig X-chromosome BAC tiling-path microarray. Putative XY-homologous BACs from regions of interest were subsequently FISH mapped.
RESULTS
We show that the porcine PAR is approximately 6.5-6.9 Mb at the beginning of the short arm of the X, with gene content reflective of the artiodactyl common ancestor. Our array-CGH data also shows an XY-homologous region close to the end of the X long arm, spanning three X BACs. These BACs were FISH mapped, and paint the entire long arm of SSCY. Further clones of interest revealed X-autosomal homology or regions containing repetitive content.
CONCLUSIONS
This study has identified regions of XY homology in the pig genome, and defined the boundary of the PAR on the X chromosome. This adds to our understanding of the evolution of the sex chromosomes in different mammalian lineages, and will prove valuable for future comparative genomic work in suids and for the construction and annotation of the genome sequence for the sex chromosomes. Our finding that the SSCYq repetitive content has corresponding sequence on the X chromosome gives further insight into structure of SSCY, and suggests further functionally important sequences remain to be discovered on the X and Y.
Topics: Animals; Biological Evolution; Comparative Genomic Hybridization; Female; Fertility; Male; Sequence Homology, Nucleic Acid; Sus scrofa; X Chromosome; Y Chromosome
PubMed: 23320497
DOI: 10.1186/1471-2156-14-3 -
Journal of Dairy Science Apr 2019In cattle, the X chromosome accounts for approximately 3 and 6% of the genome in bulls and cows, respectively. In spite of the large size of this chromosome, very few...
In cattle, the X chromosome accounts for approximately 3 and 6% of the genome in bulls and cows, respectively. In spite of the large size of this chromosome, very few studies report analysis of the X chromosome in genome-wide association studies and genomic selection. This lack of genetic interrogation is likely due to the complexities of undertaking these studies given the hemizygous state of some, but not all, of the X chromosome in males. The first step in facilitating analysis of this gene-rich chromosome is to accurately identify coordinates for the pseudoautosomal boundary (PAB) to split the chromosome into a region that may be treated as autosomal sequence (pseudoautosomal region) and a region that requires more complex statistical models. With the recent release of ARS-UCD1.2, a more complete and accurate assembly of the cattle genome than was previously available, it is timely to fine map the PAB for the first time. Here we report the use of SNP chip genotypes, short-read sequences, and long-read sequences to fine map the PAB (X chromosome:133,300,518) and simultaneously determine the neighboring regions of reduced homology and true pseudoautosomal region. These results greatly facilitate the inclusion of the X chromosome in genome-wide association studies, genomic selection, and other genetic analysis undertaken on this reference genome.
Topics: Animals; Cattle; Chromosome Mapping; Dairying; Female; Genome; Genome-Wide Association Study; Male; Pseudoautosomal Regions; X Chromosome
PubMed: 30712931
DOI: 10.3168/jds.2018-15638 -
Journal of Evolutionary Biology Dec 2022Evolution of a non-recombining sex-specific region on the Y (or W) chromosome (NRY) is a key step in sex chromosome evolution, but how recombination suppression evolves...
Evolution of a non-recombining sex-specific region on the Y (or W) chromosome (NRY) is a key step in sex chromosome evolution, but how recombination suppression evolves is not well understood. Studies in many different organisms indicated that NRY evolution often involves several expansion steps. Why such NRY expansions occur remains unclear, although it is though that they are likely driven by sexually antagonistic selection. This paper describes a recent NRY expansion due to shift of the pseudoautosomal boundary on the sex chromosomes of a dioecious plant Silene latifolia. The shift resulted in inclusion of at least 16 pseudoautosomal genes into the NRY. This region is pseudoautosomal in closely related Silene dioica and Silene diclinis, indicating that the NRY expansion occurred in S. latifolia after it speciated from the other species ~120 thousand years ago. As S. latifolia and S. dioica actively hybridise across Europe, interspecific gene flow could blur the PAR boundary in these species. The pseudoautosomal genes have significantly elevated genetic diversity (π ~ 3% at synonymous sites), which is consistent with balancing selection maintaining diversity in this region. The recent shift of the PAR boundary in S. latifolia offers an opportunity to study the process of on-going NRY expansion.
Topics: Silene; Chromosomes, Plant; Genes, Plant; Recombination, Genetic; Sex Chromosomes; Evolution, Molecular
PubMed: 35834179
DOI: 10.1111/jeb.14063