A map of human genome variation from population-scale sequencing
Карта вариабельности генома человека на основе секвенирования в масштабах популяций
2010-10-26
SCID: 54.1/w3dfxwdd
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1000 Genomes Projecthuman genome variationsingle nucleotide polymorphismsstructural variantswhole-genome sequencing
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Abstract (AI)
The 1000 Genomes Project aims to provide a deep characterization of human genome sequence variation as a foundation for investigating the relationship between genotype and phenotype. Here we present results of the pilot phase of the project, designed to develop and compare different strategies for genome-wide sequencing with high-throughput platforms. We undertook three projects: low-coverage whole-genome sequencing of 179 individuals from four populations; high-coverage sequencing of two mother–father–child trios; and exon-targeted sequencing of 697 individuals from seven populations. We describe the location, allele frequency and local haplotype structure of approximately 15 million single nucleotide polymorphisms, 1 million short insertions and deletions, and 20,000 structural variants, most of which were previously undescribed. We show that, because we have catalogued the vast majority of common variation, over 95% of the currently accessible variants found in any individual are present in this data set. On average, each person is found to carry approximately 250 to 300 loss-of-function variants in annotated genes and 50 to 100 variants previously implicated in inherited disorders. We demonstrate how these results can be used to inform association and functional studies. From the two trios, we directly estimate the rate of de novo germline base substitution mutations to be approximately 10−8 per base pair per generation. We explore the data with regard to signatures of natural selection, and identify a marked reduction of genetic variation in the neighbourhood of genes, due to selection at linked sites. These methods and public data will support the next phase of human genetic research. This issue of Nature contains the first publication from The 1000 Genomes Project, an international collaboration that will produce an extensive public catalogue of human genetic variation. The plan, in fact, is to sequence about 2,000 unidentified individuals from 20 populations around the world. This first paper presents the results from the project's pilot phase, testing three different strategies for genome-wide sequencing with high-throughput platforms: low-coverage whole-genome sequencing of 179 individuals in three population groups, high-coverage sequencing of two mother–father–child trios, and exon-targeted sequencing of 697 individuals from seven populations. The goal of the 1000 Genomes Project is to provide in-depth information on variation in human genome sequences. In the pilot phase reported here, different strategies for genome-wide sequencing, using high-throughput sequencing platforms, were developed and compared. The resulting data set includes more than 95% of the currently accessible variants found in any individual, and can be used to inform association and functional studies.
Key Findings
1
Analysis of two parent–offspring trios estimated the de novo germline base-substitution mutation rate at approximately 10−8 per base pair per generation.
2
Because the dataset captures most common human variation, more than 95% of currently accessible variants in any individual are represented.
3
Each person carries approximately 250–300 loss-of-function variants in annotated genes and 50–100 variants previously implicated in inherited disorders.
4
Genetic variation is markedly reduced near genes, consistent with natural selection acting through linked sites; the public data support association and functional studies.
5
The pilot 1000 Genomes Project catalogued approximately 15 million SNPs, 1 million short indels, and 20,000 structural variants across diverse populations, most previously undescribed.
Research Object
Human genome sequence variation catalog from population-scale sequencing (1000 Genomes Project pilot data)
Research Subject
the distribution, allele frequencies, haplotype structure, functional consequences, mutation rate, and natural-selection signatures of human genetic variants
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2010-10-26
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