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Scientific Reports Jul 2023The genetic architecture of the QT interval, defined as the period from onset of depolarisation to completion of repolarisation of the ventricular myocardium, is...
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 K channels restoring the systolic duration, whereas overexpression of SLC25A6 shortened QTc, which was normalized by pharmacological activation of K channels. Our study demonstrate an inverse relationship between SLC25A6 dosage and QTc interval indicating that SLC25A6 contributes to QT interval variation.
Topics: Animals; Female; Humans; Male; Adenosine Triphosphate; Electrocardiography; Klinefelter Syndrome; Long QT Syndrome; Turner Syndrome; X Chromosome; Zebrafish; Adenine Nucleotide Translocator 3
PubMed: 37495650
DOI: 10.1038/s41598-023-38867-3 -
Frontiers in Oncology 2023Acute lymphoblastic leukemia (ALL) patients with a gain of chromosome 21, intrachromosomal amplification of chromosome 21 (iAMP21), or Down syndrome (DS), have increased...
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, . 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 (), is a common feature in ~60% of DS-ALL and ~40% of iAMP21 patients, suggesting a link between chromosome 21 and . In an Australian cohort of pediatric B-ALL patients with ( = 38), eight patients harbored gain of chromosome 21 (+21), and two patients had iAMP21, resulting in a significantly increased expression. An inducible CRISPR/Cas9 system was used to model and investigate its cooperation with . This model was then used to validate as an influencing factor for development. Using Cas9 to cleave the DNA at the pseudoautosomal region without directed repair, cells expressing favored repair, resulting in generation, compared with cells without . CRISPR/Cas9 cells expressing exhibit increased proliferation, thymic stromal lymphopoietin receptor (TSLPR) expression, and JAK/STAT signaling, consistent with cells from patients with . Our patient expression data and unique CRISPR/Cas9 modeling, when taken together, suggest that increases the propensity for development. This has important implications for patients with DS, +21, or iAMP21.
PubMed: 37483494
DOI: 10.3389/fonc.2023.1177871 -
PLoS Genetics Jun 2023Sex 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....
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.
Topics: Male; Animals; Female; Struthioniformes; Evolution, Molecular; Recombination, Genetic; Sex Chromosomes; Biological Evolution; Mammals
PubMed: 37390104
DOI: 10.1371/journal.pgen.1010801 -
BMC Biology May 2023The Western mosquitofish, Gambusia affinis, is a model for sex chromosome organization and evolution of female heterogamety. We previously identified a G. affinis...
BACKGROUND
The Western mosquitofish, Gambusia affinis, is a model for sex chromosome organization and evolution of female heterogamety. We previously identified a G. affinis female-specific marker, orthologous to the aminomethyl transferase (amt) gene of the related platyfish (Xiphophorus maculatus). Here, we have analyzed the structure and differentiation of the G. affinis W-chromosome, using a cytogenomics and bioinformatics approach.
RESULTS
The long arm of the G. affinis W-chromosome (Wq) is highly enriched in dispersed repetitive sequences, but neither heterochromatic nor epigenetically silenced by hypermethylation. In line with this, Wq sequences are highly transcribed, including an active nucleolus organizing region (NOR). Female-specific SNPs and evolutionary young transposable elements were highly enriched and dispersed along the W-chromosome long arm, suggesting constrained recombination. Wq copy number expanded elements also include female-specific transcribed sequences from the amt locus with homology to TE. Collectively, the G. affinis W-chromosome is actively differentiating by sex-specific copy number expansion of transcribed TE-related elements, but not (yet) by extensive sequence divergence or gene decay.
CONCLUSIONS
The G. affinis W-chromosome exhibits characteristic genomic properties of an evolutionary young sex chromosome. Strikingly, the observed sex-specific changes in the genomic landscape are confined to the W long arm, which is separated from the rest of the W-chromosome by a neocentromere acquired during sex chromosome evolution and may thus have become functionally insulated. In contrast, W short arm sequences were apparently shielded from repeat-driven differentiation, retained Z-chromosome like genomic features, and may have preserved pseudo-autosomal properties.
Topics: Male; Female; Animals; DNA Transposable Elements; Polymorphism, Single Nucleotide; Sex Chromosomes; Genomics; Cyprinodontiformes; Evolution, Molecular
PubMed: 37189152
DOI: 10.1186/s12915-023-01607-0 -
BioRxiv : the Preprint Server For... Jul 2023Meiotic DNA double-strand breaks (DSBs) initiate homologous recombination and are crucial for ensuring proper chromosome segregation. In mice, ANKRD31 recently emerged...
Meiotic DNA double-strand breaks (DSBs) initiate homologous recombination and are crucial for ensuring proper chromosome segregation. In mice, ANKRD31 recently emerged as a regulator of DSB timing, number, and location, with a particularly important role in targeting DSBs to the pseudoautosomal regions (PARs) of sex chromosomes. ANKRD31 interacts with multiple proteins, including the conserved and essential DSB-promoting factor REC114, so it was hypothesized to be a modular scaffold that "anchors" other proteins together and to meiotic chromosomes. To determine if and why the REC114 interaction is important for ANKRD31 function, we generated mice with mutations that either reduced (missense mutation) or eliminated (C-terminal truncation) the ANKRD31-REC114 interaction without diminishing contacts with other known partners. A complete lack of the ANKRD31-REC114 interaction mimicked an null, with delayed DSB formation and recombination, defects in DSB repair, and altered DSB locations including failure to target DSBs to the PARs. In contrast, when the ANKRD31-REC114 interaction was substantially but not completely disrupted, spermatocytes again showed delayed DSB formation globally, but recombination and repair were hardly affected and DSB locations were similar to control mice. The missense allele showed a dosage effect, wherein combining it with the null or C-terminal truncation allele resulted in intermediate phenotypes for DSB formation, recombination, and DSB locations. Our results show that ANKRD31 function is critically dependent on its interaction with REC114, and that defects in ANKRD31 activity correlate with the severity of the disruption of the interaction.
PubMed: 37162821
DOI: 10.1101/2023.04.27.538541 -
Frontiers in Cell and Developmental... 2023During the pachytene stage in mammalian meiosis, the X and Y chromosomes remain largely unsynapsed outside the pseudoautosomal region, while autosomes are fully... (Review)
Review
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.
PubMed: 37123420
DOI: 10.3389/fcell.2023.1165745 -
Endocrine Connections May 2023The transcriptional landscape of Klinefelter syndromeduring early embryogenesis remains elusive. This study aimed to evaluate the impact of X chromosome overdosage in...
OBJECTIVE
The transcriptional landscape of Klinefelter syndromeduring early embryogenesis remains elusive. This study aimed to evaluate the impact of X chromosome overdosage in 47,XXY males induced pluripotent stem cells (iPSCs) obtained from patients with different genomic backgrounds and ethnicities.
DESIGN AND METHOD
We derived and characterized 15 iPSC lines from four Saudi 47,XXY KS patients and one Saudi 46,XY male. We performed a comparative transcriptional analysis using the Saudi KS-iPSCs and a cohort of European and North American KS-iPSCs.
RESULTS
We identified a panel of X-linked and autosomal genes commonly dysregulated in Saudi and European/North American KS-iPSCs vs 46,XY controls. Our findings demonstrate that seven PAR1 and nine non-PAR escape genes are consistently dysregulated and mostly display comparable transcriptional levels in both groups. Finally, we focused on genes commonly dysregulated in both iPSC cohorts and identified several gene-ontology categories highly relevant to KS physiopathology, including aberrant cardiac muscle contractility, skeletal muscle defects, abnormal synaptic transmission, and behavioral alterations.
CONCLUSIONS
Our results indicate that a transcriptomic signature of X chromosome overdosage in KS is potentially attributable to a subset of X-linked genes sensitive to sex chromosome dosage and escaping X inactivation, regardless of the geographical area of origin, ethnicity, and genetic makeup.
PubMed: 36971776
DOI: 10.1530/EC-22-0515 -
Cellular and Molecular Life Sciences :... Mar 2023In 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...
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.
Topics: Animals; Male; Lysine; RNA-Binding Protein FUS; Histone-Lysine N-Methyltransferase; Homologous Recombination; DNA; Meiosis; Mammals
PubMed: 36967403
DOI: 10.1007/s00018-023-04744-5 -
Alzheimer's & Dementia (New York, N. Y.) 2023Alzheimer's disease (AD) is a neurodegenerative disorder involving interactions between different cell types in the brain. Previous single-cell and bulk expression...
INTRODUCTION
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.
METHODS
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.
RESULTS
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, , may contribute to the difference in sex incidence of Alzheimer's disease. , 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.
DISCUSSION
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.
HIGHLIGHTS
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 , , , whose X-inactivation status is heterogeneous may contribute to the higher incidence in females of Alzheimer's disease.
PubMed: 36873924
DOI: 10.1002/trc2.12373 -
Genes Feb 2023The 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...
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.
Topics: Animals; Humans; Chickens; Isoantigens; Genome-Wide Association Study; Phylogeny; DNA; Alleles; 12E7 Antigen
PubMed: 36833329
DOI: 10.3390/genes14020402