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1.
Nature ; 536(7616): 285-91, 2016 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-27535533

RESUMO

Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes.


Assuntos
Exoma/genética , Variação Genética/genética , Análise Mutacional de DNA , Conjuntos de Dados como Assunto , Humanos , Fenótipo , Proteoma/genética , Doenças Raras/genética , Tamanho da Amostra
2.
Nature ; 506(7487): 185-90, 2014 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-24463508

RESUMO

Schizophrenia is a common disease with a complex aetiology, probably involving multiple and heterogeneous genetic factors. Here, by analysing the exome sequences of 2,536 schizophrenia cases and 2,543 controls, we demonstrate a polygenic burden primarily arising from rare (less than 1 in 10,000), disruptive mutations distributed across many genes. Particularly enriched gene sets include the voltage-gated calcium ion channel and the signalling complex formed by the activity-regulated cytoskeleton-associated scaffold protein (ARC) of the postsynaptic density, sets previously implicated by genome-wide association and copy-number variation studies. Similar to reports in autism, targets of the fragile X mental retardation protein (FMRP, product of FMR1) are enriched for case mutations. No individual gene-based test achieves significance after correction for multiple testing and we do not detect any alleles of moderately low frequency (approximately 0.5 to 1 per cent) and moderately large effect. Taken together, these data suggest that population-based exome sequencing can discover risk alleles and complements established gene-mapping paradigms in neuropsychiatric disease.


Assuntos
Herança Multifatorial/genética , Mutação/genética , Esquizofrenia/genética , Transtorno Autístico/genética , Canais de Cálcio/genética , Proteínas do Citoesqueleto/genética , Variações do Número de Cópias de DNA/genética , Proteína 4 Homóloga a Disks-Large , Feminino , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Estudo de Associação Genômica Ampla , Humanos , Deficiência Intelectual/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Receptores de N-Metil-D-Aspartato/genética
3.
Nature ; 485(7397): 242-5, 2012 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-22495311

RESUMO

Autism spectrum disorders (ASD) are believed to have genetic and environmental origins, yet in only a modest fraction of individuals can specific causes be identified. To identify further genetic risk factors, here we assess the role of de novo mutations in ASD by sequencing the exomes of ASD cases and their parents (n = 175 trios). Fewer than half of the cases (46.3%) carry a missense or nonsense de novo variant, and the overall rate of mutation is only modestly higher than the expected rate. In contrast, the proteins encoded by genes that harboured de novo missense or nonsense mutations showed a higher degree of connectivity among themselves and to previous ASD genes as indexed by protein-protein interaction screens. The small increase in the rate of de novo events, when taken together with the protein interaction results, are consistent with an important but limited role for de novo point mutations in ASD, similar to that documented for de novo copy number variants. Genetic models incorporating these data indicate that most of the observed de novo events are unconnected to ASD; those that do confer risk are distributed across many genes and are incompletely penetrant (that is, not necessarily sufficient for disease). Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5- to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case-control study provide strong evidence in favour of CHD8 and KATNAL2 as genuine autism risk factors.


Assuntos
Transtorno Autístico/genética , Proteínas de Ligação a DNA/genética , Éxons/genética , Predisposição Genética para Doença/genética , Mutação/genética , Fatores de Transcrição/genética , Estudos de Casos e Controles , Exoma/genética , Saúde da Família , Humanos , Modelos Genéticos , Herança Multifatorial/genética , Fenótipo , Distribuição de Poisson , Mapas de Interação de Proteínas
4.
PLoS Genet ; 9(4): e1003443, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23593035

RESUMO

We report on results from whole-exome sequencing (WES) of 1,039 subjects diagnosed with autism spectrum disorders (ASD) and 870 controls selected from the NIMH repository to be of similar ancestry to cases. The WES data came from two centers using different methods to produce sequence and to call variants from it. Therefore, an initial goal was to ensure the distribution of rare variation was similar for data from different centers. This proved straightforward by filtering called variants by fraction of missing data, read depth, and balance of alternative to reference reads. Results were evaluated using seven samples sequenced at both centers and by results from the association study. Next we addressed how the data and/or results from the centers should be combined. Gene-based analyses of association was an obvious choice, but should statistics for association be combined across centers (meta-analysis) or should data be combined and then analyzed (mega-analysis)? Because of the nature of many gene-based tests, we showed by theory and simulations that mega-analysis has better power than meta-analysis. Finally, before analyzing the data for association, we explored the impact of population structure on rare variant analysis in these data. Like other recent studies, we found evidence that population structure can confound case-control studies by the clustering of rare variants in ancestry space; yet, unlike some recent studies, for these data we found that principal component-based analyses were sufficient to control for ancestry and produce test statistics with appropriate distributions. After using a variety of gene-based tests and both meta- and mega-analysis, we found no new risk genes for ASD in this sample. Our results suggest that standard gene-based tests will require much larger samples of cases and controls before being effective for gene discovery, even for a disorder like ASD.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/genética , Exoma , Estudo de Associação Genômica Ampla , Estudos de Casos e Controles , Criança , Transtornos Globais do Desenvolvimento Infantil/fisiopatologia , Predisposição Genética para Doença , Variação Genética , Humanos , Controle da População , Análise de Sequência de DNA , Software
5.
Hum Mol Genet ; 20(7): 1285-9, 2011 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-21212097

RESUMO

Exome sequencing is a powerful tool for discovery of the Mendelian disease genes. Previously, we reported a novel locus for autosomal recessive non-syndromic mental retardation (NSMR) in a consanguineous family [Nolan, D.K., Chen, P., Das, S., Ober, C. and Waggoner, D. (2008) Fine mapping of a locus for nonsyndromic mental retardation on chromosome 19p13. Am. J. Med. Genet. A, 146A, 1414-1422]. Using linkage and homozygosity mapping, we previously localized the gene to chromosome 19p13. The parents of this sibship were recently included in an exome sequencing project. Using a series of filters, we narrowed the putative causal mutation to a single variant site that segregated with NSMR: the mutation was homozygous in five affected siblings but in none of eight unaffected siblings. This mutation causes a substitution of a leucine for a highly conserved proline at amino acid 182 in TECR (trans-2,3-enoyl-CoA reductase), a synaptic glycoprotein. Our results reveal the value of massively parallel sequencing for identification of novel disease genes that could not be found using traditional approaches and identifies only the seventh causal mutation for autosomal recessive NSMR.


Assuntos
Cromossomos Humanos Par 19/genética , Doenças Genéticas Inatas/genética , Deficiência Intelectual/genética , Glicoproteínas de Membrana/genética , Mutação , Oxirredutases/genética , Membranas Sinápticas/genética , Feminino , Doenças Genéticas Inatas/enzimologia , Humanos , Deficiência Intelectual/enzimologia , Masculino , Glicoproteínas de Membrana/metabolismo , Oxirredutases/metabolismo , Linhagem , Membranas Sinápticas/enzimologia
6.
Curr Protoc Bioinformatics ; 43: 11.10.1-11.10.33, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-25431634

RESUMO

This unit describes how to use BWA and the Genome Analysis Toolkit (GATK) to map genome sequencing data to a reference and produce high-quality variant calls that can be used in downstream analyses. The complete workflow includes the core NGS data processing steps that are necessary to make the raw data suitable for analysis by the GATK, as well as the key methods involved in variant discovery using the GATK.


Assuntos
Variação Genética , Genoma Humano , Software , Calibragem , Bases de Dados Genéticas , Haploidia , Haplótipos/genética , Humanos , Anotação de Sequência Molecular , Polimorfismo de Nucleotídeo Único/genética , Alinhamento de Sequência
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