Arrhythmogenic right ventricular cardiomyopathy (ARVC) presents as the progressive fibrofatty replacement of the cardiomyocytes particularly in the right ventricular wall. Here, we report two cases ...with ARVC. In family A, the proband carries a
(
) gene complex heterozygous mutation NM_001943.4:c.146G>A/p.(Arg49His)and NM_001943.3:c.1592T>G/p.(Phe531Cys). In family B, the proband carries a homozygous mutation NM_001943.3:c.1592T>G/p.(Phe531Cys).
The Chinese Crested Tern, Thalasseus bernsteini, is one of the most endangered seabird species in the world, with only small breeding populations of around 100 individuals. To profile the genetic ...properties of this population, we screened 200 short tandem repeat sequences from a de novo assembled genome of the Great Crested Tern, T. bergii, which is the sister species of T. bernsteini. We designed a panel of 12 novel microsatellites, and genotyped nine and 23 individuals of T. bernsteini and T. bergii, respectively. The results showed that T. bernsteini genetic diversity was lower than that of T. bergii, and no inbreeding was detected. There was no sign of recent bottleneck events in the two species, but T. bernsteini showed signals of a post-bottleneck population expansion. Gene flow analysis indicated introgression between the two species, but the magnitude from T. bernsteini to T. bergii was higher than the opposite. This could be explained by Hubb’s principle, which states that there is a propensity of rarer species to reproduce with abundant congeners. Overall, our efforts provide useful genetic tools for conservation genetic studies of T. bernsteini and potentially other crested terns which face several natural and anthropogenic threats. The findings of this study further highlight that introgression may be a neglected factor in species conservation that needs to be seriously considered for conservation management.
The dataset of all microsatellite are available from the corresponding author upon request.
Microcephaly (MCPH) is a genetically heterogeneous disorder characterized by non-progressive intellectual disability, small head circumference, and small brain size compared with the age- and ...sex-matched population. MCPH manifests as an isolated condition or part of another clinical syndrome; so far, 25 genes have been linked with MCPH. Many of these genes are reported in Pakistani population, but due to a high rate of consanguinity, a significant proportion of MCPH cohort is yet to be explored. MCPH5 is the most frequently reported type, accounting for up to 68.75% alone in a genetically constrained population like Pakistan. In the current study, whole exome sequencing (WES) was performed on probands from 10 families sampled from South Waziristan and two families from rural areas of the Pakistani Punjab. Candidate variants were validated through Sanger sequencing in all available family members. Variant filtering and
in silico
analysis identified three known mutations in
ASPM
, a MCPH5-associated gene. The founder mutation p.Trp1326
*
was segregating in 10 families, which further confirmed the evidence that it is the most prominent mutation in Pashtun ethnicity living in Pakistan and Afghanistan. Furthermore, the previously known mutations p.Arg3244
*
and p.Arg1019
*
were inherited in two families with Punjab ethnic profile. Collectively, this study added 12 more families to the mutational paradigm of
ASPM
and expanded the Pakistani MCPH cohort.
Background
Atrioventricular nodal reentry tachycardia (AVNRT) is the most common manifestation of paroxysmal supraventricular tachycardia (PSVT). Increasing data have indicated familial clustering ...and participation of genetic factors in AVNRT, and no pathogenic genes related to AVNRT have been reported.
Methods
Whole‐exome sequencing (WES) was performed in 82 patients with AVNRT and 100 controls. Reference genes, genome‐wide association analysis, gene‐based collapsing, and pathway enrichment analysis were performed. A protein‐protein interaction (PPI) network was then established; WES database in the UK Biobank and one only genetic study of AVNRT in Denmark were used for external data validation.
Results
Among 95 reference genes, 126 rare variants in 48 genes were identified in the cases (minor allele frequency < 0.001). Gene‐based collapsing analysis and pathway enrichment analysis revealed six functional pathways related to AVNRT as with neuronal system/neurotransmitter release cycles and ion channel/cardiac conduction among the top 30 enriched pathways, and then 36 candidate pathogenic genes were selected. By combining with PPI analysis, 10 candidate genes were identified, including RYR2, NOS1, SCN1A, CFTR, EPHB4, ROBO1, PRKAG2, MMP2, ASPH, and ABCC8. From the UK Biobank database, 18 genes from candidate genes including SCN1A, PRKAG2, NOS1, and CFTR had rare variants in arrhythmias, and the rare variants in PIK3CB, GAD2, and HIP1R were in patients with PSVT. Moreover, one rare variant of RYR2 (c.4652A > G, p.Asn1551Ser) in our study was also detected in the Danish study. Considering the gene functional roles and external data validation, the most likely candidate genes were SCN1A, PRKAG2, RYR2, CFTR, NOS1, PIK3CB, GAD2, and HIP1R.
Conclusion
The preliminary results first revealed potential candidate genes such as SCN1A, PRKAG2, RYR2, CFTR, NOS1, PIK3CB, GAD2, and HIP1R, and the pathways mediated by these genes, including neuronal system/neurotransmitter release cycles or ion channels/cardiac conduction, might be involved in AVNRT.
This case reports a novel hemizygous frameshift EMD mutation (c.487delA, p.Ser163fs) in twins of an Emery–Dreifuss muscular dystrophy family with severe cardiac involvement and mild muscle weakness. ...Their mother carried the same heterozygous mutation.
Keshan disease is an endemic fatal dilated cardiomyopathy that can cause heart enlargement, heart failure, and cardiogenic death. Selenium deficiency is considered to be the main cause of Keshan ...disease. However, the molecular mechanism underlying Keshan disease remains unclear. Our whole-exome sequencing from 68 patients with Keshan disease and 100 controls found 199 candidate genes by gene-level burden tests. Interestingly, using multiomics data, the selenium-related gene ALAD (δ-aminolevulinic acid dehydratase) was the only candidate causative gene identified by three different analysis approaches. Based on single-cell transcriptome data, ALAD was highly expressed in cardiomyocytes and double mutations of human ALAD dramatically reduced its enzyme activity in vitro compared to negative control. Functional analysis of ALAD inhibition in mice resulted in a Keshan phenotype with left ventricular enlargement and cardiac dysfunction, whereas administration of sodium selenite markedly reversed the changes caused by ALAD inhibition. In addition, sodium selenite reversed Keshan phenotypes by affecting energy metabolism and mitochondrial function in mice as shown by the transcriptomic and proteomic data and the ultrastructure of cardiac myocytes. Our findings are the first to demonstrate that the selenium-related gene ALAD is essential for cardiac function by maintaining normal mitochondrial activity, providing strong molecular evidence supporting the hypothesis of selenium deficiency in Keshan disease. These results identified ALAD as a novel target for therapeutic intervention in Keshan disease and Keshan disease-related dilated cardiomyopathy.
Blood samples were collected and analyzed with whole-exome sequencing from 68 patients with Keshan disease and 100 healthy individuals, and the selenium-related gene ALAD is the only candidate pathogenic gene identified by three different analysis approaches. The inhibition of ALAD in mice promoted left ventricular enlargement and cardiac dysfunction, but the addition of sodium selenite remarkably reserved the changes caused by inhibition of ALAD. Our data showed that a large number of proteins associated with energy metabolism were upregulated and mitochondrial function was impaired by ALAD inhibition, while widespread upregulated proteins were returned to normal expression with the addition of sodium selenite. Display omitted
•Selenium-related gene ALAD is a novel target for therapeutic intervention in Keshan disease.•ALAD inhibition in mice resulted in left ventricular enlargement and cardiac dysfunction, and sodium selenite reversed KD phenotypes.
Abstract
Speciation in the face of gene flow is usually associated with a heterogeneous genomic landscape of divergence in nascent species pairs. However, multiple factors, such as divergent ...selection and local recombination rate variation, can influence the formation of these genomic islands. Examination of the genomic landscapes of species pairs that are still in the early stages of speciation provides an insight into this conundrum. In this study, population genomic analyses were undertaken using a wide range of sampling and whole-genome resequencing data from 96 unrelated individuals of Kentish plover (Charadrius alexandrinus) and white-faced plover (Charadrius dealbatus). We suggest that the two species exhibit varying levels of population admixture along the Chinese coast and on the Taiwan Island. Genome-wide analyses for introgression indicate that ancient introgression had occurred in Taiwan population, and gene flow is still ongoing in mainland coastal populations. Furthermore, we identified a few genomic regions with significant levels of interspecific differentiation and local recombination suppression, which contain several genes potentially associated with disease resistance, coloration, and regulation of plumage molting and thus may be relevant to the phenotypic and ecological divergence of the two nascent species. Overall, our findings suggest that divergent selection in low recombination regions may be a main force in shaping the genomic islands in two incipient shorebird species.
Aims
The canonical Wnt signaling pathway plays an essential role in blood‐brain barrier integrity and intracerebral hemorrhage in preclinical stroke models. Here, we sought to explore the association ...between canonical Wnt signaling and hemorrhagic transformation (HT) following intravenous thrombolysis (IVT) in acute ischemic stroke (AIS) patients as well as to determine the underlying cellular mechanisms.
Methods
355 consecutive AIS patients receiving IVT were included. Blood samples were collected on admission, and HT was detected at 24 hours after IVT. 117 single‐nucleotide polymorphisms (SNPs) of 28 Wnt signaling genes and exon sequences of 4 core cerebrovascular Wnt signaling components (GPR124, RECK, FZD4, and CTNNB1) were determined using a customized sequencing chip. The impact of identified genetic variants was further studied in HEK 293T cells using cellular and biochemical assays.
Results
During the study period, 80 patients experienced HT with 27 parenchymal hematoma (PH). Compared to the non‐PH patients, WNT7A SNPs (rs2163910, P = .001, OR 2.727; rs1124480, P = .002, OR 2.404) and GPR124 SNPs (rs61738775, P = .012, OR 4.883; rs146016051, P < .001, OR 7.607; rs75336000, P = .044, OR 2.503) were selectively enriched in the PH patients. Interestingly, a missense variant of GPR124 (rs75336000, c.3587G>A) identified in the PH patients resulted in a single amino acid alteration (p.Cys1196Tyr) in the intracellular domain of GPR124. This variant substantially reduced the activity of WNT7B‐induced canonical Wnt signaling by decreasing the ability of GPR124 to recruit cytoplasmic DVL1 to the cellular membrane.
Conclusion
Variants of WNT7A and GPR124 are associated with increased risk of PH in patients with AIS after intravenous thrombolysis, likely through regulating the activity of canonical Wnt signaling.
Alternative splicing exists in most multi-exonic genes, and exploring these complex alternative splicing events and their resultant isoform expressions is essential. However, it has become ...conventional that RNA sequencing results have often been summarized into gene-level expression counts mainly due to the multiple ambiguous mapping of reads at highly similar regions. Transcript-level quantification and interpretation are often overlooked, and biological interpretations are often deduced based on combined transcript information at the gene level. Here, for the most variable tissue of alternative splicing, the brain, we estimate isoform expressions in 1,191 samples collected by the Genotype-Tissue Expression (GTEx) Consortium using a powerful method that we previously developed. We perform genome-wide association scans on the isoform ratios per gene and identify isoform-ratio quantitative trait loci (irQTL), which could not be detected by studying gene-level expressions alone. By analyzing the genetic architecture of the irQTL, we show that isoform ratios regulate educational attainment via multiple tissues including the frontal cortex (BA9), cortex, cervical spinal cord, and hippocampus. These tissues are also associated with different neuro-related traits, including Alzheimer’s or dementia, mood swings, sleep duration, alcohol intake, intelligence, anxiety or depression, etc. Mendelian randomization (MR) analysis revealed 1,139 pairs of isoforms and neuro-related traits with plausible causal relationships, showing much stronger causal effects than on general diseases measured in the UK Biobank (UKB). Our results highlight essential transcript-level biomarkers in the human brain for neuro-related complex traits and diseases, which could be missed by merely investigating overall gene expressions.
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