Pseudoautosomal Research Articles

Dosage of the pseudoautosomal gene SLC25A6 is implicated in QTc interval duration

The genetic architecture of the QT interval, defined as the period from onset of depolarisation to completion of repolarisation of the ventricular myocardium, is incompletely understood. Only a minor part of the QT interval variation in the general population has been linked to autosomal variant loci. Altered X chromosome dosage in humans, as seen in sex chromosome aneuploidies such as Turner syndrome (TS) and Klinefelter syndrome (KS), is associated with altered QTc interval (heart rate corrected QT), indicating that genes, located in the pseudoautosomal region 1 of the X and Y chromosomes may contribute to QT interval variation. We investigate the dosage effect of the pseudoautosomal gene SLC25A6, encoding the membrane ADP/ATP translocase 3 in the inner mitochondrial membrane, on QTc interval duration. To this end we used human participants and in vivo zebrafish models. Analyses in humans, based on 44 patients with KS, 44 patients with TS, 59 male and 22 females, revealed a significant negative correlation between SLC25A6 expression level and QTc interval duration. Similarly, downregulation of slc25a6 in zebrafish increased QTc interval duration with pharmacological inhibition of KATP channels restoring the systolic duration, whereas overexpression of SLC25A6 shortened QTc, which was normalized by pharmacological activation of KATP channels. Our study demonstrate an inverse relationship between SLC25A6 dosage and QTc interval indicating that SLC25A6 contributes to QT interval variation.

Gain of chromosome 21 increases the propensity for P2RY8::CRLF2 acute lymphoblastic leukemia via increased HMGN1 expression.

Acute lymphoblastic leukemia (ALL) patients with a gain of chromosome 21, intrachromosomal amplification of chromosome 21 (iAMP21), or Down syndrome (DS), have increased expression of genes in the DS critical region (DSCR) of chromosome 21, including the high-mobility group nucleosome-binding protein 1, HMGN1. Children with DS are predisposed to develop hematologic malignancies, providing insight into the role of chromosome 21 in the development of leukemias. A 320-kb deletion in the pseudoautosomal region of the X/Y chromosome in leukemic cells, resulting in a gene fusion between the purinergic receptor and cytokine receptor-like factor-2 (P2Y Receptor Family Member 8 (P2RY8)::CRLF2), is a common feature in ~60% of DS-ALL and ~40% of iAMP21 patients, suggesting a link between chromosome 21 and P2RY8::CRLF2. In an Australian cohort of pediatric B-ALL patients with P2RY8::CRLF2 (n = 38), eight patients harbored gain of chromosome 21 (+21), and two patients had iAMP21, resulting in a significantly increased HMGN1 expression. An inducible CRISPR/Cas9 system was used to model P2RY8::CRLF2 and investigate its cooperation with HMGN1. This model was then used to validate HMGN1 as an influencing factor for P2RY8::CRLF2 development. Using Cas9 to cleave the DNA at the pseudoautosomal region without directed repair, cells expressing HMGN1 favored repair, resulting in P2RY8::CRLF2 generation, compared with cells without HMGN1. CRISPR/Cas9 P2RY8::CRLF2 cells expressing HMGN1 exhibit increased proliferation, thymic stromal lymphopoietin receptor (TSLPR) expression, and JAK/STAT signaling, consistent with cells from patients with P2RY8::CRLF2. Our patient expression data and unique CRISPR/Cas9 modeling, when taken together, suggest that HMGN1 increases the propensity for P2RY8::CRLF2 development. This has important implications for patients with DS, +21, or iAMP21.

Evolution of the spinach sex-linked region within a rarely recombining pericentromeric region.

Sex chromosomes have evolved independently in many different plant lineages. Here, we describe reference genomes for spinach (Spinacia oleracea) X and Y haplotypes by sequencing homozygous XX females and YY males. The long arm of the 185 Mb chromosome 4 carries a 13 Mb X-linked region (XLR) and 24.1 Mb Y-linked region (YLR), of which 10 Mb is Y-specific. We describe evidence that this reflects insertions of autosomal sequences creating a "Y duplication region" or "YDR" whose presence probably directly reduces genetic recombination in the immediately flanking regions, although both the X and Y Sex-Linked Regions are within a large pericentromeric region of chromosome 4 that recombines rarely in meiosis of both sexes. Sequence divergence estimates using synonymous sites indicate that YDR genes started diverging from their likely autosomal progenitors about 3 MYA, around the time when the flanking YLR stopped recombining with the XLR. These flanking regions have a higher density of repetitive sequences in the YY than the XX assembly and include slightly more pseudogenes compared with the XLR, and the YLR has lost about 11% of the ancestral genes, suggesting some degeneration. Insertion of a male-determining factor would have caused Y-linkage across the entire pericentromeric region, creating physically small, highly recombining, terminal pseudo-autosomal regions. These findings provide a broader understanding of the origin of sex chromosomes in spinach.

The evolutionary maintenance of ancient recombining sex chromosomes in the ostrich.

Sex chromosomes have evolved repeatedly across the tree of life and often exhibit extreme size dimorphism due to genetic degeneration of the sex-limited chromosome (e.g. the W chromosome of some birds and Y chromosome of mammals). However, in some lineages, ancient sex-limited chromosomes have escaped degeneration. Here, we study the evolutionary maintenance of sex chromosomes in the ostrich (Struthio camelus), where the W remains 65% the size of the Z chromosome, despite being more than 100 million years old. Using genome-wide resequencing data, we show that the population scaled recombination rate of the pseudoautosomal region (PAR) is higher than similar sized autosomes and is correlated with pedigree-based recombination rate in the heterogametic females, but not homogametic males. Genetic variation within the sex-linked region (SLR) (π = 0.001) was significantly lower than in the PAR, consistent with recombination cessation. Conversely, genetic variation across the PAR (π = 0.0016) was similar to that of autosomes and dependent on local recombination rates, GC content and to a lesser extent, gene density. In particular, the region close to the SLR was as genetically diverse as autosomes, likely due to high recombination rates around the PAR boundary restricting genetic linkage with the SLR to only ~50Kb. The potential for alleles with antagonistic fitness effects in males and females to drive chromosome degeneration is therefore limited. While some regions of the PAR had divergent male-female allele frequencies, suggestive of sexually antagonistic alleles, coalescent simulations showed this was broadly consistent with neutral genetic processes. Our results indicate that the degeneration of the large and ancient sex chromosomes of the ostrich may have been slowed by high recombination in the female PAR, reducing the scope for the accumulation of sexually antagonistic variation to generate selection for recombination cessation.

Sex body: A nest of protein mixture.

During the pachytene stage in mammalian meiosis, the X and Y chromosomes remain largely unsynapsed outside the pseudoautosomal region, while autosomes are fully synapsed. Then, the sex chromosomes are compartmentalized into a "sex body" in the nucleus and are subjected to meiotic sex chromosome inactivation (MSCI). For decades, the formation and functioning of the sex body and MSCI have been subjects worth exploring. Notably, a series of proteins have been reported to be located on the sex body area and inferred to play an essential role in MSCI; however, the proteins that are actually located in this area and how these proteins promote sex body formation and establish MSCI remain unclear. Collectively, the DNA damage response factors, downstream fanconi anemia proteins, and other canonical repressive histone modifications have been reported to be associated with the sex body. Here, this study reviews the factors located on the sex body area and tries to provide new insights into studying this mysterious domain.

Chromosome-length genome assemblies and cytogenomic analyses of pangolins reveal remarkable chromosome counts and plasticity.

We report the first chromosome-length genome assemblies for three species in the mammalian order Pholidota: the white-bellied, Chinese, and Sunda pangolins. Surprisingly, we observe extraordinary karyotypic plasticity within this order and, in female white-bellied pangolins, the largest number of chromosomes reported in a Laurasiatherian mammal: 2n = 114. We perform the first karyotype analysis of an African pangolin and report a Y-autosome fusion in white-bellied pangolins, resulting in 2n = 113 for males. We employ a novel strategy to confirm the fusion and identify the autosome involved by finding the pseudoautosomal region (PAR) in the female genome assembly and analyzing the 3D contact frequency between PAR sequences and the rest of the genome in male and female white-bellied pangolins. Analyses of genetic variability show that white-bellied pangolins have intermediate levels of genome-wide heterozygosity relative to Chinese and Sunda pangolins, consistent with two moderate declines of historical effective population size. Our results reveal a remarkable feature of pangolin genome biology and highlight the need for further studies of these unique and endangered mammals.

The RNA-binding protein FUS/TLS interacts with SPO11 and PRDM9 and localize at meiotic recombination hotspots

In mammals, meiotic recombination is initiated by the introduction of DNA double strand breaks (DSBs) into narrow segments of the genome, defined as hotspots, which is carried out by the SPO11/TOPOVIBL complex. A major player in the specification of hotspots is PRDM9, a histone methyltransferase that, following sequence-specific DNA binding, generates trimethylation on lysine 4 (H3K4me3) and lysine 36 (H3K36me3) of histone H3, thus defining the hotspots. PRDM9 activity is key to successful meiosis, since in its absence DSBs are redirected to functional sites and synapsis between homologous chromosomes fails. One protein factor recently implicated in guiding PRDM9 activity at hotspots is EWS, a member of the FET family of proteins that also includes TAF15 and FUS/TLS. Here, we demonstrate that FUS/TLS partially colocalizes with PRDM9 on the meiotic chromosome axes, marked by the synaptonemal complex component SYCP3, and physically interacts with PRDM9. Furthermore, we show that FUS/TLS also interacts with REC114, one of the axis-bound SPO11-auxiliary factors essential for DSB formation. This finding suggests that FUS/TLS is a component of the protein complex that promotes the initiation of meiotic recombination. Accordingly, we document that FUS/TLS coimmunoprecipitates with SPO11 in vitro and in vivo. The interaction occurs with both SPO11β and SPO11α splice isoforms, which are believed to play distinct functions in the formation of DSBs in autosomes and male sex chromosomes, respectively. Finally, using chromatin immunoprecipitation experiments, we show that FUS/TLS is localized at H3K4me3-marked hotspots in autosomes and in the pseudo-autosomal region, the site of genetic exchange between the XY chromosomes.

XY sex determination in a cnidarian

BackgroundSex determination occurs across animal species, but most of our knowledge about its mechanisms comes from only a handful of bilaterian taxa. This limits our ability to infer the evolutionary history of sex determination within animals.ResultsIn this study, we generated a linkage map of the genome of the colonial cnidarian Hydractinia symbiolongicarpus and used it to demonstrate that this species has an XX/XY sex determination system. We demonstrate that the X and Y chromosomes have pseudoautosomal and non-recombining regions. We then use the linkage map and a method based on the depth of sequencing coverage to identify genes encoded in the non-recombining region and show that many of them have male gonad-specific expression. In addition, we demonstrate that recombination rates are enhanced in the female genome and that the haploid chromosome number in Hydractinia is n = 15.ConclusionsThese findings establish Hydractinia as a tractable non-bilaterian model system for the study of sex determination and the evolution of sex chromosomes.

CD99 and the Chicken Alloantigen D Blood System.

The chicken D blood system is one of 13 alloantigen systems found on chicken red blood cells. Classical recombinant studies located the D blood system on chicken chromosome 1, but the candidate gene was unknown. Multiple resources were utilized to identify the chicken D system candidate gene, including genome sequence information from both research and elite egg production lines for which D system alloantigen alleles were reported, and DNA from both pedigree and non-pedigree samples with known D alleles. Genome-wide association analyses using a 600 K or a 54 K SNP chip plus DNA from independent samples identified a strong peak on chicken chromosome 1 at 125-131 Mb (GRCg6a). Cell surface expression and the presence of exonic non-synonymous SNP were used to identify the candidate gene. The chicken CD99 gene showed the co-segregation of SNP-defined haplotypes and serologically defined D blood system alleles. The CD99 protein mediates multiple cellular processes including leukocyte migration, T-cell adhesion, and transmembrane protein transport, affecting peripheral immune responses. The corresponding human gene is found syntenic to the pseudoautosomal region 1 of human X and Y chromosomes. Phylogenetic analyses show that CD99 has a paralog, XG, that arose by duplication in the last common ancestor of the amniotes.

Why and how do Y chromosome stop recombining?

Why and how do Y chromosome stop recombining?

Relating pathogenic loss-of-function mutations in humans to their evolutionary fitness costs.

Causal loss-of-function (LOF) variants for Mendelian and severe complex diseases are enriched in 'mutation intolerant' genes. We show how such observations can be interpreted in light of a model of mutation-selection balance and use the model to relate the pathogenic consequences of LOF mutations at present to their evolutionary fitness effects. To this end, we first infer posterior distributions for the fitness costs of LOF mutations in 17,318 autosomal and 679 X-linked genes from exome sequences in 56,855 individuals. Estimated fitness costs for the loss of a gene copy are typically above 1%; they tend to be largest for X-linked genes, whether or not they have a Y homolog, followed by autosomal genes and genes in the pseudoautosomal region. We compare inferred fitness effects for all possible de novo LOF mutations to those of de novo mutations identified in individuals diagnosed with one of six severe, complex diseases or developmental disorders. Probands carry an excess of mutations with estimated fitness effects above 10%; as we show by simulation, when sampled in the population, such highly deleterious mutations are typically only a couple of generations old. Moreover, the proportion of highly deleterious mutations carried by probands reflects the typical age of onset of the disease. The study design also has a discernible influence: a greater proportion of highly deleterious mutations is detected in pedigree than case-control studies, and for autism, in simplex than multiplex families and in female versus male probands. Thus, anchoring observations in human genetics to a population genetic model allows us to learn about the fitness effects of mutations identified by different mapping strategies and for different traits.

The Genetic and Genomic Landscape of Human Reproductive Disorders: An Overview with Our Experience

Genetics and genomics play a role in the causation of various human diseases. A large number of human reproductive disorders also arise as a result of genetic and genomic abnormalities. Reproductive disorders associated with predominantly genetics and genomic abnormalities are infertility, early pregnancy loss, congenital malformations, difference or disorder of sex development and reproductive cancers. The genetic etiology of human reproductive disorders is increasing with improved molecular biology techniques such as DNA microarray and next-generation sequencing. Infertility is one of the significant areas of reproductive disorders where genetics/genomics plays a substantial role and may result from chromosomal, copy number variation, Yq & pseudo autosomal region microdeletion/microduplication, gene mutation (monogenic, oligogenic, polygenic), multifactorial, epigenetic, mitochondrial, etc. abnormalities. All idiopathic infertile couples should be screened for genetic disorders before assisted reproduction to prevent transmission, if any, in offspring. Pregnancy wastage in early pregnancy is very high (about 70%) and is mainly related to chromosome number, copy number variation, and some monogenic or epigenetic abnormalities. Therefore, all early pregnancy loss cases should also be tested for genetic causes. Congenital malformations are structural defects in embryo, fetus, or newborns and affect about 3% (major malformations) of all births. The malformations could be due to the abnormalities of chromosomes, copy number variation, monogenic, oligogenic, multifactorial, or environmental. Array CGH &/or NGS should be used as the first step to screen congenital malformations. Differences/disorder of sex development is a developmental defect in which the determination and/or differentiation of chromosomal, gonadal, or phenotypic/anatomic sex is abnormal. It is a common disorder and is primarily related to genetic abnormalities. Therefore, a precise diagnosis, mainly through an array CGH and/or NGS, is crucial for the proper management to prevent future psychosexual problems and another birth with the disorder. Cancer is a genomic disorder characterized by genomic instability (due to a defect in DNA repair mechanism), uncontrolled replication (due to lack of response to inhibitory factors/loss of contact inhibition), neo-angiogenesis, invasion and metastasis. All cancer cases should be investigated for genomic markers (both hereditary and somatic) for precise diagnosis, prognosis, and genetic counseling. In this review, we will try to evaluate the role of genetics and genomics in the above-mentioned reproductive disorders, along with genetic & genomic techniques used and reproductive counseling in addition to our experiences.

Altered gene expression in excitatory neurons is associated with Alzheimer's disease and its higher incidence in women.

Alzheimer's disease (AD) is a neurodegenerative disorder involving interactions between different cell types in the brain. Previous single-cell and bulk expression Alzheimer's studies have reported conflicting findings about the key cell types and cellular pathways whose expression is primarily altered in this disease. We re-analyzed these data in a uniform, coherent manner aiming to resolve and extend past findings. Our analysis sheds light on the observation that females have higher AD incidence than males. We re-analyzed three single-cell transcriptomics datasets. We used the software Model-based Analysis of Single-cell Transcriptomics (MAST) to seek differentially expressed genes comparing AD cases to matched controls for both sexes together and each sex separately. We used the GOrilla software to search for enriched pathways among the differentially expressed genes. Motivated by the male/female difference in incidence, we studied genes on the X-chromosome, focusing on genes in the pseudoautosomal region (PAR) and on genes that are heterogeneous across individuals or tissues for X-inactivation. We validated findings by analyzing bulk AD datasets from the cortex in the Gene Expression Omnibus. Our results resolve a contradiction in the literature, showing that by comparing AD patients to unaffected controls, excitatory neurons have more differentially expressed genes than do other cell types. Synaptic transmission and related pathways are altered in a sex-specific analysis of excitatory neurons. PAR genes and X-chromosome heterogeneous genes, including, for example, BEX1 and ELK1, may contribute to the difference in sex incidence of Alzheimer's disease. GRIN1, stood out as an overexpressed autosomal gene in cases versus controls in all three single-cell datasets and as a functional candidate gene contributing to pathways upregulated in cases. Taken together, these results point to a potential linkage between two longstanding questions concerning AD pathogenesis, involving which cell type is the most important and why females have a higher incidence than males. By reanalyzing three, published, single-cell RNAseq datasets, we resolved a contradiction in the literature and showed that when comparing AD patients to unaffected controls, excitatory neurons have more differentially expressed genes than do other cell types.Further analysis of the published single-cell datasets showed that synaptic transmission and related pathways are altered in a sex-specific analysis of excitatory neurons.Combining analysis of single-cell datasets and publicly available bulk transcriptomics datasets revealed that X-chromosome genes, such as BEX1, ELK1, and USP11, whose X-inactivation status is heterogeneous may contribute to the higher incidence in females of Alzheimer's disease.

Chromosome-level genome and recombination map of the male buffalo.

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. 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. The male genome and sperm sequencing will facilitate the understanding of the buffalo genomic evolution and functional research.

Deviations from Mendelian Inheritance on Bovine X-Chromosome Revealing Recombination, Sex-of-Offspring Effects and Fertility-Related Candidate Genes.

Transmission ratio distortion (TRD), or significant deviations from Mendelian inheritance, is a well-studied phenomenon on autosomal chromosomes, but has not yet received attention on sex chromosomes. TRD was analyzed on 3832 heterosomal single nucleotide polymorphisms (SNPs) and 400 pseudoautosomal SNPs spanning the length of the X-chromosome using 436,651 genotyped Holstein cattle. On the pseudoautosomal region, an opposite sire-TRD pattern between male and female offspring was identified for 149 SNPs. This finding revealed unique SNPs linked to a specific-sex (Y- or X-) chromosome and describes the accumulation of recombination events across the pseudoautosomal region. On the heterosomal region, 13 SNPs and 69 haplotype windows were identified with dam-TRD. Functional analyses for TRD regions highlighted relevant biological functions responsible to regulate spermatogenesis, development of Sertoli cells, homeostasis of endometrium tissue and embryonic development. This study uncovered the prevalence of different TRD patterns across both heterosomal and pseudoautosomal regions of the X-chromosome and revealed functional candidate genes for bovine reproduction.

A multiplex PCR-based sensitive and specific method for detecting Y chromosome material in patients with Turner syndrome

To develop a multiplex PCR method for a rapid detection of Y chromosome-specific sequences in patients with Turner syndrome. Nine genes were selected from various regions of the Y chromosome for designing the primers, which included SRY, TBL1Y, TSPY on the short arm of the Y chromosome, DDX3Y, HSFY1, RPS4Y2 and CDY1 on the long arm of Y chromosome and SHOX in the short arm and SPRY3 in the long arm of the pseudoautosomal region (PAR) of X and Y chromosomes. A multiplex PCR method for the nine genes in Y chromosome was established and optimized. The sensitivity was tested by using different amounts of genomic DNA. A total of 36 patients with Turner syndrome and a patient with male dwarfism with karyotype of 46, X, +mar were examined by the multiplex PCR method for the existence of materials from the Y chromosome. The optimization results of the multiplex PCR reaction system (50 μL) showed that when the final concentration of upstream and downstream of each pair of primers was 0.1 μM, the multiplex PCR reaction of the 9 pairs of primers clearly amplified the target with the expected band size, and there was no non-specific amplification. The bands were clearly visible when the amount of genomic DNA in the multiple PCR reaction system was as low as 1 ng. By using the method, we have examined the 36 patients with Turner syndrome. One patient with Turner syndrome with karyotype of 45,X[40]/47XYY[21] amplified specific seven genes on Y chromosome, 35 patients with Turner syndrome amplified only two target genes SHOX and SPRY3, but not the other seven specific genes on the Y chromosome, which was in keeping with the clinical manifestations of such patients. This study established a multiplex PCR reaction system with nine genes, which can quickly and accurately screen Y chromosome materials in patients with Turner syndrome. It has the advantages of low cost, simple operation, high specificity and rapid turn-around time, and can be used to detect Turner syndrome patients with Y chromosome material in time. The method has provided a diagnostic basis for preventive gonad resection to prevent malignant gonadal tumors.

Interrogating the Human Diplome: Computational Methods, Emerging Applications, and Challenges.

Human DNA sequencing protocols have revolutionized human biology, biomedical science, and clinical practice, but still have very important limitations. One limitation is that most protocols do not separate or assemble (i.e., "phase") the nucleotide content of each of the maternally and paternally derived chromosomal homologs making up the 22 autosomal pairs and the chromosomal pair making up the pseudo-autosomal region of the sex chromosomes. This has led to a dearth of studies and a consequent underappreciation of many phenomena of fundamental importance to basic and clinical genomic science. We discuss a few protocols for obtaining phase information as well as their limitations, including those that could be used in tumor phasing settings. We then describe a number of biological and clinical phenomena that require phase information. These include phenomena that require precise knowledge of the nucleotide sequence in a chromosomal segment from germline or somatic cells, such as DNA binding events, and insight into unique cis vs. trans-acting functionally impactful variant combinations-for example, variants implicated in a phenotype governed by compound heterozygosity. In addition, we also comment on the need for reliable and consensus-based diploid-context computational workflows for variant identification as well as the need for laboratory-based functional verification strategies for validating cis vs. trans effects of variant combinations. We also briefly describe available resources, example studies, as well as areas of further research, and ultimately argue that the science behind the study of human diploidy, referred to as "diplomics," which will be enabled by nucleotide-level resolution of phased genomes, is a logical next step in the analysis of human genome biology.

Evolutionary dynamics of pseudoautosomal region 1 in humans and great apes

BackgroundThe pseudoautosomal region 1 (PAR1) is a 2.7 Mb telomeric region of human sex chromosomes. PAR1 has a crucial role in ensuring proper segregation of sex chromosomes during male meiosis, exposing it to extreme recombination and mutation processes. We investigate PAR1 evolution using population genomic datasets of extant humans, eight populations of great apes, and two archaic human genome sequences.ResultsWe find that PAR1 is fast evolving and closer to evolutionary nucleotide equilibrium than autosomal telomeres. We detect a difference between substitution patterns and extant diversity in PAR1, mainly driven by the conflict between strong mutation and recombination-associated fixation bias at CpG sites. We detect excess C-to-G mutations in PAR1 of all great apes, specific to the mutagenic effect of male recombination. Despite recent evidence for Y chromosome introgression from humans into Neanderthals, we find that the Neanderthal PAR1 retained similarity to the Denisovan sequence. We find differences between substitution spectra of these archaics suggesting rapid evolution of PAR1 in recent hominin history. Frequency analysis of alleles segregating in females and males provided no evidence for recent sexual antagonism in this region. We study repeat content and double-strand break hotspot regions in PAR1 and find that they may play roles in ensuring the obligate X-Y recombination event during male meiosis.ConclusionsOur study provides an unprecedented quantification of population genetic forces governing PAR1 biology across extant and extinct hominids. PAR1 evolutionary dynamics are predominantly governed by recombination processes with a strong impact on mutation patterns across all species.

Monosomy X in isogenic human iPSC-derived trophoblast model impacts expression modules preserved in human placenta

Mammalian sex chromosomes encode homologous X/Y gene pairs that were retained on the Y chromosome in males and escape X chromosome inactivation (XCI) in females. Inferred to reflect X/Y pair dosage sensitivity, monosomy X is a leading cause of miscarriage in humans with near full penetrance. This phenotype is shared with many other mammals but not the mouse, which offers sophisticated genetic tools to generate sex chromosomal aneuploidy but also tolerates its developmental impact. To address this critical gap, we generated X-monosomic human induced pluripotent stem cells (hiPSCs) alongside otherwise isogenic euploid controls from male and female mosaic samples. Phased genomic variants in these hiPSC panels enable systematic investigation of X/Y dosage-sensitive features using invitro models of human development. Here, we demonstrate the utility of these validated hiPSC lines to test how X/Y-linked gene dosage impacts a widely used model for human syncytiotrophoblast development. While these isogenic panels trigger a GATA2/3- and TFAP2A/C-driven trophoblast gene circuit irrespective of karyotype, differential expression implicates monosomy X in altered levels of placental genes and in secretion of placental growth factor (PlGF) and human chorionic gonadotropin (hCG). Remarkably, weighted gene coexpression network modules that significantly reflect these changes are also preserved in first-trimester chorionic villi and term placenta. Our results suggest monosomy X may skew trophoblast cell type composition and function, and that the combined haploinsufficiency of the pseudoautosomal region likely plays a key role in these changes.

Genetic background of anti-Xga producers in Japanese blood donors.

The Xg blood group is composed of two antigens, Xga (XG1) and CD99 (XG2 and MIC2). The XG and CD99 are homologous genes located on pseudoautosomal region 1 of the X and Y chromosomes. The expressions of Xga and CD99 are co-regulated by a single nucleotide polymorphism (rs311103) in the GATA-1 binding region. Another mechanism of the Xg(a-) phenotype is the genomic deletion of approximately 114 kb, including the XG gene. Anti-Xga seems to be naturally occurring by detection in males who have never been transfused. In this study, we identified 23 anti-Xga producers among 580,115 donors (0.004%). Additional 12 anti-Xga producers were also identified from a separate cohort. All 35 anti-Xga producers were male. Genomic DNA was obtained from 34 of 35 producers, and all 34 producers were confirmed to carry the XG-gene-deficient allele (XGdel). The breakpoints of all 34 producers were identical. The XGdel was also identified in 12 non-producers of anti-Xga among 860 donors who have no antibodies against RBCs, and the breakpoints were also identical with the anti-Xga producers. Our results will serve as the basis for a more complete understanding of Xg blood group polymorphisms.