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Journal of Translational Medicine Nov 2022Previous studies on European (EUR) samples have obtained inconsistent results regarding the genetic correlation between type 2 diabetes mellitus (T2DM) and Schizophrenia...
BACKGROUND
Previous studies on European (EUR) samples have obtained inconsistent results regarding the genetic correlation between type 2 diabetes mellitus (T2DM) and Schizophrenia (SCZ). A large-scale trans-ethnic genetic analysis may provide additional evidence with enhanced power.
OBJECTIVE
We aimed to explore the genetic basis for both T2DM and SCZ based on large-scale genetic analyses of genome-wide association study (GWAS) data from both East Asian (EAS) and EUR subjects.
METHODS
A range of complementary approaches were employed to cross-validate the genetic correlation between T2DM and SCZ at the whole genome, autosomes (linkage disequilibrium score regression, LDSC), loci (Heritability Estimation from Summary Statistics, HESS), and causal variants (MiXeR and Mendelian randomization, MR) levels. Then, genome-wide and transcriptome-wide cross-trait/ethnic meta-analyses were performed separately to explore the effective shared organs, cells and molecular pathways.
RESULTS
A weak genome-wide negative genetic correlation between SCZ and T2DM was found for the EUR (r = - 0.098, P = 0.009) and EAS (r =- 0.053 and P = 0.032) populations, which showed no significant difference between the EUR and EAS populations (P = 0.22). After Bonferroni correction, the r remained significant only in the EUR population. Similar results were obtained from analyses at the levels of autosomes, loci and causal variants. 25 independent variants were firstly identified as being responsible for both SCZ and T2DM. The variants associated with the two disorders were significantly correlated to the gene expression profiles in the brain (P = 1.1E-9) and pituitary gland (P = 1.9E-6). Then, 61 protein-coding and non-coding genes were identified as effective genes in the pituitary gland (P < 9.23E-6) and were enriched in metabolic pathways related to glutathione mediated arsenate detoxification and to D-myo-inositol-trisphosphate.
CONCLUSION
Here, we show that a negative genetic correlation exists between SCZ and T2DM at the whole genome, autosome, locus and causal variant levels. We identify pituitary gland as a common effective organ for both diseases, in which non-protein-coding effective genes, such as lncRNAs, may be responsible for the negative genetic correlation. This highlights the importance of molecular metabolism and neuroendocrine modulation in the pituitary gland, which may be responsible for the initiation of T2DM in SCZ patients.
Topics: Humans; Schizophrenia; Genome-Wide Association Study; Diabetes Mellitus, Type 2; Ethnicity; Pituitary Gland; Polymorphism, Single Nucleotide; Genetic Predisposition to Disease
PubMed: 36329495
DOI: 10.1186/s12967-022-03704-0 -
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 -
Clinical Epigenetics May 2022Sex differences are known to play a role in disease aetiology, progression and outcome. Previous studies have revealed autosomal epigenetic differences between males and...
BACKGROUND
Sex differences are known to play a role in disease aetiology, progression and outcome. Previous studies have revealed autosomal epigenetic differences between males and females in some tissues, including differences in DNA methylation patterns. Here, we report for the first time an analysis of autosomal sex differences in DNAme using the Illumina EPIC array in human whole blood by performing a discovery (n = 1171) and validation (n = 2471) analysis.
RESULTS
We identified and validated 396 sex-associated differentially methylated CpG sites (saDMPs) with the majority found to be female-biased CpGs (74%). These saDMP's are enriched in CpG islands and CpG shores and located preferentially at 5'UTRs, 3'UTRs and enhancers. Additionally, we identified 266 significant sex-associated differentially methylated regions overlapping genes, which have previously been shown to exhibit epigenetic sex differences, and novel genes. Transcription factor binding site enrichment revealed enrichment of transcription factors related to critical developmental processes and sex determination such as SRY and ESR1.
CONCLUSION
Our study reports a reliable catalogue of sex-associated CpG sites and elucidates several characteristics of these sites using large-scale discovery and validation data sets. This resource will benefit future studies aiming to investigate sex specific epigenetic signatures and further our understanding of the role of DNA methylation in sex differences in human whole blood.
Topics: CpG Islands; DNA Methylation; Epigenesis, Genetic; Epigenomics; Female; Humans; Male; Sex Characteristics
PubMed: 35568878
DOI: 10.1186/s13148-022-01279-7 -
Nature Ecology & Evolution Dec 2021Sex chromosomes are susceptible to the evolution of selfish meiotic drive elements that bias transmission and distort progeny sex ratios. Conflict between such sex-ratio...
Sex chromosomes are susceptible to the evolution of selfish meiotic drive elements that bias transmission and distort progeny sex ratios. Conflict between such sex-ratio drivers and the rest of the genome can trigger evolutionary arms races resulting in genetically suppressed 'cryptic' drive systems. The Winters cryptic sex-ratio drive system of Drosophila simulans comprises a driver, Distorter on the X (Dox) and an autosomal suppressor, Not much yang, a retroduplicate of Dox that suppresses via production of endogenous small interfering RNAs (esiRNAs). Here we report that over 22 Dox-like (Dxl) sequences originated, amplified and diversified over the ~250,000-year history of the three closely related species, D. simulans, D. mauritiana and D. sechellia. The Dxl sequences encode a rapidly evolving family of protamines. Dxl copy numbers amplified by ectopic exchange among euchromatic islands of satellite DNAs on the X chromosome and separately spawned four esiRNA-producing suppressors on the autosomes. Our results reveal the genomic consequences of evolutionary arms races and highlight complex interactions among different classes of selfish DNAs.
Topics: Animals; DNA, Satellite; Drosophila; Evolution, Molecular; Sex Ratio; X Chromosome
PubMed: 34489561
DOI: 10.1038/s41559-021-01543-8 -
Molecular Cytogenetics 2017Reciprocal Y autosome translocations are rare but frequently associated with male infertility. We report on the meiotic outcome in embryos fathered by two males with the...
BACKGROUND
Reciprocal Y autosome translocations are rare but frequently associated with male infertility. We report on the meiotic outcome in embryos fathered by two males with the karyotypes 46,X,t(Y;4)(q12;p15.32) and 46,X,t(Y;16)(q12;q13). The two couples underwent preimplantation genetic diagnosis (PGD) enabling determination of the segregation types that were compatible with fertilization and preimplantation embryo development. Both PGD and follow up analysis were carried out via fluorescence in situ hybridization (FISH) or array comparative genomic hybridization (aCGH) allowing the meiotic segregation types to be determined in a total of 27 embryos.
RESULTS
Interestingly, it was seen that the number of female embryos resulting from alternate segregation with the chromosome combination of X and the autosome from the carrier gamete differed from the corresponding balanced males with derivative Y and the derivative autosome by a ratio of 7:1 in each case ( = 0.003) while from the adjacent-1 mode of segregation, the unbalanced male embryos with the combination of der Y and the autosome were seen in all embryos from couple A and in couple B with the exception of one embryo only that had the other chromosome combination of X and derivative autosome ( = 0.011). In both cases the deficit groups have in common the der autosome chromosome that includes the segment Yq12 to qter.
CONCLUSION
The most likely explanation may be that this chromosome is associated with the X chromosome at PAR2 (pseudoautosomal region 2) in the sex-body leading to inactivation of genes on the autosomal segment that are required for the meiotic process and that this has led to degeneration of this class of spermatocytes during meiosis.
PubMed: 28184250
DOI: 10.1186/s13039-017-0303-y -
Animals : An Open Access Journal From... May 2022The regulation of gene expression is a complex process involving organism function and phenotypic diversity, and is caused by cis- and trans- regulation. While prior...
The regulation of gene expression is a complex process involving organism function and phenotypic diversity, and is caused by cis- and trans- regulation. While prior studies identified the regulatory pattern of the autosome rewiring in hybrids, the role of gene regulation in W sex chromosomes is not clear due to their degradation and sex-limit expression. Here, we developed reciprocal crosses of two chicken breeds, White Leghorn and Cornish Game, which exhibited broad differences in gender-related traits, and assessed the expression of the genes on the W chromosome to disentangle the contribution of cis- and trans-factors to expression divergence. We found that female-specific selection does not have a significant effect on W chromosome gene-expression patterns. For different tissues, there were most parental divergence expression genes in muscle, and also more heterosis compared with two other tissues. Notably, a broader pattern of trans regulation in the W chromosome was observed, which is consistent with autosomes. Taken together, this work describes the regulatory divergence of W-linked genes between two contrasting breeds and indicates sex chromosomes have a unique regulation and expression mechanism.
PubMed: 35565645
DOI: 10.3390/ani12091218 -
Proceedings. Biological Sciences Aug 2020Females and males may face different selection pressures. Accordingly, alleles that confer a benefit for one sex often incur a cost for the other. Classic evolutionary...
Females and males may face different selection pressures. Accordingly, alleles that confer a benefit for one sex often incur a cost for the other. Classic evolutionary theory holds that the X chromosome, whose sex-biased transmission sees it spending more time in females, should value females more than males, whereas autosomes, whose transmission is unbiased, should value both sexes equally. However, recent mathematical and empirical studies indicate that male-beneficial alleles may be more favoured by the X chromosome than by autosomes. Here we develop a gene's-eye-view approach that reconciles the classic view with these recent discordant results, by separating a gene's valuation of female versus male fitness from its ability to induce fitness effects in either sex. We use this framework to generate new comparative predictions for sexually antagonistic evolution in relation to dosage compensation, sex-specific mortality and assortative mating, revealing how molecular mechanisms, ecology and demography drive variation in masculinization versus feminization across the genome.
Topics: Alleles; Animals; Biological Evolution; Dosage Compensation, Genetic; Female; Male; Reproduction; Selection, Genetic; Sex; Sex Characteristics; X Chromosome
PubMed: 32781951
DOI: 10.1098/rspb.2020.1633 -
PLoS Genetics Aug 2023Evidence of interbreeding between archaic hominins and humans comes from methods that infer the locations of segments of archaic haplotypes, or 'archaic coverage' using...
Evidence of interbreeding between archaic hominins and humans comes from methods that infer the locations of segments of archaic haplotypes, or 'archaic coverage' using the genomes of people living today. As more estimates of archaic coverage have emerged, it has become clear that most of this coverage is found on the autosomes- very little is retained on chromosome X. Here, we summarize published estimates of archaic coverage on autosomes and chromosome X from extant human samples. We find on average 7 times more archaic coverage on autosomes than chromosome X, and identify broad continental patterns in this ratio: greatest in European samples, and least in South Asian samples. We also perform extensive simulation studies to investigate how the amount of archaic coverage, lengths of coverage, and rates of purging of archaic coverage are affected by sex-bias caused by an unequal sex ratio within the archaic introgressors. Our results generally confirm that, with increasing male sex-bias, less archaic coverage is retained on chromosome X. Ours is the first study to explicitly model such sex-bias and its potential role in creating the dearth of archaic coverage on chromosome X.
Topics: Animals; Humans; Male; Asian People; Genome; Genome, Human; Hominidae; Neanderthals; X Chromosome; Sex Factors; Haplotypes; Genetic Introgression; Chromosomes, Human; Female; South Asian People; European People
PubMed: 37578977
DOI: 10.1371/journal.pgen.1010399 -
NPJ Genomic Medicine Nov 2023Birth defect is a global threat to the public health systems. Mitigating neonatal anomalies is hampered by elusive molecular mechanisms of pathogenic mutations and poor...
Birth defect is a global threat to the public health systems. Mitigating neonatal anomalies is hampered by elusive molecular mechanisms of pathogenic mutations and poor subsequent translation into preventative measures. Applying appropriate strategies in China to promote reproductive health is particularly challenging, as the Chinese population compromises complex genomic diversity due to the inclusion of many ethnic groups with distinct genetic backgrounds. To investigate and evaluate the feasibility of implementing a pan-ethnic screening strategy, and guide future reproductive counselling, high-quality variants associated with autosome recessive (AR) diseases derived from the largest publicly available cohort of the Chinese population were re-analysed using a bottom-up approach. The analyses of gene carrier rates (GCRs) across distinct ethnic groups revealed that substantial heterogeneity existed potentially due to diverse evolutionary selection. The sampling population, sequencing coverage and underlying population structure contributed to the differential variants observed between ChinaMAP and the East Asian group in gnomAD. Beyond characteristics of GCR, potential druggable targets were additionally explored according to genomic features and functional roles of investigated genes, demonstrating that phase separation could be a therapeutic target for autosomal recessive diseases. A further examination of estimated GCR across ethnic groups indicated that most genes shared by at least two populations could be utilised to direct the design of a pan-ethnic screening application once sequencing and interpreting costs become negligible. To this end, a list of autosomal recessive disease genes is proposed based on the prioritised rank of GCR to formulate a tiered screening strategy.
PubMed: 37985665
DOI: 10.1038/s41525-023-00383-8 -
Molecular Biology and Evolution Aug 2023Though the phylogenetic signal of loci on sex chromosomes can differ from those on autosomes, chromosomal-level genome assemblies for nonvertebrates are still relatively...
Though the phylogenetic signal of loci on sex chromosomes can differ from those on autosomes, chromosomal-level genome assemblies for nonvertebrates are still relatively scarce and conservation of chromosomal gene content across deep phylogenetic scales has therefore remained largely unexplored. We here assemble a uniquely large and diverse set of samples (17 anchored hybrid enrichment, 24 RNA-seq, and 70 whole-genome sequencing samples of variable depth) for the medically important assassin bugs (Reduvioidea). We assess the performance of genes based on multiple features (e.g., nucleotide vs. amino acid, nuclear vs. mitochondrial, and autosomal vs. X chromosomal) and employ different methods (concatenation and coalescence analyses) to reconstruct the unresolved phylogeny of this diverse (∼7,000 spp.) and old (>180 Ma) group. Our results show that genes on the X chromosome are more likely to have discordant phylogenies than those on autosomes. We find that the X chromosome conflict is driven by high gene substitution rates that impact the accuracy of phylogenetic inference. However, gene tree clustering showed strong conflict even after discounting variable third codon positions. Alternative topologies were not particularly enriched for sex chromosome loci, but spread across the genome. We conclude that binning genes to autosomal or sex chromosomes may result in a more accurate picture of the complex evolutionary history of a clade.
Topics: Animals; Phylogeny; Reduviidae; Biological Evolution; Genome; X Chromosome
PubMed: 37494292
DOI: 10.1093/molbev/msad168