A map of human genome variation from population-scale sequencing
The 1000 Genomes Project Consortium*
The 1000 Genomes Project aims to provide a deepcharacterization 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 todevelop 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 fourpopulations; 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 haplotypestructure 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 showthat, 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 isfound 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 toinform association and functional studies. From the two trios, we directly estimate the rate of de novo germline base substitution mutations to be approximately 1028 per base pair per generation. Weexplore 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 andpublic data will support the next phase of human genetic research. Understanding the relationship between genotype and phenotype is one of the central goals in biology and medicine. The reference...