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Frontiers in Cell and Developmental... 2021Klinefelter syndrome (KS) is the most prevalent aneuploidy in males and is characterized by a 47,XXY karyotype. Less frequently, higher grade sex chromosome aneuploidies...
Klinefelter syndrome (KS) is the most prevalent aneuploidy in males and is characterized by a 47,XXY karyotype. Less frequently, higher grade sex chromosome aneuploidies (HGAs) can also occur. Here, using a paradigmatic cohort of KS and HGA induced pluripotent stem cells (iPSCs) carrying 49,XXXXY, 48,XXXY, and 47,XXY karyotypes, we identified the genes within the pseudoautosomal region 1 (PAR1) as the most susceptible to dosage-dependent transcriptional dysregulation and therefore potentially responsible for the progressively worsening phenotype in higher grade X aneuploidies. By contrast, the biallelically expressed non-PAR escape genes displayed high interclonal and interpatient variability in iPSCs and differentiated derivatives, suggesting that these genes could be associated with variable KS traits. By interrogating KS and HGA iPSCs at the single-cell resolution we showed that PAR1 and non-PAR escape genes are not only resilient to the X-inactive specific transcript (XIST)-mediated inactivation but also that their transcriptional regulation is disjointed from the absolute XIST expression level. Finally, we explored the transcriptional effects of X chromosome overdosage on autosomes and identified the nuclear respiratory factor 1 (NRF1) as a key regulator of the zinc finger protein X-linked (ZFX). Our study provides the first evidence of an X-dosage-sensitive autosomal transcription factor regulating an X-linked gene in low- and high-grade X aneuploidies.
PubMed: 35186953
DOI: 10.3389/fcell.2021.801597 -
Philosophical Transactions of the Royal... May 2022Sex chromosomes or sex-determining regions (SDR) have been discovered in many dioecious plant species, including the iconic 'living fossil' , though the location and...
Sex chromosomes or sex-determining regions (SDR) have been discovered in many dioecious plant species, including the iconic 'living fossil' , though the location and size of the SDR in remain contradictory. Here we resolve these controversies and analyse the evolution of the SDR in this species. Based on transcriptome sequencing data from four genetic crosses we reconstruct male- and female-specific genetic maps and locate the SDR to the middle of chromosome 2. Integration of the genetic maps with the genome sequence reveals that recombination in and around the SDR is suppressed in a region of about 50 Mb in both males and females. However, occasional recombination does occur except a small, less than 5 Mb long region that does not recombine in males. Based on synonymous divergence between homologous X- and Y-linked genes in this region, we infer that the SDR is fairly old-at least of Cretaceous origin. The analysis of substitution rates and gene expression reveals only slight Y-degeneration. These results are consistent with findings in other dioecious plants with homomorphic sex chromosomes, where the SDR is typically small and evolves in a region with pre-existing reduced recombination, surrounded by long actively recombining pseudoautosomal regions. This article is part of the theme issue 'Sex determination and sex chromosome evolution in land plants'.
Topics: Chromosomes, Plant; Evolution, Molecular; Ginkgo biloba; Plants; Sex Chromosomes
PubMed: 35306884
DOI: 10.1098/rstb.2021.0229 -
Journal of Genetics and Genomics = Yi... Feb 2022Many paleognaths (ratites and tinamous) have a pair of homomorphic ZW sex chromosomes in contrast to the highly differentiated sex chromosomes of most other birds. To...
Many paleognaths (ratites and tinamous) have a pair of homomorphic ZW sex chromosomes in contrast to the highly differentiated sex chromosomes of most other birds. To understand the evolutionary causes for the different tempos of sex chromosome evolution, we produced female genomes of 12 paleognathous species and reconstructed the phylogeny and the evolutionary history of paleognathous sex chromosomes. We uncovered that Palaeognathae sex chromosomes had undergone stepwise recombination suppression and formed a pattern of "evolutionary strata". Nine of the 15 studied species' sex chromosomes have maintained homologous recombination in their long pseudoautosomal regions extending more than half of the entire chromosome length. We found that in the older strata, the W chromosome suffered more serious functional gene loss. Their homologous Z-linked regions, compared with other genomic regions, have produced an excess of species-specific autosomal duplicated genes that evolved female-specific expression, in contrast to their broadly expressed progenitors. We speculate such "defeminization" of Z chromosome with underrepresentation of female-biased genes and slow divergence of sex chromosomes of paleognaths might be related to their distinctive mode of sexual selection targeting females rather than males, which evolved in their common ancestors.
Topics: Animals; Birds; Evolution, Molecular; Female; Genome; Male; Palaeognathae; Phylogeny; Sex Chromosomes
PubMed: 34872841
DOI: 10.1016/j.jgg.2021.06.013 -
Atherosclerosis Jul 2015Sex differences in incidence and prevalence of and morbidity and mortality from cardiovascular disease are well documented. However, many studies examining the genetic... (Review)
Review
Sex differences in incidence and prevalence of and morbidity and mortality from cardiovascular disease are well documented. However, many studies examining the genetic basis for cardiovascular disease fail to consider sex as a variable in the study design, in part, because there is an inherent difficulty in studying the contribution of the sex chromosomes in women due to X chromosome inactivation. This paper will provide general background on the X and Y chromosomes (including gene content, the pseudoautosomal regions, and X chromosome inactivation), discuss how sex chromosomes have been ignored in Genome-wide Association Studies (GWAS) of cardiovascular diseases, and discuss genetics influencing development of cardiovascular risk factors and atherosclerosis with particular attention to carotid intima-medial thickness, and coronary arterial calcification based on sex-specific studies. In addition, a brief discussion of how ethnicity and hormonal status act as confounding variables in sex-based analysis will be considered along with methods for statistical analysis to account for sex in cardiovascular disease.
Topics: Age Factors; Cardiovascular Diseases; Chromosomes, Human, X; Chromosomes, Human, Y; Comorbidity; Female; Genetic Association Studies; Genetic Predisposition to Disease; Gonadal Hormones; Health Status Disparities; Humans; Male; Phenotype; Prognosis; Racial Groups; Risk Assessment; Risk Factors; Sex Factors
PubMed: 25817330
DOI: 10.1016/j.atherosclerosis.2015.03.021 -
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 -
American Journal of Medical Genetics.... Jun 2020One of the two X chromosomes in females is epigenetically inactivated, thereby compensating for the dosage difference in X-linked genes between XX females and XY males.... (Review)
Review
One of the two X chromosomes in females is epigenetically inactivated, thereby compensating for the dosage difference in X-linked genes between XX females and XY males. Not all X-linked genes are completely inactivated, however, with 12% of genes escaping X chromosome inactivation and another 15% of genes varying in their X chromosome inactivation status across individuals, tissues or cells. Expression of these genes from the second and otherwise inactive X chromosome may underlie sex differences between males and females, and feature in many of the symptoms of XXY Klinefelter males, who have both an inactive X and a Y chromosome. We review the approaches used to identify genes that escape from X-chromosome inactivation and discuss the nature of their sex-biased expression. These genes are enriched on the short arm of the X chromosome, and, in addition to genes in the pseudoautosomal regions, include genes with and without Y-chromosomal counterparts. We highlight candidate escape genes for some of the features of Klinefelter syndrome and discuss our current understanding of the mechanisms underlying silencing and escape on the X chromosome as well as additional differences between the X in males and females that may contribute to Klinefelter syndrome.
Topics: Animals; Chromosomes, Human, X; Chromosomes, Human, Y; Female; Gene Expression Regulation; Genes, X-Linked; Humans; Klinefelter Syndrome; Male; X Chromosome Inactivation
PubMed: 32441398
DOI: 10.1002/ajmg.c.31800 -
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 -
Molecular Genetics and Metabolism May 2019Histone demethylases remove transcriptional repressive marks from histones in the nucleus. KDM6A (also known as UTX) is a lysine demethylase which acts on the... (Review)
Review
Histone demethylases remove transcriptional repressive marks from histones in the nucleus. KDM6A (also known as UTX) is a lysine demethylase which acts on the trimethylated lysine at position 27 in histone 3. The KDM6A gene is located on the X chromosome but escapes X inactivation even though it is not located in the pseudoautosomal region. There is a homologue of KDM6A on the Y chromosome, known as UTY. UTY was thought to have lost its demethylase activity and to represent a non-functional remnant of the ancestral KDM6A gene. However, results with knockout mice suggest that the gene is expressed and the protein performs some function within the cell. Female mice with homozygous deletion of Kdm6a do not survive, but hemizygous males are viable, attributed to the presence of the Uty gene. KDM6A is mutated in the human condition Kabuki syndrome type 2 (OMIM 300867) and in many cases of cancer. The amino acid sequence of KDM6A has been conserved across animal phyla, although it is only found on the X chromosome in eutherian mammals. In this review, we reanalyse existing data from various sources (protein sequence comparison, evolutionary genetics, transcription factor binding and gene expression analysis) to determine the function, expression and evolution of KDM6A and UTY and show that UTY has a functional role similar to KDM6A in metabolism and development.
Topics: Amino Acid Sequence; Animals; Female; Gene Expression Regulation, Developmental; Histone Demethylases; Histones; Humans; Male; Mice; Mice, Knockout; Minor Histocompatibility Antigens; Nuclear Proteins; X Chromosome Inactivation; Y Chromosome
PubMed: 31097364
DOI: 10.1016/j.ymgme.2019.04.012 -
Genes May 2020Y-chromosomes contain a non-recombining region (NRY), and in many organisms it was shown that the NRY expanded over time. How and why the NRY expands remains unclear....
Y-chromosomes contain a non-recombining region (NRY), and in many organisms it was shown that the NRY expanded over time. How and why the NRY expands remains unclear. Young sex chromosomes, where NRY expansion occurred recently or is on-going, offer an opportunity to study the causes of this process. Here, we used the plant , where sex chromosomes evolved ~11 million years ago, to study the location of the boundary between the NRY and the recombining pseudoautosomal region (PAR). The previous work devoted to the NRY/PAR boundary in was based on a handful of genes with locations approximately known from the genetic map. Here, we report the analysis of 86 pseudoautosomal and sex-linked genes adjacent to the NRY/PAR boundary to establish the location of the boundary more precisely. We take advantage of the dense genetic map and polymorphism data from wild populations to identify 20 partially sex-linked genes located in the "fuzzy boundary", that rarely recombines in male meiosis. Genes proximal to this fuzzy boundary show no evidence of recombination in males, while the genes distal to this partially-sex-linked region are actively recombining in males. Our results provide a more accurate location for the PAR boundary in , which will help to elucidate the causes of PAR boundary shifts leading to NRY expansion over time.
Topics: Animals; Chromosome Mapping; Chromosomes, Plant; Evolution, Molecular; Genetic Linkage; Polymorphism, Genetic; Recombination, Genetic; Sex Chromosomes; Sex Determination Processes; Silene; Y Chromosome
PubMed: 32486434
DOI: 10.3390/genes11060610 -
ELife Nov 2020Sex chromosomes are typically comprised of a non-recombining region and a recombining pseudoautosomal region. Accurately quantifying the relative size of these regions...
Sex chromosomes are typically comprised of a non-recombining region and a recombining pseudoautosomal region. Accurately quantifying the relative size of these regions is critical for sex-chromosome biology both from a functional and evolutionary perspective. The evolution of the pseudoautosomal boundary (PAB) is well documented in haplorrhines (apes and monkeys) but not in strepsirrhines (lemurs and lorises). Here, we studied the PAB of seven species representing the main strepsirrhine lineages by sequencing a male and a female genome in each species and using sex differences in coverage to identify the PAB. We found that during primate evolution, the PAB has remained unchanged in strepsirrhines whereas several recombination suppression events moved the PAB and shortened the pseudoautosomal region in haplorrhines. Strepsirrhines are well known to have much lower sexual dimorphism than haplorrhines. We suggest that mutations with antagonistic effects between males and females have driven recombination suppression and PAB evolution in haplorrhines.
Topics: Animals; Evolution, Molecular; Female; Male; Polymorphism, Single Nucleotide; Sex Chromosomes; Species Specificity; Strepsirhini
PubMed: 33205751
DOI: 10.7554/eLife.63650