Autosomal Gene Research Articles

Reconciling theories of dominance with the relative rates of adaptive substitution on sex chromosomes and autosomes.

The dominance of beneficial mutations is a key evolutionary parameter affecting the rate and genetic basis of adaptation, yet it is notoriously difficult to estimate. A leading method to infer it is to compare the relative rates of adaptive substitution for X-linked and autosomal genes, which-according to a classic model by Charlesworth et al. (1987)-is a simple function of the dominance of new beneficial mutations. Recent evidence that rates of adaptive substitution are faster for X-linked genes implies, accordingly, that beneficial mutations are usually recessive. However, this conclusion is incompatible with leading theories of dominance, which predict that beneficial mutations tend to be dominant or overdominant with respect to fitness. To address this incompatibility, we use Fisher's geometric model to predict the distribution of fitness effects of new mutations and the relative rates of positively selected substitution on the X and autosomes. Previous predictions of faster-X theory emerge as a special case of our model in which the phenotypic effects of mutations are small relative to the distance to the phenotypic optimum. But as mutational effects become large relative to the optimum, we observe an elevated tempo of positively selected substitutions on the X relative to the autosomes across a broader range of dominance conditions, including those predicted by theories of dominance. Our results imply that, contrary to previous models, dominant and overdominant beneficial mutations can plausibly generate patterns of faster-X adaptation. We discuss resulting implications for genomic studies of adaptation and inferences of dominance.

Increased evolutionary rate in the Z-chromosome of sympatric and allopatric species of Morpho butterflies.

Divergent evolution of genomes among closely related species is shaped by both neutral processes and ecological forces, such as local adaptation and reinforcement. These factors can drive accelerated evolution of sex chromosomes relative to autosomes. Comparative genomic analyses between allopatric and sympatric species with overlapping or divergent ecological niches offer insights into reinforcement and ecological specialization on genome evolution. In the butterfly genus Morpho, several species coexist in sympatry, with specialization across forest strata and temporal niches. We analyzed the genomes of eight Morpho species, along with previously published genomes of three others, to compare chromosomal rearrangements and signs of positive selection in the Z chromosome vs autosomes. We found extensive chromosomal rearrangements in Z chromosome, particularly in sympatric species with similar ecological niches, suggesting a role for inversions in restricting gene flow at a postzygotic level. Z-linked genes also exhibited significantly higher dN/dS ratios than autosomal genes across the genus, with pronounced differences in closely related species living in sympatry. Additionally, we examined the evolution of eight circadian clock genes, detecting positive selection in Period, located on the Z chromosome. Our findings suggest that the Z chromosome evolves more rapidly than autosomes, particularly among closely related species, raising questions about its role in pre- and post-zygotic isolation mechanisms.

Whole exome sequencing analysis of 167 men with primary infertility

BackgroundSpermatogenic failure is one of the leading causes of male infertility and its genetic etiology has not yet been fully understood.MethodsThe study screened a cohort of patients (n = 167) with primary male infertility in contrast to 210 normally fertile men using whole exome sequencing (WES). The expression analysis of the candidate genes based on public single cell sequencing data was performed using the R language Seurat package.ResultsNo pathogenic copy number variations (CNVs) related to male infertility were identified using the the GATK-gCNV tool. Accordingly, variants of 17 known causative (five X-linked and twelve autosomal) genes, including ACTRT1, ADAD2, AR, BCORL1, CFAP47, CFAP54, DNAH17, DNAH6, DNAH7, DNAH8, DNAH9, FSIP2, MSH4, SLC9C1, TDRD9, TTC21A, and WNK3, were identified in 23 patients. Variants of 12 candidate (seven X-linked and five autosomal) genes were identified, among which CHTF18, DDB1, DNAH12, FANCB, GALNT3, OPHN1, SCML2, UPF3A, and ZMYM3 had altered fertility and semen characteristics in previously described knockout mouse models, whereas MAGEC1,RBMXL3, and ZNF185 were recurrently detected in patients with male factor infertility. The human testis single cell-sequencing database reveals that CHTF18, DDB1 and MAGEC1 are preferentially expressed in spermatogonial stem cells. DNAH12 and GALNT3 are found primarily in spermatocytes and early spermatids. UPF3A is present at a high level throughout spermatogenesis except in elongating spermatids. The testicular expression profiles of these candidate genes underlie their potential roles in spermatogenesis and the pathogenesis of male infertility.ConclusionWES is an effective tool in the genetic diagnosis of primary male infertility. Our findings provide useful information on precise treatment, genetic counseling, and birth defect prevention for male factor infertility.

Management Targeted Genetic Evaluation of an Idiopathic Neuropathy Cohort Through ATTRv Amyloidosis Screening.

While the reported prevalence of polyneuropathies is 1%-3%, the incidence of hereditary transthyretin amyloidosis in the United States is estimated to be 1 in 100 000 individuals. Polyneuropathies are known to be difficult to treat and lead to significant morbidity. The aim of pain management is symptomatic treatment, with varying approaches to progression prevention being based on the causative pathophysiology.We assessed the prevalence of hereditary amyloid transthyretin variant (ATTRv) amyloidosis, a progressive autosomal dominant multisystem disease caused by the abnormal formation and extracellular deposition of transthyretin protein fibrils in various tissues, in an idiopathic polyneuropathy population by using genetic analysis. Individuals aged 18 and over with an established diagnosis of polyneuropathy, via electromyography testing that was deemed to be idiopathic, at a large, urban neurology clinic consented to an institutional review board-approved protocol for genetic testing. No further exclusions were made regarding age of onset, family history, axonal neuropathy subtype, comorbidities suggestive of ATTRv amyloidosis, etc. Clinical genetic testing was performed on 134 participants via an 81-gene panel associated with inherited neuromuscular disorders or targeted TTR gene sequencing with deletion and duplication analysis. Within our cohort, 38.06% had at least one reportable finding in one of 38 distinct genes, for a total of 76 reported alterations. Four individuals were identified as having a single pathogenic alteration in an autosomal recessive gene, consistent with carrier status for the 4 following disorders: congenital insensitivity to pain with anhidrosis (NTRK1), Charcot-Marie-Tooth disease type IIP (LRSAM1), Brown-Vialetto-Van Laere syndrome type II (SLC52A2), hereditary sensory and autonomic neuropathy type III (IKBKAP). One individual was found to have a variant of uncertain significance (VUS) (p.G103D) in the TTR gene. Precision medicine on the molecular level with genetic testing in the identification of specific neuropathies may provide clinicians with more detailed information for developing a more direct therapeutic and treatment modality for better-targeted management. Further investigation is needed to expand on the knowledge and understanding of the clinical relevance surrounding the alterations found in the genetic evaluation of idiopathic neuropathy.

Clinical and molecular findings in children with retinitis pigmentosa

ABSTRACT Purpose To study the clinical and genetic features of a cohort of RP children. Methods We identified 46 RP patients with pathogenic or likely pathogenic mutations among 96 patients with a clinical diagnosis of retinitis pigmentosa. All of the patients underwent comprehensive clinical examinations and genetic testing. A retrospective study was conducted on 46 children with retinitis pigmentosa. The genetic and clinical characteristics of children with different genotypes were analyzed. Results Among the 46 children, 13 inherited X-linked gene mutations, including 9 RPGR and 4 RP2 mutations. There were 10 cases of autosomal dominant genes and 23 cases of autosomal recessive genes. XLRP accounted for a larger proportion of children, as observed in previous studies on RP. We found that RPGR genes were the most commonly mutated genes in RP children. The most frequently mutated gene was RPGR (9.3%), followed by RP2 (4.2%) and RPE65 (4.2%). Forty-six patients had mutations in 21 different genes, 19 of which were novel mutations. Most children with XLRP have a high degree of myopia, poor vision, and severe clinical symptoms. Frameshift mutations were more common in XLRP, followed by nonsense mutations. The onset of XLRP is relatively serious since childhood. Most children with ADRP have relatively good visual acuity and mild clinical symptoms, and missense mutations are common. The clinical manifestations of ARRP in children are more severe than those of ADRP in children but milder than those of XLRP in children, and missense mutations are common. The manifestations of RPE65 mutations are also severe and appear early. Conclusions Our results revealed that XLRP gene mutations were more common in children than in adults, as observed in previous studies on RP. The proportion of RP children with ADRP is relatively small. The new findings in our study polished the spectrum of novel mutations and the proportions of different genotypes in pediatric patients. The onset of XLRP occurred earlier. The genes with a high incidence in children were all relatively severe gene types of RP. This comprehensive database may provide essential information regarding the initial stage of RP.

Bayesian Estimation of Allele-Specific Expression in the Presence of Phasing Uncertainty.

Allele-specific expression (ASE) analyses aim to detect imbalanced expression of maternal versus paternal copies of an autosomal gene. Such allelic imbalance can result from a variety of cis-acting causes, including disruptive mutations within one copy of a gene that impact the stability of transcripts, as well as regulatory variants outside the gene that impact transcription initiation. Current methods for ASE estimation suffer from a number of shortcomings, such as relying on only one variant within a gene, assuming perfect phasing information across multiple variants within a gene, or failing to account for alignment biases and possible genotyping errors. We developed BEASTIE, a Bayesian hierarchical model designed for precise ASE quantification at the gene level, based on given genotypes and RNA-Seq data. BEASTIE addresses the complexities of allelic mapping bias, genotyping error, and phasing errors by incorporating empirical phasing error rates derived from Genome-in-a-Bottle individual NA12878. BEASTIE surpasses existing methods in accuracy, especially in scenarios with high phasing errors. This improvement is critical for identifying rare genetic variants often obscured by such errors. Through rigorous validation on simulated data and application to real data from the 1000 Genomes Project, we establish the robustness of BEASTIE. These findings underscore the value of BEASTIE in revealing patterns of ASE across gene sets and pathways. The software is freely available from https://github.com/x811zou/BEASTIE . BEASTIE is available as Python source code and as a Docker image. Additional information is available online.

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 invitro studies of human sex chromosome aneuploidy showed that the Xi ("inactive" X) and Y chromosomes broadly modulate autosomal and Xa ("active" X) gene expression. We tested these findings invivo. Linear modeling of CD4+ Tcells and monocytes from individuals with one to three X chromosomes and zero to two Y chromosomes revealed 82 sex-chromosomal and 344 autosomal genes whose expression changed significantly with Xi and/or Y dosage invivo. Changes in sex-chromosomal expression were remarkably constant invivo and invitro; autosomal responses to Xi and/or Y dosage were largely cell-type specific (∼2.6-fold more variation than sex-chromosomal responses). Targets of the sex-chromosomal transcription factors ZFX and ZFY accounted for a significant fraction of these autosomal responses both invivo and invitro. We conclude that the human Xi and Y transcriptomes are surprisingly robust and stable, yet they modulate autosomal and Xa genes in a cell-type-specific fashion.

Exome sequencing reveals neurodevelopmental genes in simplex consanguineous Iranian families with syndromic autism

Background and objectiveAutosomal recessive genetic disorders pose significant health challenges in regions where consanguineous marriages are prevalent. The utilization of exome sequencing as a frequently employed methodology has enabled a clear delineation of diagnostic efficacy and mode of inheritance within multiplex consanguineous families. However, these aspects remain less elucidated within simplex families.MethodsIn this study involving 12 unrelated simplex Iranian families presenting syndromic autism, we conducted singleton exome sequencing. The identified genetic variants were validated using Sanger sequencing, and for the missense variants in FOXG1 and DMD, 3D protein structure modeling was carried out to substantiate their pathogenicity. To examine the expression patterns of the candidate genes in the fetal brain, adult brain, and muscle, RT-qPCR was employed.ResultsIn four families, we detected an autosomal dominant gene (FOXG1), an autosomal recessive gene (CHKB), and two X-linked autism genes (IQSEC2 and DMD), indicating diverse inheritance patterns. In the remaining eight families, we were unable to identify any disease-associated genes. As a result, our variant detection rate stood at 33.3% (4/12), surpassing rates reported in similar studies of smaller cohorts. Among the four newly identified coding variants, three are de novo (heterozygous variant p.Trp546Ter in IQSEC2, heterozygous variant p.Ala188Glu in FOXG1, and hemizygous variant p.Leu211Met in DMD), while the homozygous variant p.Glu128Ter in CHKB was inherited from both healthy heterozygous parents. 3D protein structure modeling was carried out for the missense variants in FOXG1 and DMD, which predicted steric hindrance and spatial inhibition, respectively, supporting the pathogenicity of these human mutants. Additionally, the nonsense variant in CHKB is anticipated to influence its dimerization – crucial for choline kinase function – and the nonsense variant in IQSEC2 is predicted to eliminate three functional domains. Consequently, these distinct variants found in four unrelated individuals with autism are likely indicative of loss-of-function mutations.ConclusionsIn our two syndromic autism families, we discovered variants in two muscular dystrophy genes, DMD and CHKB. Given that DMD and CHKB are recognized for their participation in the non-cognitive manifestations of muscular dystrophy, it indicates that some genes transcend the boundary of apparently unrelated clinical categories, thereby establishing a novel connection between ASD and muscular dystrophy. Our findings also shed light on the complex inheritance patterns observed in Iranian consanguineous simplex families and emphasize the connection between autism spectrum disorder and muscular dystrophy. This underscores a likely genetic convergence between neurodevelopmental and neuromuscular disorders.

A genetic basis for sex differences in Xp11 translocation renal cell carcinoma

Xp11 translocation renal cell carcinoma (tRCC) is a rare, female-predominant cancer driven by a fusion between the transcription factor binding to IGHM enhancer 3 (TFE3) gene on chromosome Xp11.2 and a partner gene on either chromosome X (chrX) or an autosome. It remains unknown what types of rearrangements underlie TFE3 fusions, whether fusions can arise from both the active (chrXa) and inactive X (chrXi) chromosomes, and whether TFE3 fusions from chrXi translocations account for the female predominance of tRCC. To address these questions, we performed haplotype-specific analyses of chrX rearrangements in tRCC whole genomes. We show that TFE3 fusions universally arise as reciprocal translocations and that oncogenic TFE3 fusions can arise from chrXi:autosomal translocations. Female-specific chrXi:autosomal translocations result in a 2:1 female-to-male ratio of TFE3 fusions involving autosomal partner genes and account for the female predominance of tRCC. Our results highlight how X chromosome genetics constrains somatic chrX alterations and underlies cancer sex differences.

Angiographic Characteristics in Mild Familial Exudative Vitreoretinopathy with Genetically Confirmed Autosomal Dominant Inheritance

PurposeTo determine the ultra-widefield fluorescein angiographic (UWFA) characteristics of patients with mild familial exudative vitreoretinopathy (FEVR) who had been confirmed to have pathogenic variants of the autosomal dominant (AD) genes of FEVR. DesignSingle center, observational case series. Subjects and ControlsThirty-seven patients with mild FEVR from 27 families who had pathogenic variants of the Norrin/β-catenin genes were studied. The controls consisted of 32 family members who had been confirmed not to carry the pathogenic variants or had heterozygous variants of the autosomal recessive inheritance gene. MethodsSixty-four UWFA images from the patients were compared to 60 UWFA images from the controls. The relative length of the temporal retina to the peripheral avascular retina was determined. The cut-off ratio of the relative lengths for a clinically significant avascular retina (csAR) associated with AD-FEVR was determined using the receiver operating characteristic (ROC) curves. Main Outcome MeasuresThe presence or absence of six peripheral vascular changes: csAR, V-shaped vascular notch, brushy vascular ends, vascular stain, loop vessels and/or anastomosis, and capillary telangiectasia were compared between the patients and the controls. ResultsThe csAR was set at >12% of the length from the ora serrata to the optic disc. The AD-FEVR patients had more frequent retinal changes than the controls for the V-shaped vascular notch (69% vs 2%, P <0.001), brushy vascular ends (78% vs 3%, P <0.001), csAR (83% vs 22%, P <0.001), and vascular stain (70% vs 33%, P <0.001). Loop vessels and/or anastomosis of peripheral vessels were found significantly less frequently in the patients than in the controls (39% vs 73%, P <0.001). No significant difference was found for capillary telangiectasia between the two groups. The combination of the V-shaped vascular notches, brushy vascular ends, and csAR had a sensitivity of 82.8% and specificity of 98.3% with the highest ROC curve of 0.9. ConclusionsThe combination of V-shaped vascular notch, brushy vascular ends, and csAR can be used as a biomarker for AD-FEVR patients who have pathogenic variants of the Norrin/β-catenin genes. These findings will allow more accurate segregation analysis in FEVR families and allow better genetic counseling.

Precision Dopaminergic Treatment in a Cohort of Parkinson's Disease Patients Carrying Autosomal Recessive Gene Variants: Clinical Cohort Data and a Mini Review.

Parkinson's disease (PD) patients harboring recessive gene variants exhibit a distinct clinical phenotype with an early disease onset and relatively mild symptoms. Data concerning individualized therapy for autosomal recessive PD forms are still scarce. Demographic and treatment data of a cohort of PD carriers of recessive genes (nine homozygous or compound heterozygous PRKN carriers, four heterozygous PRKN carriers, and three biallelic PINK1 carriers) were evaluated. The average levodopa equivalent daily dose (LEDD) was 806.8 ± 453.5 (range 152-1810) in PRKN carriers and 765 ± 96.6 (range 660-850) in PINK1 carriers. The majority responded to low/moderate doses of levodopa. The response to dopamine agonists (DAs) was often favorable both as initial and longitudinal therapy. In total, 8/13 PRKN and 1/3 PINK1 carriers were treated with amantadine successfully, and this also applied to patients who could not tolerate levodopa or DAs. In the era of personalized treatment, the therapeutic approach in recessive PD gene carriers might differ as compared to idiopathic PD. Lower LEDD doses were efficient even in patients with a very long disease duration, while a few patients were doing well without any levodopa treatment decades after disease initiation. DAs or amantadine could be used as a first and main line treatment regimen if well tolerated. Literature data on therapeutic strategies in carriers of pathogenic mutations in recessive PD genes, including device-aided treatments, will be further discussed.

Laparoscopic cholecystectomy for chronic stone cholecystitis in a patient with situs inversus totalis managed at the Delfina Torres De Concha Hospital in Esmeraldas; case report

Situs Inversus Totalis (SIT) is when all the organs of the body are inverted towards the opposite side. Its incidence varies between 1 in 5.000 and 1 in 20.000 people, and it is due to an autosomal recessive gene. This disorder is characterized by the mirror arrangement of the thoracic and abdominal viscera, and can lead to cardiac, intestinal and vascular complications. Although laparoscopic cholecystectomy is the standard treatment for cholelithiasis, it can present technical challenges in cases of situs inversus, especially for right-handed surgeons, and it is preferable to be performed by a left-handed surgeon, although this is not strictly essential. Although there is no evidence of a higher incidence of cholelithiasis in patients with situs inversus totalis, more variations and abnormalities are expected in these patients. This report presents the case of a female patient with SIT who underwent laparoscopic cholecystectomy, demonstrating that the procedure can be performed safely with minimal adaptations, such as in this case the variant of using an 11 mm trocar in the third port for the handling of the clipper for skilled surgeons in any health home that has the equipment and trained personnel, given the rarity of this condition, these cases provide valuable information and challenge to the conventional understanding of organ positioning

Specificity of Key Sex Determination Genes in a Mammal with Ovotestes: The European Mole Talpa europaea.

Here, for the first time, the structure of genes involved in sex determination in mammals (full Sry and partial Rspo1, Eif2s3x, and Eif2s3y) was analyzed for the European mole Talpa europaea with ovotestes in females. We confirmed male-specificity for Eif2s3y and Sry. Five exons were revealed for Rspo1 and the deep similarity with the structure of this gene in T. occidentalis was proved. The most intriguing result was obtained for the Sry gene, which, in placental mammals, initiates male development. We described two exons for this canonically single-exon gene: the first (initial) exon is only 15 bp while the second exon includes 450 bp. The exons are divided by an extended intron of about 1894 bp, including the fragment of the LINE retroposon. Moreover, in chromatogram fragments, which correspond to intron and DNA areas, flanking both exons, we revealed double peaks, similar to heterozygous nucleotide sites of autosomal genes. This may indicate the existence of two or more copies of the Sry gene. Proof of copies requires an additional in-depth study. We hypothesize that unusual structure and possible supernumerary copies of Sry may be involved in ovotestes formation.

Analysis of sex-biased gene expression in a Eurasian admixed population.

Sex-biased gene expression differs across human populations; however, the underlying genetic basis and molecular mechanisms remain largely unknown. Here, we explore the influence of ancestry on sex differences in the human transcriptome and its genetic effects on a Eurasian admixed population: Uyghurs living in Xinjiang (XJU), by analyzing whole-genome sequencing data and transcriptome data of 90 XJU and 40 unrelated Han Chinese individuals. We identified 302 sex-biased expressed genes and 174 sex-biased cis-expression quantitative loci (sb-cis-eQTLs) in XJU, which were enriched in innate immune-related functions, indicating sex differences in immunity. Notably, approximately one-quarter of the sb-cis-eQTLs showed a strong correlation with ancestry composition; i.e. populations of similar ancestry tended to show similar patterns of sex-biased gene expression. Our analysis further suggested that genetic admixture induced a moderate degree of sex-biased gene expression. Interestingly, analysis of chromosome interactions revealed that the X chromosome acted on autosomal immunity-associated genes, partially explaining the sex-biased phenotypic differences. Our work extends the knowledge of sex-biased gene expression from the perspective of genetic admixture and bridges the gap in the exploration of sex-biased phenotypes shaped by autosome and X-chromosome interactions. Notably, we demonstrated that sex chromosomes cannot fully explain sex differentiation in immune-related phenotypes.

Genetic Characteristics of a Large Pediatric Cohort of Patients with Inborn Errors of Immunity: Single-Center Experience.

More than 450 genetic defects result in inborn errors of immunity (IEI). Their individual prevalence in specific cohorts is influenced by national characteristics and other factors. We present results of genetic testing conducted in 1809 Russian children with IEI. Genetic defects confirming IEI were found in 1112 out of 1809 (61.5%) probands. These defects included variants in 118 single genes (87.9% of patients) and aberrations in 6 chromosomes (11.8%). Notably, three patients harbored pathogenic variants in more than one IEI gene. Large deletions constituted 5% of all defects. Out of the 799 original variants, 350 (44%) have not been described previously. Rare genetic defects (10 or fewer patients per gene) were identified in 20% of the patients. Among 967 probands with germline variants, defects were inherited in an autosomal dominant manner in 29%, X-linked in 34%, and autosomal recessive in 37%. Four females with non-random X-inactivation exhibited symptoms of X-linked diseases (BTK, WAS, CYBB, IKBKG gene defects). Despite a relatively low rate of consanguinity in Russia, 47.9% of autosomal recessive gene defects were found in a homozygous state. Notably, 28% of these cases carried "Slavic" mutation of the NBN gene or known hot-spot mutations in other genes. The diversity of IEI genetic forms and the high frequency of newly described variants underscore the genetic heterogeneity within the Russian IEI group. The new variants identified in this extensive cohort will enrich genetic databases.

Xist RNA binds select autosomal genes and depends on Repeat B to regulate their expression.

Xist, a pivotal player in X chromosome inactivation (XCI), has long been perceived as a cis-acting long noncoding RNA that binds exclusively to the inactive X chromosome (Xi). However, Xist's ability to diffuse under select circumstances has also been documented, leading us to suspect that Xist RNA may have targets and functions beyond the Xi. Here, using female mouse embryonic stem cells (ES) and mouse embryonic fibroblasts (MEF) as models, we demonstrate that Xist RNA indeed can localize beyond the Xi. However, its binding is limited to ~100 genes in cells undergoing XCI (ES cells) and in post-XCI cells (MEFs). The target genes are diverse in function but are unified by their active chromatin status. Xist binds discretely to promoters of target genes in neighborhoods relatively depleted for Polycomb marks, contrasting with the broad, Polycomb-enriched domains reported for human XIST RNA. We find that Xist binding is associated with down-modulation of autosomal gene expression. However, unlike on the Xi, Xist binding does not lead to full silencing and also does not spread beyond the target gene. Over-expressing Xist in transgenic ES cells similarly lead to autosomal gene suppression, while deleting Xist's Repeat B motif reduces autosomal binding and perturbs autosomal down-regulation. Furthermore, treating female ES cells with the Xist inhibitor, X1, leads to loss of autosomal suppression. Altogether, our findings reveal Xist targets ~100 genes beyond the Xi, identify Repeat B as a crucial domain for its in-trans function in mice, and indicate that autosomal targeting can be disrupted by the X1 small molecule inhibitor.

Single cell regulatory architecture of human pancreatic islets suggests sex differences in β cell function and the pathogenesis of type 2 diabetes.

Type 2 and type 1 diabetes (T2D, T1D) exhibit sex differences in insulin secretion, the mechanisms of which are unknown. We examined sex differences in human pancreatic islets from 52 donors with and without T2D combining single cell RNA-seq (scRNA-seq), single nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq), hormone secretion, and bioenergetics. In nondiabetic (ND) donors, sex differences in islet cells gene accessibility and expression predominantly involved sex chromosomes. Islets from T2D donors exhibited similar sex differences in sex chromosomes differentially expressed genes (DEGs), but also exhibited sex differences in autosomal genes. Comparing β cells from T2D vs. ND donors, gene enrichment of female β cells showed suppression in mitochondrial respiration, while male β cells exhibited suppressed insulin secretion. Thus, although sex differences in gene accessibility and expression of ND β cells predominantly affect sex chromosomes, the transition to T2D reveals sex differences in autosomes highlighting mitochondrial failure in females.

Association of common genetic variants with chronic axonal polyneuropathy in the general population: a genome-wide association study.

IntroductionDisease susceptibility of chronic axonal polyneuropathy is not fully explained by clinical risk factors. Therefore, we determined the contribution of common genetic variants in chronic axonal polyneuropathy in the general population.MethodsThis study was performed in two population-based studies. Polyneuropathy diagnosis was based on screening in the Rotterdam Study and on ICD-10 codes in the UK Biobank. We determined the heritability of the sural nerve amplitude and performed genome-wide association studies of chronic axonal polyneuropathy and sural sensory nerve amplitude. Furthermore, we zoomed in on variants in and surrounding 100 autosomal genes known to cause polyneuropathy based on literature and expert knowledge (candidate genes), and we performed a gene-based analysis. Analyses were adjusted for age, sex and population stratification.ResultsChronic axonal polyneuropathy was present in 2,357 of the 458,567 participants and 54.3% of the total population was female. Heritability of sural nerve amplitude was 0.49 (p = 0.067) (N = 1,153). No variants (p &amp;lt; 5.0×10−8) or genes (p &amp;lt; 2.7×10−6) reached genome-wide significance for its association with polyneuropathy. Focusing on variants in and surrounding the candidate genes in the GWAS (p &amp;lt; 3.9×10−6) and on these genes in the gene-based analysis (p &amp;lt; 5.0×10−4) neither yielded significant results.DiscussionWe did not find common variants associated with chronic axonal polyneuropathy in the general population. Larger studies are needed to determine if genetic susceptibility based on both common and rare genetic variants affect the risk for chronic axonal polyneuropathy in the general population.

Targeted RNAseq from patients’ urinary cells to validate pathogenic noncoding variants in autosomal dominant polycystic kidney disease genes: a proof of concept

Targeted RNAseq from patients’ urinary cells to validate pathogenic noncoding variants in autosomal dominant polycystic kidney disease genes: a proof of concept

Carrier screening for 223 monogenic diseases in Chinese population: a multi-center study in 33 104 individuals

To investigate the epidemiological characteristics and mutation spectrum of monogenic diseases in Chinese population through a large-scale, multicenter carrier screening. This study was conducted among a total of 33 104 participants (16 610 females) from 12 clinical centers across China.Carrier status for 223 genes was analyzed using high-throughput sequencing and different PCR methods. The overall combined carrier frequency was 55.58% for 197 autosomal genes and 1.84% for 26 X-linked genes in these participants.Among the 16 669 families, 874 at-risk couples (5.24%) were identified.Specifically, 584 couples (3.50%) were at risk for autosomal genes, 306(1.84%) for X-linked genes, and 16 for both autosomal and X-linked genes.The most frequently detected autosomal at-risk genes included GJB2(autosomal recessive deafness type 1A, 393 couples), HBA1/HBA2(α-thalassemia, 36 couples), PAH (phenylketonuria, 14 couples), and SMN1(spinal muscular atrophy, 14 couples).The most frequently detected X-linked at-risk genes were G6PD (G6PD deficiency, 236 couples), DMD (Duchenne muscular dystrophy, 23 couples), and FMR1(fragile X syndrome, 17 couples).After excluding GJB2 c.109G>A, the detection rate of at-risk couples was 3.91%(651/16 669), which was lowered to 1.72%(287/16 669) after further excluding G6PD.The theoretical incidence rate of severe monogenic birth defects was approximately 4.35‰(72.5/16 669).Screening for a battery of the top 22 most frequent genes in the at-risk couples could detect over 95% of at-risk couples, while screening for the top 54 genes further increased the detection rate to over 99%. This study reveals the carrier frequencies of 223 monogenic genetic disorders in the Chinese population and provides evidence for carrier screening strategy development and panel design tailored to the Chinese population.In carrier testing, genetic counseling for specific genes or gene variants can be challenging, and the couples need to be informed of these difficulties before testing and provided with options for not screening these genes or gene variants.