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Page, D. C.

Publications and source records attributed to Page, D. C..

At least 19 recordsLinked to original sources

Hybrid Drosophila genomes rapidly purge minority ancestry but repeatedly retain selected regions

Hybridization is increasingly recognized as a widespread evolutionary process across animals, plants, and fungi, and plays a key role in driving speciation, shaping genetic diversity, and facilitating adaptation. Initial hybrid genomes are rarely observed empirically, making it challenging to observe in real time how competing forces like purifying selection and adaptive introgression interact to shape post-hybridization genomes. Here, we use replicated experimental hybrid populations between Drosophila simulans and D. sechellia to track directly genome-wide evolutionary dynamics across approximately 45 generations post-hybridization. We show that hybrid populations with primarily D. simulans ancestry rapidly recover wild-type levels of fertility and fecundity, whereas populations carrying predominantly D. sechellia ancestry experience persistent fitness reductions and frequent extinction. Genome-wide ancestry trajectories show pervasive purifying selection against minority-ancestry alleles, leading to rapid regression toward majority ancestry across the genome, with stronger purging on the X chromosome than autosomes. Following the initial purging, neutral minority ancestry stabilized at low frequencies across the genome. In striking contrast, we observe repeated increases in D. sechellia ancestry on chromosome 4 and multiple regions on chromosome 3R within D. simulans-majority populations, providing evidence for adaptive introgression. High-density sequencing revealed that these regions were repeatedly retained across independently evolving populations despite near-complete genome-wide purging. Simulations support a model in which recombination rapidly uncouples beneficial introgressed alleles from linked incompatibility-associated alleles during the initial generations, allowing positive selection to act. Our temporal allele-frequency analyses suggest that hybrid genome stabilization of the introgressed regions is highly repeatable but not identical, yielding parallel outcomes across replicate populations. We establish a tractable experimental framework to directly observe how hybrid genomes reorganize in real time, and demonstrate how purifying selection, positive selection, recombination, and stochastic processes interact to restructure hybrid genomes shortly after admixture.

genetics↗

Track Display Jockey (trackDJ): a user-friendly R package for visualization of epigenomic data

BackgroundVisualization of epigenomic data such as coverage tracks, peak calls, and chromatin interactions is a critical task in genomic data analysis. Although genome browsers such as the Integrative Genomics Viewer (IGV) and the UCSC Genome Browser permit user-friendly exploration of genomic tracks, they are not optimized for fully programmatic and reproducible generation of publication-quality figures. In contrast, existing programmatic tools lack a user-friendly interface and require extensive configuration. ResultsWe present trackDJ (Track Display Jockey), an R package for visualization of epigenomic data. trackDJ prioritizes usability by favoring convention over configuration; it provides high-level plotting functions with sensible defaults, allowing users with minimal programming experience to generate clear, publication-quality figures with relatively little coding. Within a unified plotting framework, users can stack and align multiple data types, including coverage tracks, peak annotations, chromatin loops, and gene annotations. trackDJ allows users to select plotted genomic regions by coordinates or by gene name, enabling rapid visualization without knowledge of precise locus boundaries. ConclusionstrackDJ provides a user-friendly and reproducible alternative to interactive genome browsers for epigenomic visualization, filling a critical gap in currently available epigenomics toolkits. By enabling scripted generation of clean, customizable genomic illustrations, trackDJ integrates naturally into R-based analysis workflows to streamline the creation of publication-quality figures.

bioinformatics↗

The SHR/Akr Y chromosome reveals repeated turnover of the rat pseudoautosomal region

Crossing-over between Chr X and Chr Y was first observed 90 years ago, in the brown rat, Rattus norvegicus. However, the sequence of the rat pseudoautosomal region (PAR) has remained a mystery. We produced a near-complete sequence of Chr Y from the SHR strain, along with nearly a megabase of sequence from both telomeres of Chr X. Both telomeric ends of Chr Y display extensive homology to Chr X, but no homology to the ancestral PAR of placental mammals. Using rat Y BACs probes for FISH on meiotic cells, we show that pairing almost always occurs between the tips of Yq and Xp, which are virtually identical in nucleotide sequence, but contain no protein-coding genes. Homology at the other ends of Chr X and Chr Y is likely the result of a recent transposition of five genes from Xq to Yp. These sequences are only 99.5% identical and pair infrequently, but show signs that it may have been pseudoautosomal in the ancestor of the rat genus. The rat Chr Y sequence presents opportunities for experimental studies of meiotic phenomena in a tractable model organism. The short PAR, with a correspondingly high recombination rate, represents a unique substrate for molecular studies of crossing-over. Likewise, the absence of extensively co-amplified testis gene families on the rat X and Y suggests they might serve as control for the intense competition between selfish elements that completely remodeled the mouse sex chromosomes.

genomics↗

Independent effects of testosterone, estradiol, and sex chromosomes on gene expression in immune cells of trans- and cisgender individuals

The origins of sex differences in human disease are elusive, in part because of difficulties in separating the effects of sex hormones and sex chromosomes. To separate these variables, we examined gene expression in four groups of trans- or cisgender individuals: XX individuals treated with exogenous testosterone (n=21), XY treated with exogenous estradiol (n=13), untreated XX (n=20), and untreated XY (n=15). We performed single-cell RNA-sequencing of 358,426 peripheral blood mononuclear cells. Across the autosomes, 8 genes responded with a significant change in expression to testosterone, 34 to estradiol, and 32 to sex chromosome complement with no overlap between the groups. No sex-chromosomal genes responded significantly to testosterone or estradiol, but X-linked genes responded to sex chromosome complement in a remarkably stable manner across cell types. Through leveraging a four-state study design, we successfully separated the independent actions of testosterone, estradiol, and sex chromosome complement on genome-wide gene expression in humans.

genomics↗

Transcriptomic Insights into Hypothalamic Aging During Menopause: A Comparative Analysis of Human and Mouse Models

The hypothalamic changes that occur after the loss of ovarian estrogen remain poorly characterized. Here, we performed a comprehensive temporal characterization of the mouse hypothalamus following ovariectomy (OVX), combining physiological measurements with bulk RNA-sequencing of the posterior hypothalamus (PH) and preoptic area (POA) at short-term (14 days) and long-term (4 months) post-OVX. Serum LH levels rose progressively and then declined, while core temperature peaked early and subsequently normalized, recapitulating the endocrine and thermoregulatory dynamics of reproductive aging in humans. Transcriptomic analysis revealed time-dependent activation of inflammatory pathways, glial markers, and KNDy neuron-related gene networks, with the most pronounced changes emerging at 4 months post-OVX, particularly in the PH. Immunofluorescence confirmed increased NKB release, declining KNDy neuronal activity, and heightened astrocytic reactivity in the arcuate nucleus after prolonged estrogen withdrawal. To contextualize these findings, we analyzed publicly available human hypothalamic RNA-seq data across chronological age. Age-related transcriptomic patterns in women, including progressive inflammatory signaling, glial activation, and altered KNDy gene expression, showed significant correlation with the OVX mouse model, particularly at the pathway level. These findings establish a temporal framework for hypothalamic molecular changes after estrogen withdrawal, identify conserved neuroinflammatory signatures across species, and provide a preclinical platform for testing interventions targeting menopausal-associated hypothalamic dysfunction.

neuroscience↗

Post-transcriptional cross- and auto-regulation buffer expression of the human RNA helicases DDX3X and DDX3Y

The Y-linked gene DDX3Y and its X-linked homolog DDX3X survived the evolution of the human sex chromosomes from ordinary autosomes. DDX3X encodes a multi-functional RNA helicase, with mutations causing developmental disorders and cancers. We find that, among X-linked genes with surviving Y homologs, DDX3X is extraordinarily dosage-sensitive. Studying cells of individuals with sex chromosome aneuploidy, we observe that when the number of Y chromosomes increases, DDX3X transcript levels fall; conversely, when the number of X chromosomes increases, DDX3Y transcript levels fall. In 46,XY cells, CRISPRi knockdown of either DDX3X or DDX3Y causes transcript levels of the homologous gene to rise. In 46,XX cells, chemical inhibition of DDX3X protein activity elicits an increase in DDX3X transcript levels. Thus, perturbation of either DDX3X or DDX3Y expression is buffered - by negative cross-regulation of DDX3X and DDX3Y in 46,XY cells, and by negative auto-regulation of DDX3X in 46,XX cells. DDX3X-DDX3Y cross-regulation is mediated through mRNA destabilization - as shown by metabolic labeling of newly transcribed RNA - and buffers total levels of DDX3X and DDX3Y protein in human cells. We infer that post-transcriptional auto-regulation of the ancestral (autosomal) DDX3 gene transmuted into auto- and cross-regulation of DDX3X and DDX3Y as these sex-linked genes evolved from ordinary alleles of their autosomal precursor.

genetics↗

Where is the boundary of the human pseudoautosomal region?

A recent publication describing the assembly of the Y chromosomes of 43 males was remarkable not only for its ambitious technical scope, but also for the startling suggestion that the boundary of the pseudoautosomal region 1 (PAR1), where the human X and Y chromosomes engage in crossing-over during male meiosis, lies 500 kb distal to its previously reported location1. Where is the boundary of the human PAR1? We first review the evidence that mapped the PAR boundary, or PAB, before the human genome draft sequence was produced, then examine post-genomic datasets for evidence of crossing-over between the X and Y, and lastly re-examine the sequence assemblies presented by Hallast and colleagues to see whether they support a more distal PAB. We find ample evidence of X-Y crossovers throughout the 500 kb in question, some as close as 246 bp to the previously reported PAB. Our new analyses, combined with previous studies over the past 40 years, provide overwhelming evidence to support the original position, and narrow the probable location of the PAB to a 201-bp window.

genetics↗

The inactive X chromosome drives sex differences in microglial inflammatory activity in human glioblastoma

Whether an individual is a biological female or male affects cancer risk, but the responsible mechanisms and cell types remain obscure. Glioblastoma multiforme (GBM) is a male-biased cancer that is highly aggressive, and resistant to treatment, with poor patient survival. Dismal prognoses in GBM are due in part to the specialized immune system of the brain, consisting largely of microglia, which regulate GBM development and progression. We hypothesized that microglia function differently in females and males and thereby contribute to the observed male bias in GBM. We sorted TAM-MGs (tumor-associated macrophages - microglia) from human GBMs and low-grade gliomas and performed bulk transcriptomic and epigenomic assays to identify sex-biased gene expression. We used published single-cell transcriptomic data from human GBMs to predict sex-biased TAM-MG interactions with other cell types. We found that female and male TAM-MGs mount different inflammatory responses, with female TAM-MGs displaying stronger interferon signaling and cytotoxic T-cell interactions that should enhance anti-tumor immunity in GBM. We validated these sex-differential inflammatory responses experimentally, and determined that genes on the sex chromosomes, specifically those expressed by Xi (the "inactive" X chromosome), drive these differences. Together, our results suggest that sex-differential TAM-MG inflammatory responses contribute to the higher incidence and mortality of GBM in males.

genomics↗

Genes of the fatty acid oxidation pathway are upregulated in female as compared to male cardiomyocytes

Human females and males differ in cardiac physiology and pathology, even after controlling for sex differences in anthropometrics, lifestyle, and environment. For example, females and males differ in cardiac stroke volume and ventricular thickness, and they exhibit different rates and symptoms of cardiovascular disease. Less is understood about molecular differences in female and male hearts, such as sex differences in gene expression. Here we present an integrative framework utilizing bulk and single-nucleus RNA-sequencing data to study sex differences in the cardiac transcriptome. We show that genes of the fatty acid oxidation (FAO) pathway, the primary source of energy in the heart, are expressed more highly in healthy female than in healthy male hearts. We demonstrate that this sex difference is due to cardiomyocyte-specific, female-biased expression of FAO genes and cannot be explained by sex differences in cardiac cellular composition or number of mitochondria, where FAO takes place. Finally, we observe increased cardiac flux and energetic utilization of free fatty acids in female compared to male hearts. Overall, our results demonstrate that male and female human hearts exhibit fundamental differences in metabolism that likely contribute to sex differences in cardiac physiology and pathology.

genomics↗

Stable and robust Xi and Y transcriptomes drive cell-type-specific autosomal and Xa responses in vivo and in vitro in four human cell types

Recent in vitro studies of human sex chromosome aneuploidy showed that the Xi ("inactive" X) and Y chromosomes broadly modulate autosomal and Xa ("active" X) gene expression in two cell types. We tested these findings in vivo in two additional cell types. Using linear modeling in CD4+ T cells and monocytes from individuals with one to three X chromosomes and zero to two Y chromosomes, we identified 82 sex-chromosomal and 344 autosomal genes whose expression changed significantly with Xi and/or Y dosage in vivo. Changes in sex-chromosomal expression were remarkably constant in vivo and in vitro across all four cell types examined. In contrast, autosomal responses to Xi and/or Y dosage were largely cell-type-specific, with up to 2.6-fold more variation than sex-chromosomal responses. Targets of the X- and Y-encoded transcription factors ZFX and ZFY accounted for a significant fraction of these autosomal responses both in vivo and in vitro. We conclude that the human Xi and Y transcriptomes are surprisingly robust and stable across the four cell types examined, yet they modulate autosomal and Xa genes - and cell function - in a cell-type-specific fashion. These emerging principles offer a foundation for exploring the wide-ranging regulatory roles of the sex chromosomes across the human body.

genomics↗

Post-transcriptional repression of mRNA enhances competence to transit from mitosis to meiosis in mouse spermatogenic cells

The specialized cell cycle of meiosis transforms diploid germ cells into haploid gametes. In mammals, diploid spermatogenic cells acquire the competence to initiate meiosis in response to retinoic acid. Previous mouse studies revealed that MEIOC interacts with RNA-binding proteins YTHDC2 and RBM46 to repress mitotic genes and promote robust meiotic gene expression in spermatogenic cells that have initiated meiosis. Here, we used the enhanced resolution of scRNA-seq, and bulk RNA-seq of developmentally synchronized spermatogenesis, to define how MEIOC molecularly supports early meiosis in spermatogenic cells. We demonstrate that MEIOC mediates transcriptomic changes before meiotic initiation, earlier than previously appreciated. MEIOC, acting with YTHDC2 and RBM46, destabilizes its mRNA targets, including transcriptional repressors E2f6 and Mga, in mitotic spermatogonia. MEIOC thereby derepresses E2F6- and MGA-repressed genes, including Meiosin and other meiosis-associated genes. This confers on spermatogenic cells the molecular competence to, in response to retinoic acid, fully activate transcriptional regulator STRA8-MEIOSIN, required for the meiotic G1/S phase transition and meiotic gene expression. We conclude that in mice, mRNA decay mediated by MEIOC-YTHDC2-RBM46 enhances the competence of spermatogenic cells to initiate meiosis. SUMMARY STATEMENTRNA-binding complex MEIOC-YTHDC2-RBM46 destabilizes its mRNA targets, including transcriptional repressors. This activity facilitates the retinoic acid-dependent activation of Meiosin gene expression and transition into meiosis.

developmental biology↗

Analysis of a mouse germ cell tumor model establishes pluripotency-associated miRNAs as conserved serum biomarkers for germ cell cancer detection

Malignant testicular germ cells tumors (TGCTs) are the most common solid cancers in young men. Current TGCT diagnostics include conventional serum protein markers, but these lack the sensitivity and specificity to serve as accurate markers across all TGCT subtypes. MicroRNAs (miRNAs) are small non-coding regulatory RNAs and informative biomarkers for several diseases. In humans, miRNAs of the miR-371-373 cluster are detectable in the serum of patients with malignant TGCTs and outperform existing serum protein markers for both initial diagnosis and subsequent disease monitoring. We previously developed a genetically engineered mouse model featuring malignant mixed TGCTs consisting of pluripotent embryonal carcinoma (EC) and differentiated teratoma that, like the corresponding human malignancies, originate in utero and are highly chemosensitive. Here, we report that miRNAs in the mouse miR-290-295 cluster, homologs of the human miR-371-373 cluster, were detectable in serum from mice with malignant TGCTs but not from tumor-free control mice or mice with benign teratomas. miR-291-293 were expressed and secreted specifically by pluripotent EC cells, and expression was lost following differentiation induced by the drug thioridazine. Notably, miR-291-293 levels were significantly higher in the serum of pregnant dams carrying tumor-bearing fetuses compared to that of control dams. These findings reveal that expression of the miR-290-295 and miR-371-373 clusters in mice and humans, respectively, is a conserved feature of malignant TGCTs, further validating the mouse model as representative of the human disease. These data also highlight the potential of serum miR-371-373 assays to improve patient outcomes through early TGCT detection, possibly even prenatally.

cancer biology↗

The human Y and inactive X chromosomes similarly modulate autosomal gene expression

Somatic cells of human males and females have 45 chromosomes in common, including the "active" X chromosome. In males the 46th chromosome is a Y; in females it is an "inactive" X (Xi). Through linear modeling of autosomal gene expression in cells from individuals with zero to three Xi and zero to four Y chromosomes, we found that Xi and Y impact autosomal expression broadly and with remarkably similar effects. Studying sex-chromosome structural anomalies, promoters of Xi- and Y-responsive genes, and CRISPR inhibition, we traced part of this shared effect to homologous transcription factors - ZFX and ZFY - encoded by Chr X and Y. This demonstrates sex-shared mechanisms by which Xi and Y modulate autosomal expression. Combined with earlier analyses of sex-linked gene expression, our studies show that 21% of all genes expressed in lymphoblastoid cells or fibroblasts change expression significantly in response to Xi or Y chromosomes.

genetics↗

A Four "Core Genotypes" rat model to distinguish mechanisms underlying sex-biased phenotypes and diseases

BackgroundPrevious research on Four Core Genotypes and XY* mice has been instrumental in establishing important effects of sex-chromosome complement that cause sex differences in physiology and disease. We have generated rat models using similar modifications of the testis-determining gene Sry, to produce XX and XY rats with the same type of gonad, as well as XO, XXY and XYY rats with varying gonads. The models permit discovery of novel sex-chromosome effects (XX vs. XY) that contribute to sex differences in any rat phenotype, and test for effects of different numbers of X or Y chromosomes. MethodsXY rats were created with an autosomal transgene of Sry, producing XX and XY progeny with testes. In other rats, CRISPR-Cas9 technology was used to remove Y chromosome factors that initiate testis differentiation, producing fertile XY gonadal females. Interbreeding of these lines produced rats with interesting combinations of sex chromosomes and gonads: XO, XX, XY, XXY rats with ovaries; and XO, XX, XY, XXY, and XYY rats with testes. These groups can be compared to detect sex differences caused by sex-chromosome complement (XX vs. XY) and/or by gonadal hormones (rats with testes vs. ovaries). Other comparisons detect the effects of X or Y chromosome number (in gonadal females: XO vs. XX, XX vs. XXY, XO vs. XY, XY vs. XXY; in gonadal males: XY vs. XXY, XY vs. XYY; XX vs. XXY, XO vs. XY). ResultsWe measured numerous phenotypes to characterize these models, including gonadal histology, breeding performance, anogenital distance, levels of reproductive hormones, body and organ weights, and central nervous system sexual dimorphisms. Serum testosterone levels were comparable in adult XX and XY gonadal males. Phenotypes previously known to be sexually differentiated by the action of gonadal hormones were found to be similar in XX and XY rats with the same type of gonad, suggesting that XX and XY rats with the same type of gonad have comparable levels of gonadal hormones at various stages of development. ConclusionThe results establish powerful new models to discriminate sex-chromosome and gonadal hormone effects that cause sexual differences in rat physiology and disease. Plain English SummaryThe Four Core Genotypes and XY* mouse models have been broadly useful for determining if sex differences in any mouse phenotype are caused by gonadal hormones, or by sex-chromosome complement (XX vs. XY), and if sex-chromosome effects are caused by X- or Y-linked mechanisms. Using gene knockout and transgenic methods, we have produced laboratory rat models that offer similar capabilities. The new rat models allow investigators to test with relative ease, for the first time, if a sex difference in a rat trait is caused by effects of XX vs. XY sex chromosomes, not mediated by effects of gonadal hormones, and to narrow the search for X or Y genes that have that role. The models produce XO, XX, XY, and XXY rats with ovaries, and XO, XX, XY, XXY, and XYY rats with testes. The four XX and XY groups represent a Four Core Genotypes rat model, comparison of which tests for sex-chromosome and gonadal hormonal effects that cause female and male rats to have different physiological or disease traits. Moreover, comparison of rats with different numbers of X chromosomes, or of Y chromosomes, but with the same type of gonad, provides evidence regarding the effects of X or Y dosage on rat traits. The new models will improve understanding of the impact of sex chromosomes on diseases or traits that are best modeled in rats. They will also improve understanding of the evolution of functional roles of sex chromosomes. HighlightsIt is advantageous to establish the factors that cause sex differences in diseases, because those factors mitigate or exacerbate diseases. We have produced new laboratory rats that have different types and numbers of sex chromosomes but the same type of gonad, allowing investigation of the role of sex chromosomes in causing sex differences in physiology and disease. The new rat lines allow comparison of XX and XY rats with the same type of gonad, to detect sex differences caused in part by the sex chromosomes. Other comparisons of rats with the same gonad but with different numbers of X chromosomes (XO vs. XX, XY vs XXY) or of Y chromosomes (XO vs. XY, XX vs. XXY, XY vs. XYY) detect effects of X or Y chromosome number. These resources can uncover sex-chromosome effects on any rat phenotype.

genetics↗

Cell type-specific role of CBX2-cPRC1 at the onset of spermatogonial differentiation

Polycomb group (PcG) proteins maintain the repressed state of lineage-inappropriate genes and are therefore essential for embryonic development and adult tissue homeostasis. One critical function of PcG complexes is modulating chromatin structure. Canonical Polycomb repressive complex 1 (cPRC1), particularly its component CBX2, can compact chromatin and phase separate in vitro. These activities are hypothesized to be critical for forming a repressed physical environment in cells. While much has been learned by studying these PcG activities in cell culture models, it is largely unexplored how cPRC1 regulates adult stem cells and their subsequent differentiation during tissue homeostasis in living animals. Here, we show that CBX2 is upregulated as spermatogonial stem cells differentiate and is required in the differentiating spermatogonia of the male germ line. CBX2 forms condensates, similar to previously described Polycomb bodies, that co-localize with repressed target genes in differentiating spermatogonia. Single cell analyses of mosaic Cbx2 mutant testes show CBX2 is specifically required to produce differentiating, A1 spermatogonia. Furthermore, the domain of CBX2 responsible for compaction and phase separation is needed for the long-term maintenance of male germ cells in the animal. These results emphasize that the regulation of chromatin structure by CBX2 at a specific stage of spermatogenesis is critical for the continued production of sperm and, ultimately, the transmission of genetic material to the next generation.

developmental biology↗

A gene-by-gene mosaic of dosage compensation strategies on the human X chromosome

Researchers have presumed that the "inactive" X chromosome (Xi) has little impact, in trans, on the "active" X (Xa). To test this, we quantified Xi and Xa gene expression in individuals with one Xa and zero to three Xis. Our linear modeling revealed modular Xi and Xa transcriptomes and significant Xi-driven expression changes for 38% (162/423) of expressed X-chromosome genes. By integrating allele-specific analyses, we found that modulation of Xa transcript levels by Xi contributes to many of these Xi-driven changes ([≥] 121 genes). By incorporating metrics of evolutionary constraint, we identified 10 X-chromosome genes most likely to drive sex differences in common disease, and sex chromosome aneuploidy syndromes. We conclude that human X chromosomes are regulated both in cis, through Xi-wide transcriptional attenuation, and in trans, through positive or negative modulation of individual Xa genes by Xi. The sum of cis and trans effects differs widely among genes.

genetics↗

GC-biased gene conversion in X-Chromosome palindromes conserved in human, chimpanzee, and rhesus macaque

Gene conversion is GC-biased across a wide range of taxa. Large palindromes on mammalian sex chromosomes undergo frequent gene conversion that maintains arm-to-arm sequence identity greater than 99%, which may increase their susceptibility to the effects of GC-biased gene conversion. Here, we demonstrate a striking history of GC-biased gene conversion in 12 palindromes conserved on the X chromosomes of human, chimpanzee, and rhesus macaque. Primate X-chromosome palindrome arms have significantly higher GC content than flanking single-copy sequences. Nucleotide replacements that occurred in human and chimpanzee palindrome arms over the past 7 million years are one-and-a-half times as GC-rich than the ancestral bases they replaced. Using simulations, we show that our observed pattern of nucleotide replacements is consistent with GC-biased gene conversion with a magnitude of 70%, similar to previously reported values based on analyses of human meioses. However, GC-biased gene conversion explains only a fraction of the observed difference in GC content between palindrome arms and flanking sequence, suggesting that additional factors are required to explain elevated GC content in palindrome arms. This work supports a greater than 2:1 preference for GC bases over AT bases during gene conversion, and demonstrates that the evolution and composition of mammalian sex chromosome palindromes is strongly influenced by GC-biased gene conversion.

genomics↗

Large palindromes on the primate X Chromosome are preserved by natural selection

Mammalian sex chromosomes carry large palindromes that harbor protein-coding gene families with testis-biased expression. However, there are few known examples of sex-chromosome palindromes conserved between species. We identified 26 palindromes on the human X Chromosome, constituting more than 2% of its sequence, and characterized orthologous palindromes in the chimpanzee and the rhesus macaque using a clone-based sequencing approach that incorporates full-length nanopore reads. Many of these palindromes are missing or misassembled in the current reference assemblies of these species genomes. We find that 12 human X palindromes have been conserved for at least 25 million years, with orthologs in both chimpanzee and rhesus macaque. Insertions and deletions between species are significantly depleted within the X palindromes protein-coding genes compared to their non-coding sequence, demonstrating that natural selection has preserved these gene families. Unexpectedly, the spacers that separate the left and right arms of palindromes are a site of localized structural instability, with 7 of 12 conserved palindromes showing no spacer orthology between human and rhesus macaque. Analysis of the 1000 Genomes Project dataset revealed that human X-palindrome spacers are enriched for deletions relative to arms and flanking sequence, including a common spacer deletion that affects 13% of human X Chromosomes. This work reveals an abundance of conserved palindromes on primate X Chromosomes, and suggests that protein-coding gene families in palindromes (most of which remain poorly characterized) promote X-palindrome survival in the face of ongoing structural instability.

genomics↗