Alzheimer's disease (AD), also known as senile dementia, is a progressive neurodegenerative disease. The etiology and pathogenesis of AD have not yet been elucidated. We examined common ...differentially expressed genes (DEGs) from different AD tissue microarray datasets by meta-analysis and screened the AD-associated genes from the common DEGs using GCBI. Then we studied the gene expression network using the STRING database and identified the hub genes using Cytoscape. Furthermore, we analyzed the microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and single nucleotide polymorphisms (SNPs) associated with the AD-associated genes, and then identified feed-forward loops. Finally, we performed SNP analysis of the AD-associated genes. Our results identified 207 common DEGs, of which 57 have previously been reported to be associated with AD. The common DEG expression network identified eight hub genes, all of which were previously known to be associated with AD. Further study of the regulatory miRNAs associated with the AD-associated genes and other genes specific to neurodegenerative diseases revealed 65 AD-associated miRNAs. Analysis of the miRNA associated transcription factor-miRNA-gene-gene associated TF (mTF-miRNA-gene-gTF) network around the AD-associated genes revealed 131 feed-forward loops (FFLs). Among them, one important FFL was found between the gene
, hsa-miR-27a, and the transcription factor MYC. Furthermore, SNP analysis of the AD-associated genes identified 173 SNPs, and also found a role in AD for miRNAs specific to other neurodegenerative diseases, including hsa-miR-34c, hsa-miR-212, hsa-miR-34a, and hsa-miR-7. The regulatory network constructed in this study describes the mechanism of cell regulation in AD, in which miRNAs and lncRNAs can be considered AD regulatory factors.
Quantifying the overall magnitude of every single locus' genetic effect on the widely measured human phenome is of great challenge. We introduce a unified modelling technique that can consistently ...provide a total genetic contribution assessment (TGCA) of a gene or genetic variant without thresholding genetic association signals. Genome-wide TGCA in five UK Biobank phenotype domains highlights loci such as the HLA locus for medical conditions, the bone mineral density locus WNT16 for physical measures, and the skin tanning locus MC1R and smoking behaviour locus CHRNA3 for lifestyle. Tissue-specificity investigation reveals several tissues associated with total genetic contributions, including the brain tissues for mental health. Such associations are driven by tissue-specific gene expressions, which share genetic basis with the total genetic contributions. TGCA can provide a genome-wide atlas for the overall genetic contributions in each particular domain of human complex traits.
Parkinson's disease (PD) is a long-term degenerative disease that is caused by environmental and genetic factors. The networks of genes and their regulators that control the progression and ...development of PD require further elucidation.
We examine common differentially expressed genes (DEGs) from several PD blood and substantia nigra (SN) microarray datasets by meta-analysis. Further we screen the PD-specific genes from common DEGs using GCBI. Next, we used a series of bioinformatics software to analyze the miRNAs, lncRNAs and SNPs associated with the common PD-specific genes, and then identify the mTF-miRNA-gene-gTF network.
Our results identified 36 common DEGs in PD blood studies and 17 common DEGs in PD SN studies, and five of the genes were previously known to be associated with PD. Further study of the regulatory miRNAs associated with the common PD-specific genes revealed 14 PD-specific miRNAs in our study. Analysis of the mTF-miRNA-gene-gTF network about PD-specific genes revealed two feed-forward loops: one involving the SPRK2 gene, hsa-miR-19a-3p and SPI1, and the second involving the SPRK2 gene, hsa-miR-17-3p and SPI. The long non-coding RNA (lncRNA)-mediated regulatory network identified lncRNAs associated with PD-specific genes and PD-specific miRNAs. Moreover, single nucleotide polymorphism (SNP) analysis of the PD-specific genes identified two significant SNPs, and SNP analysis of the neurodegenerative disease-specific genes identified seven significant SNPs. Most of these SNPs are present in the 3'-untranslated region of genes and are controlled by several miRNAs.
Our study identified a total of 53 common DEGs in PD patients compared with healthy controls in blood and brain datasets and five of these genes were previously linked with PD. Regulatory network analysis identified PD-specific miRNAs, associated long non-coding RNA and feed-forward loops, which contribute to our understanding of the mechanisms underlying PD. The SNPs identified in our study can determine whether a genetic variant is associated with PD. Overall, these findings will help guide our study of the complex molecular mechanism of PD.
Understanding how incipient species are maintained with gene flow is a fundamental question in evolutionary biology. Whole genome sequencing of multiple individuals holds great potential to ...illustrate patterns of genomic differentiation as well as the associated evolutionary histories. Kentish (
Charadrius alexandrinus
) and the white-faced (
C. dealbatus
) plovers, which differ in their phenotype, ecology and behavior, are two incipient species and parapatrically distributed in East Asia. Previous studies show evidence of genetic diversification with gene flow between the two plovers. Under this scenario, it is of great importance to explore the patterns of divergence at the genomic level and to determine whether specific regions are involved in reproductive isolation and local adaptation. Here we present the first population genomic analysis of the two incipient species based on the
de novo
Kentish plover reference genome and resequenced populations. We show that the two plover lineages are distinct in both nuclear and mitochondrial genomes. Using model-based coalescence analysis, we found that population sizes of Kentish plover increased whereas white-faced plovers declined during the Last Glaciation Period. Moreover, the two plovers diverged allopatrically, with gene flow occurring after secondary contact. This has resulted in low levels of genome-wide differentiation, although we found evidence of a few highly differentiated genomic regions in both the autosomes and the Z-chromosome. This study illustrates that incipient shorebird species with gene flow after secondary contact can exhibit discrete divergence at specific genomic regions and provides basis to further exploration on the genetic basis of relevant phenotypic traits.
Systemic sclerosis is a chronic multisystem autoimmune disease that is associated with polyclonal B cell hyperreactivity. The CDR3 of BCRs is the major site of antigen recognition. Therefore, we ...analyzed the BCR repertoire of patients with SSc. The BCR repertoires in 12 subjects including eight SSc patients and four healthy controls were characterized by high-throughput sequencing, and bioinformatics analysis were studied. The average CDR3 length in the SSc group was significantly shorter. The SSc patient displayed more diverse BCR. Moreover, SSc patients with mild skin sclerosis, anti-Scl70, interstitial lung disease or female sex were more diversified. B cells from the SSc patients showed a differential V and J gene usage. SSc patients had distinct BCR repertoires.These findings reflected the differences of BCR repertoires between SSc patients and controls. The higher-usage genes for the BCR sequence might be potential biomarkers of B cell-targeted therapies or diagnosis for SSc.
Familial dilated cardiomyopathy (DCM) is a genetic cardiomyopathy that is associated with reduced left ventricle function or systolic function. Fifty-one DCM-causative genes have been reported, most ...of which are inherited in an autosomal dominant manner. However, recessive DCM-causative gene is rarely observed. Whole-exome sequencing (WES) was performed in a consanguineous family with DCM to identify candidate variants. Sanger sequencing was utilized to confirm the variant. We then checked the DCM candidate gene in 210 sporadic DCM cases. We next explored BICD2 function in both embryonic and adult bicd2-knockout zebrafish models. In vivo cardiac function of bicd2-knockout fish was detected by echocardiography and RNA-seq. We identified an autosomal recessive and evolutionarily conserved missense variant, NM_001003800.1:c.2429G > A, in BICD2, which segregated with the disease phenotype in a consanguineous family with DCM. Furthermore, we confirmed the presence of BICD2 variants in 3 sporadic cases. Knockout of bicd2 resulted in partial embryonic lethality in homozygotes, suggesting a vital role for bicd2 in embryogenesis. Heart dilation and decreased ejection fraction, cardiac output and stroke volume were observed in bicd2-knockout zebrafish, suggesting a phenotype similar to human DCM. Furthermore, RNA-seq confirmed a larger transcriptome shift in in bicd2 homozygotes than in heterozygotes. Gene set enrichment analysis of bicd2-deficient fish showed the enrichment of altered gene expression in cardiac pathways and mitochondrial energy metabolism. Our study first shows that BICD2 is a novel candidate gene associated with familial DCM, and our findings will facilitate further insights into the molecular pathological mechanisms of DCM.
CRISPR-Cas is a powerful genome editing tool for various species and human cell lines, widely used in many research areas including studying the mechanisms, targets, and gene therapies of human ...diseases. Recent developments have even allowed high-throughput genetic screening using the CRISPR system. However, due to the practical and ethical limitations in human gene editing research, little is known about whether CRISPR-editable DNA segments could influence human complex traits or diseases. Here, we investigated the human genomic regions condensed with different CRISPR Cas enzymes' protospacer-adjacent motifs (PAMs). We found that Cas enzymes with GC-rich PAMs could interfere more with the genomic regions that harbor enriched heritability for human complex traits and diseases. The results linked GC content across the genome to the functional genomic elements in the heritability enrichment of human complex traits. We provide a genetic overview of the effects of high-throughput genome editing on human complex traits.
The White-eared Night-Heron (Gorsachius magnificus, G. magnificus) is a critically endangered heron that is very poorly known and only found in southern China and northern Vietnam, with an estimated ...population of 250 to 999 mature individuals. However, the lack of a reference genome has hindered the implementation of conservation management efforts. In this study, we present the first high-quality chromosome-scale reference genome, which was assembled by integrating PacBio long-reads sequencing, Illumina paired-end sequencing, and Hi-C technology. The genome has a total length of 1.176 Gb, with a scaffold N50 of 84.77 Mb and a contig N50 of 18.46 Mb. Utilizing Hi-C data, we anchored 99.89% of the scaffold sequences onto 29 pairs of chromosomes. Additionally, we identified 18,062 protein-coding genes in the genome, with 95.00% of which were functionally annotated. Notably, BUSCO assessment confirmed the presence of 97.2% of highly conserved Aves genes within the genome. This chromosome-level genome assembly and annotation will be valuable for future investigating the G. magnificus's evolutionary adaptation and conservation.
Background
Atrioventricular nodal reentrant tachycardia (AVNRT) is a common arrhythmia. Growing evidence suggests that family aggregation and genetic factors are involved in AVNRT. However, in ...families with a history of AVNRT, disease-causing genes have not been reported.
Objective
To investigate the genetic contribution of familial AVNRT using a whole-exome sequencing (WES) approach.
Methods
Blood samples were collected from 20 patients from nine families with a history of AVNRT and 100 control participants, and we systematically analyzed mutation profiles using WES. Gene-based burden analysis, integration of previous sporadic AVNRT data, pedigree-based co-segregation, protein-protein interaction network analysis, single-cell RNA sequencing, and confirmation of animal phenotype were performed.
Results
Among 95 related reference genes, seven candidate pathogenic genes have been identified both in sporadic and familial AVNRT, including
CASQ2
,
AGXT
,
ANK2
,
SYNE2
,
ZFHX3
,
GJD3
, and
SCN4A
. Among the 37 reference genes from sporadic AVNRT, five candidate pathogenic genes were identified in patients with both familial and sporadic AVNRT:
LAMC1
, ryanodine receptor 2 (
RYR2
),
COL4A3
,
NOS1
, and
ATP2C2
. To identify the common pathogenic mechanisms in all AVNRT cases, five pathogenic genes were identified in patients with both familial and sporadic AVNRT:
LAMC1
,
RYR2
,
COL4A3
,
NOS1
, and
ATP2C2
. Considering the unique internal candidate pathogenic gene within pedigrees, three genes,
TRDN
,
CASQ2
, and
WNK1
, were likely to be the pathogenic genes in familial AVNRT. Notably, the core calcium-signaling pathway may be closely associated with the occurrence of AVNRT, including
CASQ2
,
RYR2
,
TRDN, NOS1
,
ANK2
, and
ATP2C2
.
Conclusion
Our pedigree-based studies demonstrate that
RYR2
and related calcium signaling pathway play a critical role in the pathogenesis of familial AVNRT using the WES approach.
Abstract
Emery-Dreifuss muscular dystrophy (EDMD) is a rare X-linked recessive disease characterized by the clinical triad of early childhood joint contractures, progressive weakness in muscles and ...cardiac involvement and can result in sudden death. Targeted next-generation sequencing was performed for a Chinese patient with EDMD and the previously reported mutation NM_000117.2: c.251_255del (p.Leu84Profs*7) in exon 3 of the emerin gene (
EMD
) was identified.
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