A global reference for human genetic variation

Abstract

The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies.

Genetic effects on gene expression across human tissues

“…This is 4.3 times more samples than reported in the GTEx pilot phase 10 . DNA was genotyped at 2.2 million sites and imputed to 12.5 million sites (11.5 million autosomal and 1 million X chromosome sites) using the multi-ethnic reference panel from 1000 Genomes Project Phase 1 v3 11 . Sampled donors were 83.7% European American and 15.1% African American.…”

A framework for exhaustively mapping functional missense variants

“…Although GnomAD attempted to exclude subjects with severe pediatric disease, the abundance of rare predicted‐deleterious variants may be understood by the disease's recessive inheritance pattern. Using phased sequence data from the 1000 Genomes Project (The 1000 Genomes Project Consortium, 2015) to determine diploid genotypes in TPK1, we assigned each subject a diploid score corresponding to the maximum (refined) score across each pair of alleles. This improved prediction performance markedly, leading to complete separation between disease and non‐disease genotypes using DMS, PROVEAN, or PolyPhen‐2 scores (Appendix Fig S9B).…”

“…Unfortunately, we have only a limited ability to interpret personal genomes, each carrying 100–400 rare missense variants (The 1000 Genomes Project Consortium, 2015) of which many must currently be classified as “variants of uncertain significance” (VUS). For example, gene panel sequencing aimed at identifying germline cancer risk variants in families yielded VUS for the majority of missense variants (Maxwell et al , 2016).…”

Epigenetic influences on aging: a longitudinal genome-wide methylation study in old Swedish twins

“…Imputation was then performed in chunks of around 5 Mb using IMPUTE2 version 2.3.2 with default parameters [33]. The imputation reference was based on the 1000 Genomes Project phase 1 [34]. Next, a QC step was performed on imputed genotype data to filter out low imputation quality variants (Info<0.6) and low minor allele frequency variants (MAF < 0.05).…”