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million bi-allelic indels and 14,000 large deletions (Table 1).

Several technologies were used to validate a frequency-matched set of sites to assess and control the false discovery rate (FDR) for all variant types.

Characterizing such variants, for both point mutations and structural changes, across a range of populations is thus likely to identify many variants of functional importance and is crucial for interpreting individual genome sequences, to help separate shared variants from those private to families, for example. H.; HHSN268201100040C to the Coriell Institute for Medical Research; a Sandler Foundation award and an American Asthma Foundation award to E. B.; an IBM Open Collaborative Research Program award to Y.

We now report on the genomes of 1,092 individuals sampled from 14 populations drawn from Europe, East Asia, sub-Saharan Africa and the Americas (Supplementary Figs 1 and 2), analysed through a combination of low-coverage (2–6×) whole-genome sequence data, targeted deep (50–100×) exome sequence data and dense SNP genotype data (Table 1 and Supplementary Tables 1–3).

5% frequency) variants were discovered in the pilot phase of the 1000 Genomes Project, lower-frequency variants, particularly those outside the coding exome, remain poorly characterized.

Low-frequency variants are enriched for potentially functional mutations, for example, protein-changing variants, under weak purifying selection.

By developing methods to integrate information across several algorithms and diverse data sources, we provide a validated haplotype map of 38million short insertions and deletions, and more than 14,000 larger deletions.

We show that individuals from different populations carry different profiles of rare and common variants, and that low-frequency variants show substantial geographic differentiation, which is further increased by the action of purifying selection.

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We show that evolutionary conservation and coding consequence are key determinants of the strength of purifying selection, that rare-variant load varies substantially across biological pathways, and that each individual contains hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites. Do.; a Howard Hughes Medical Institute International Fellowship award to P. This resource, which captures up to 98% of accessible single nucleotide polymorphisms at a frequency of 1% in related populations, enables analysis of common and low-frequency variants in individuals from diverse, including admixed, populations.

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