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1.
J Invest Dermatol ; 139(11): 2302-2312.e14, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31078570

RESUMO

Genetic studies based on single-nucleotide polymorphisms have provided valuable insights into the genetic architecture of complex diseases. However, a large fraction of heritability for most of these diseases remains unexplained, and the impact of small insertions and deletions (InDels) has been neglected. We performed a comprehensive screen on the exome sequence data of 1,326 genes using the SOAP-PopIndel method for InDels in 32,043 Chinese Han individuals and identified 29 unreported InDels within 25 susceptibility genes associated with psoriasis. Specifically, we identified 12 common, 9 low-frequency, and 8 rare InDels that explained approximately 1.29% of the heritability of psoriasis. Further analyses identified KIAA0319, RELN, NCAPG, ABO, AADACL2, LMAN1, FLG, HERC5, CCDC66, LEKR1, AFF3, ABCG2, ANXA7, SYTL2,GIPR, METTL1, and FYCO1 as unreported genes for psoriasis. In addition, identified InDels were associated with the following reported genes: IFIH1, ERAP1, ERAP2, LNPEP, UBLCP1, and STAT3; unreported independent associations for exonic InDels were found within GJB2 and ZNF816A. Our study enriched the genetic basis and pathogenesis of psoriasis and highlighted the non-negligible impact of InDels on complex human diseases.

2.
Sci Rep ; 8(1): 16616, 2018 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-30413723

RESUMO

The majority of human chromosome ends remain incompletely assembled due to their highly repetitive structure. In this study, we use BioNano data to anchor and extend chromosome ends from two European trios as well as two unrelated Asian genomes. At least 11 BioNano assembled chromosome ends are structurally divergent from the reference genome, including both missing sequence and extensions. These extensions are heritable and in some cases divergent between Asian and European samples. Six out of nine predicted extension sequences from NA12878 can be confirmed and filled by nanopore data. We identify two multi-kilobase sequence families both enriched more than 100-fold in extension sequence (p-values < 1e-5) whose origins can be traced to interstitial sequence on ancestral primate chromosome 7. Extensive sub-telomeric duplication of these families has occurred in the human lineage subsequent to divergence from chimpanzees.

3.
BMC Bioinformatics ; 19(1): 261, 2018 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-30001702

RESUMO

BACKGROUND: Detection of genomic inversions remains challenging. Many existing methods primarily target inzversions with a non repetitive breakpoint, leaving inverted repeat (IR) mediated non-allelic homologous recombination (NAHR) inversions largely unexplored. RESULT: We present npInv, a novel tool specifically for detecting and genotyping NAHR inversion using long read sub-alignment of long read sequencing data. We benchmark npInv with other tools in both simulation and real data. We use npInv to generate a whole-genome inversion map for NA12878 consisting of 30 NAHR inversions (of which 15 are novel), including all previously known NAHR mediated inversions in NA12878 with flanking IR less than 7kb. Our genotyping accuracy on this dataset was 94%. We used PCR to confirm the presence of two of these novel inversions. We show that there is a near linear relationship between the length of flanking IR and the minimum inversion size, without inverted repeats. CONCLUSION: The application of npInv shows high accuracy in both simulation and real data. The results give deeper insight into understanding inversion.

4.
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
5.
Nat Genet ; 48(6): 593-9, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27111036

RESUMO

We report the sequences of 1,244 human Y chromosomes randomly ascertained from 26 worldwide populations by the 1000 Genomes Project. We discovered more than 65,000 variants, including single-nucleotide variants, multiple-nucleotide variants, insertions and deletions, short tandem repeats, and copy number variants. Of these, copy number variants contribute the greatest predicted functional impact. We constructed a calibrated phylogenetic tree on the basis of binary single-nucleotide variants and projected the more complex variants onto it, estimating the number of mutations for each class. Our phylogeny shows bursts of extreme expansion in male numbers that have occurred independently among each of the five continental superpopulations examined, at times of known migrations and technological innovations.


Assuntos
Cromossomos Humanos Y , Demografia , Haplótipos , Humanos , Masculino , Mutação , Filogenia , Polimorfismo de Nucleotídeo Único
6.
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
7.
Nucleic Acids Res ; 41(3): e46, 2013 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-23221639

RESUMO

Insertion and deletion polymorphisms (indels) are an important source of genomic variation in plant and animal genomes, but accurate genotyping from low-coverage and exome next-generation sequence data remains challenging. We introduce an efficient population clustering algorithm for diploids and polyploids which was tested on a dataset of 2000 exomes. Compared with existing methods, we report a 4-fold reduction in overall indel genotype error rates with a 9-fold reduction in low coverage regions.


Assuntos
Algoritmos , Técnicas de Genotipagem , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Mutação INDEL , Exoma , Modelos Genéticos , População/genética
8.
Nat Biotechnol ; 29(8): 723-30, 2011 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-21785424

RESUMO

Here we use whole-genome de novo assembly of second-generation sequencing reads to map structural variation (SV) in an Asian genome and an African genome. Our approach identifies small- and intermediate-size homozygous variants (1-50 kb) including insertions, deletions, inversions and their precise breakpoints, and in contrast to other methods, can resolve complex rearrangements. In total, we identified 277,243 SVs ranging in length from 1-23 kb. Validation using computational and experimental methods suggests that we achieve overall <6% false-positive rate and <10% false-negative rate in genomic regions that can be assembled, which outperforms other methods. Analysis of the SVs in the genomes of 106 individuals sequenced as part of the 1000 Genomes Project suggests that SVs account for a greater fraction of the diversity between individuals than do single-nucleotide polymorphisms (SNPs). These findings demonstrate that whole-genome de novo assembly is a feasible approach to deriving more comprehensive maps of genetic variation.


Assuntos
Genoma Humano , Genômica/métodos , Análise de Sequência de DNA/métodos , Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Asiático/genética , Sequência de Bases , Mapeamento Cromossômico , Variação Genética , Humanos , Dados de Sequência Molecular , Reprodutibilidade dos Testes
9.
BMC Evol Biol ; 10: 81, 2010 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-20334646

RESUMO

BACKGROUND: Mitochondria are a valuable resource for studying the evolutionary process and deducing phylogeny. A few mitochondria genomes have been sequenced, but a comprehensive picture of the domestication event for silkworm mitochondria remains to be established. In this study, we integrate the extant data, and perform a whole genome resequencing of Japanese wild silkworm to obtain breakthrough results in silkworm mitochondrial (mt) population, and finally use these to deduce a more comprehensive phylogeny of the Bombycidae. RESULTS: We identified 347 single nucleotide polymorphisms (SNPs) in the mt genome, but found no past recombination event to have occurred in the silkworm progenitor. A phylogeny inferred from these whole genome SNPs resulted in a well-classified tree, confirming that the domesticated silkworm, Bombyx mori, most recently diverged from the Chinese wild silkworm, rather than from the Japanese wild silkworm. We showed that the population sizes of the domesticated and Chinese wild silkworms both experience neither expansion nor contraction. We also discovered that one mt gene, named cytochrome b, shows a strong signal of positive selection in the domesticated clade. This gene is related to energy metabolism, and may have played an important role during silkworm domestication. CONCLUSIONS: We present a comparative analysis on 41 mt genomes of B. mori and B. mandarina from China and Japan. With these, we obtain a much clearer picture of the evolution history of the silkworm. The data and analyses presented here aid our understanding of the silkworm in general, and provide a crucial insight into silkworm phylogeny.


Assuntos
Bombyx/genética , Evolução Molecular , Genoma de Inseto , Genoma Mitocondrial , Filogenia , Animais , Bombyx/classificação , Hibridização Genômica Comparativa , Citocromos b/genética , DNA Mitocondrial/genética , Genes de Insetos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Densidade Demográfica , Seleção Genética , Alinhamento de Sequência , Análise de Sequência de DNA
10.
Science ; 326(5951): 433-6, 2009 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-19713493

RESUMO

A single-base pair resolution silkworm genetic variation map was constructed from 40 domesticated and wild silkworms, each sequenced to approximately threefold coverage, representing 99.88% of the genome. We identified ~16 million single-nucleotide polymorphisms, many indels, and structural variations. We find that the domesticated silkworms are clearly genetically differentiated from the wild ones, but they have maintained large levels of genetic variability, suggesting a short domestication event involving a large number of individuals. We also identified signals of selection at 354 candidate genes that may have been important during domestication, some of which have enriched expression in the silk gland, midgut, and testis. These data add to our understanding of the domestication processes and may have applications in devising pest control strategies and advancing the use of silkworms as efficient bioreactors.


Assuntos
Bombyx/genética , Genes de Insetos , Variação Genética , Genoma de Inseto , Análise de Sequência de DNA , Animais , Bombyx/classificação , Sistema Digestório/metabolismo , Glândulas Exócrinas/metabolismo , Feminino , Expressão Gênica , Mutação INDEL , Desequilíbrio de Ligação , Masculino , Filogenia , Polimorfismo de Nucleotídeo Único , Análise de Componente Principal , Seleção Genética , Testículo/metabolismo
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