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1.
J Genet Genomics ; 45(10): 527-538, 2018 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-30392784

RESUMO

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with considerable clinical and genetic heterogeneity. In this study, we identified all classes of genomic variants from whole-genome sequencing (WGS) dataset of 32 Chinese trios with ASD, including de novo mutations, inherited variants, copy number variants (CNVs) and genomic structural variants. A higher mutation rate (Poisson test, P < 2.2 × 10-16) in exonic (1.37 × 10-8) and 3'-UTR regions (1.42 × 10-8) was revealed in comparison with that of whole genome (1.05 × 10-8). Using an integrated model, we identified 87 potentially risk genes (P < 0.01) from 4832 genes harboring various rare deleterious variants, including CHD8 and NRXN2, implying that the disorders may be in favor to multiple-hit. In particular, frequent rare inherited mutations of several microcephaly-associated genes (ASPM, WDR62, and ZNF335) were found in ASD. In chromosomal structure analyses, we found four de novo CNVs and one de novo chromosomal rearrangement event, including a de novo duplication of UBE3A-containing region at 15q11.2-q13.1, which causes Angelman syndrome and microcephaly, and a disrupted TNR due to de novo chromosomal translocation t(1; 5)(q25.1; q33.2). Taken together, our results suggest that abnormalities of centrosomal function and chromatin remodeling of the microcephaly-associated genes may be implicated in pathogenesis of ASD. Adoption of WGS as a new yet efficient technique to illustrate the full genetic spectrum in complex disorders, such as ASD, could provide novel insights into pathogenesis, diagnosis and treatment.

2.
Proc Natl Acad Sci U S A ; 115(45): 11567-11572, 2018 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-30348779

RESUMO

Whole-exome sequencing has been successful in identifying genetic factors contributing to familial or sporadic Parkinson's disease (PD). However, this approach has not been applied to explore the impact of de novo mutations on PD pathogenesis. Here, we sequenced the exomes of 39 early onset patients, their parents, and 20 unaffected siblings to investigate the effects of de novo mutations on PD. We identified 12 genes with de novo mutations (MAD1L1, NUP98, PPP2CB, PKMYT1, TRIM24, CEP131, CTTNBP2, NUS1, SMPD3, MGRN1, IFI35, and RUSC2), which could be functionally relevant to PD pathogenesis. Further analyses of two independent case-control cohorts (1,852 patients and 1,565 controls in one cohort and 3,237 patients and 2,858 controls in the other) revealed that NUS1 harbors significantly more rare nonsynonymous variants (P = 1.01E-5, odds ratio = 11.3) in PD patients than in controls. Functional studies in Drosophila demonstrated that the loss of NUS1 could reduce the climbing ability, dopamine level, and number of dopaminergic neurons in 30-day-old flies and could induce apoptosis in fly brain. Together, our data suggest that de novo mutations could contribute to early onset PD pathogenesis and identify NUS1 as a candidate gene for PD.

3.
Front Plant Sci ; 8: 495, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28443105

RESUMO

The microRNA (miRNA) can regulate the transcripts that are involved in eukaryotic cell proliferation, differentiation, and metabolism. Especially for plants, our understanding of miRNA targets, is still limited. Early attempts of prediction on sequence alignments have been plagued by enormous false positives. It is helpful to improve target prediction specificity by incorporating the other data sources such as the dependency between miRNA and transcript expression or even cleaved transcripts by miRNA regulations, which are referred to as trans-omics data. In this paper, we developed MiRTrans (Prediction of MiRNA targets by Trans-omics data) to explore miRNA targets by incorporating miRNA sequencing, transcriptome sequencing, and degradome sequencing. MiRTrans consisted of three major steps. First, the target transcripts of miRNAs were predicted by scrutinizing their sequence characteristics and collected as an initial potential targets pool. Second, false positive targets were eliminated if the expression of miRNA and its targets were weakly correlated by lasso regression. Third, degradome sequencing was utilized to capture the miRNA targets by examining the cleaved transcripts that regulated by miRNAs. Finally, the predicted targets from the second and third step were combined by Fisher's combination test. MiRTrans was applied to identify the miRNA targets for Capsicum spp. (i.e., pepper). It can generate more functional miRNA targets than sequence-based predictions by evaluating functional enrichment. MiRTrans identified 58 miRNA-transcript pairs with high confidence from 18 miRNA families conserved in eudicots. Most of these targets were transcription factors; this lent support to the role of miRNA as key regulator in pepper. To our best knowledge, this work is the first attempt to investigate the miRNA targets of pepper, as well as their regulatory networks. Surprisingly, only a small proportion of miRNA-transcript pairs were shared between degradome sequencing and expression dependency predictions, suggesting that miRNA targets predicted by a single technology alone may be prone to report false negatives.

4.
Medicine (Baltimore) ; 95(51): e5687, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28002340

RESUMO

To explore the correlation between platelet endothelial aggregation receptor-1 (PEAR1) genetic polymorphism and pulmonary thromboembolism (PTE).Variant loci of the PEAR1 gene were screened in a PTE pedigree, followed by verification using Sanger sequencing. These polymorphic loci were validated in 101 PTE patients and 132 matched normal patients using MassARRAY single nucleotide polymorphism (SNP) genotyping methods. The frequency differences between the allele and genotypes were compared using the Hardy-Weinberg equilibrium test and Chi-square test. The correlation between the PEAR1 gene SNP and PTE was analyzed by comparing the between-group variance differences using the χ test.Three SNPs were identified in the PTE pedigree. There was a heterozygous transition of T>C in rs1952294, and a transition of C>T in rs778026543 in 2 members in the pedigree; however, the rs778026543 was not identified in the 101 PTE patients and 132 healthy controls. The genotype and allele frequencies of rs822442 did not differ significantly between PTE patients and healthy controls (P > 0.05). The variance difference at rs778026543 between pedigree members and healthy controls was significant (P < 0.001), supporting its potential heredity.The PEAR1 polymorphism, rs778026543, but not rs1952294 and rs822442, may be a susceptibility SNP for PTE.


Assuntos
Polimorfismo de Nucleotídeo Único/genética , Embolia Pulmonar/genética , Receptores de Superfície Celular/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Linhagem , Adulto Jovem
5.
Nat Genet ; 48(7): 740-6, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27213287

RESUMO

The human major histocompatibility complex (MHC) region has been shown to be associated with numerous diseases. However, it remains a challenge to pinpoint the causal variants for these associations because of the extreme complexity of the region. We thus sequenced the entire 5-Mb MHC region in 20,635 individuals of Han Chinese ancestry (10,689 controls and 9,946 patients with psoriasis) and constructed a Han-MHC database that includes both variants and HLA gene typing results of high accuracy. We further identified multiple independent new susceptibility loci in HLA-C, HLA-B, HLA-DPB1 and BTNL2 and an intergenic variant, rs118179173, associated with psoriasis and confirmed the well-established risk allele HLA-C*06:02. We anticipate that our Han-MHC reference panel built by deep sequencing of a large number of samples will serve as a useful tool for investigating the role of the MHC region in a variety of diseases and thus advance understanding of the pathogenesis of these disorders.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Complexo Principal de Histocompatibilidade/genética , Polimorfismo de Nucleotídeo Único/genética , Psoríase/genética , Butirofilinas/genética , Estudos de Casos e Controles , China/epidemiologia , Predisposição Genética para Doença , Antígenos HLA-B/genética , Antígenos HLA-C/genética , Cadeias beta de HLA-DP/genética , Humanos , Psoríase/epidemiologia
6.
Nat Commun ; 6: 6687, 2015 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-25872646

RESUMO

Age-related macular degeneration (AMD) is a leading cause of irreversible central blindness among the elderly worldwide. We use exome sequencing to analyse nonsynonymous single-nucleotide variants (SNVs) across the whole genome of 216 neovascular AMD cases and 1,553 controls. As a follow-up validation, we evaluate 3,772 neovascular AMD cases and 6,942 controls from five independent cohorts in the East Asian population. Here we show strong evidence of an association at a novel, missense SNV, rs7739323, which is located in the ubiquitin protein ligase E3D (UBE3D) gene (Pmeta=1.46 × 10(-9), odds ratio (OR)=0.74, 95% confidence interval (CI): 0.63-0.88). Furthermore, ablation of the UBE3D protein lead to an abnormal amount of pigment granules deposited in retinal pigment epithelium microvilli area and an abnormal response on electroretinography (ERG) in UBE3D(+/-) heterozygous mice. Our findings indicate that the ubiquitin-proteasome system may play a role in the pathogenesis of neovascular AMD.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Degeneração Macular/genética , Ubiquitina-Proteína Ligases/genética , Idoso , Angiografia , Animais , Estudos de Casos e Controles , China , Corantes , Eletrorretinografia , Exoma/genética , Feminino , Predisposição Genética para Doença , Hong Kong , Humanos , Verde de Indocianina , Japão , Degeneração Macular/patologia , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Epitélio Pigmentado da Retina/patologia , Análise de Sequência de DNA , Singapura , Tomografia de Coerência Óptica
7.
PLoS One ; 9(9): e106388, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25181484

RESUMO

Dopa-responsive dystonia, a rare disorder typically presenting in early childhood with lower limb dystonia and gait abnormality, responds well to levodopa. However, it is often misdiagnosed with the wide spectrum of phenotypes. By exome sequencing, we make a rapid genetic diagnosis for two atypical dopa-responsive dystonia pedigrees. One pedigree, presented with prominent parkinsonism, was misdiagnosed as Parkinson's disease until a known mutation in GCH1 (GTP cyclohydrolase 1) gene (NM_000161.2: c.631_632delAT, p.Met211ValfsX38) was found. The other pedigree was detected with a new compound heterozygous mutation in TH (tyrosine hydroxylase) gene [(NM_000360.3: c.911C>T, p.Ala304Val) and (NM_000360.3: c.1358G>A, p.Arg453His)], whose proband, a pregnant woman, required a rapid and less-biased genetic diagnosis. In conclusion, we demonstrated that exome sequencing could provide a precise and rapid genetic testing in the diagnosis of Mendelian diseases, especially for diseases with wide phenotypes.


Assuntos
Distúrbios Distônicos/diagnóstico , Distúrbios Distônicos/genética , Exoma/genética , Testes Genéticos , Análise de Sequência de DNA/métodos , Adolescente , Sequência de Aminoácidos , Sequência de Bases , Extratos Celulares , Pré-Escolar , Feminino , GTP Cicloidrolase/química , GTP Cicloidrolase/genética , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Proteínas Mutantes/metabolismo , Mutação/genética , Transfecção , Tirosina 3-Mono-Oxigenase/metabolismo , Adulto Jovem
8.
Nat Commun ; 5: 4331, 2014 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-25006012

RESUMO

In a previous large-scale exome sequencing analysis for psoriasis, we discovered seven common and low-frequency missense variants within six genes with genome-wide significance. Here we describe an in-depth analysis of noncoding variants based on sequencing data (10,727 cases and 10,582 controls) with replication in an independent cohort of Han Chinese individuals consisting of 4,480 cases and 6,521 controls to identify additional psoriasis susceptibility loci. We confirmed four known psoriasis susceptibility loci (IL12B, IFIH1, ERAP1 and RNF114; 2.30 × 10(-20)≤P≤2.41 × 10(-7)) and identified three new susceptibility loci: 4q24 (NFKB1) at rs1020760 (P=2.19 × 10(-8)), 12p13.3 (CD27-LAG3) at rs758739 (P=4.08 × 10(-8)) and 17q12 (IKZF3) at rs10852936 (P=1.96 × 10(-8)). Two suggestive loci, 3p21.31 and 17q25, are also identified with P<1.00 × 10(-6). The results of this study increase the number of confirmed psoriasis risk loci and provide novel insight into the pathogenesis of psoriasis.


Assuntos
Antígenos CD/genética , Grupo com Ancestrais do Continente Asiático/genética , Predisposição Genética para Doença , Fator de Transcrição Ikaros/genética , Subunidade p50 de NF-kappa B/genética , Psoríase/genética , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Adulto , Estudos de Casos e Controles , China , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto Jovem
9.
Nat Genet ; 46(1): 45-50, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24212883

RESUMO

To explore the contribution of functional coding variants to psoriasis, we analyzed nonsynonymous single-nucleotide variants (SNVs) across the genome by exome sequencing in 781 psoriasis cases and 676 controls and through follow-up validation in 1,326 candidate genes by targeted sequencing in 9,946 psoriasis cases and 9,906 controls from the Chinese population. We discovered two independent missense SNVs in IL23R and GJB2 of low frequency and five common missense SNVs in LCE3D, ERAP1, CARD14 and ZNF816A associated with psoriasis at genome-wide significance. Rare missense SNVs in FUT2 and TARBP1 were also observed with suggestive evidence of association. Single-variant and gene-based association analyses of nonsynonymous SNVs did not identify newly associated genes for psoriasis in the regions subjected to targeted resequencing. This suggests that coding variants in the 1,326 targeted genes contribute only a limited fraction of the overall genetic risk for psoriasis.


Assuntos
Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Psoríase/genética , Adulto , Aminopeptidases/genética , Grupo com Ancestrais do Continente Asiático/genética , Proteínas Adaptadoras de Sinalização CARD/genética , Estudos de Casos e Controles , Conexina 26 , Conexinas/genética , Feminino , Fucosiltransferases/genética , Estudo de Associação Genômica Ampla , Guanilato Ciclase/genética , Haplótipos , Humanos , Masculino , Proteínas de Membrana/genética , Antígenos de Histocompatibilidade Menor , Mutação de Sentido Incorreto , Proteínas Nucleares/genética , Proteínas de Ligação a RNA/genética , Receptores de Interleucina/genética , Adulto Jovem
10.
Am J Hum Genet ; 93(2): 249-63, 2013 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-23849776

RESUMO

Autism Spectrum Disorder (ASD) demonstrates high heritability and familial clustering, yet the genetic causes remain only partially understood as a result of extensive clinical and genomic heterogeneity. Whole-genome sequencing (WGS) shows promise as a tool for identifying ASD risk genes as well as unreported mutations in known loci, but an assessment of its full utility in an ASD group has not been performed. We used WGS to examine 32 families with ASD to detect de novo or rare inherited genetic variants predicted to be deleterious (loss-of-function and damaging missense mutations). Among ASD probands, we identified deleterious de novo mutations in six of 32 (19%) families and X-linked or autosomal inherited alterations in ten of 32 (31%) families (some had combinations of mutations). The proportion of families identified with such putative mutations was larger than has been previously reported; this yield was in part due to the comprehensive and uniform coverage afforded by WGS. Deleterious variants were found in four unrecognized, nine known, and eight candidate ASD risk genes. Examples include CAPRIN1 and AFF2 (both linked to FMR1, which is involved in fragile X syndrome), VIP (involved in social-cognitive deficits), and other genes such as SCN2A and KCNQ2 (linked to epilepsy), NRXN1, and CHD7, which causes ASD-associated CHARGE syndrome. Taken together, these results suggest that WGS and thorough bioinformatic analyses for de novo and rare inherited mutations will improve the detection of genetic variants likely to be associated with ASD or its accompanying clinical symptoms.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/genética , Predisposição Genética para Doença , Genoma , Mutação , Adulto , Criança , Feminino , Heterogeneidade Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Linhagem
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