High coverage whole genome sequencing of the expanded 1000 Genomes Project cohort including 602 trios

ABSTRACT

The 1000 Genomes Project (1kGP), launched in 2008, is the largest fully open resource of whole genome sequencing (WGS) data consented for public distribution of raw sequence data without access or use restrictions. The final (phase 3) 2015 release of 1kGP included 2,504 unrelated samples from 26 populations, representing five continental regions of the world and was based on a combination of technologies including low coverage WGS (mean depth 7.4X), high coverage whole exome sequencing (mean depth 65.7X), and microarray genotyping. Here, we present a new, high coverage WGS resource encompassing the original 2,504 1kGP samples, as well as an additional 698 related samples that result in 602 complete trios in the 1kGP cohort. We sequenced this expanded 1kGP cohort of 3,202 samples to a targeted depth of 30X using Illumina NovaSeq 6000 instruments. We performed SNV/INDEL calling against the GRCh38 reference using GATK’s HaplotypeCaller, and generated a comprehensive set of SVs by integrating multiple analytic methods through a sophisticated machine learning model, upgrading the 1kGP dataset to current state-of-the-art standards. Using this strategy, we defined over 111 million SNVs, 14 million INDELs, and ∼170 thousand SVs across the entire cohort of 3,202 samples with estimated false discovery rate (FDR) of 0.3%, 1.0%, and 1.8%, respectively. By comparison to the low-coverage phase 3 callset, we observed substantial improvements in variant discovery and estimated FDR that were facilitated by high coverage re-sequencing and expansion of the cohort. Specifically, we called 7% more SNVs, 59% more INDELs, and 170% more SVs per genome than the phase 3 callset. Moreover, we leveraged the presence of families in the cohort to achieve superior haplotype phasing accuracy and we demonstrate improvements that the high coverage panel brings especially for INDEL imputation. We make all the data generated as part of this project publicly available and we envision this updated version of the 1kGP callset to become the new de facto public resource for the worldwide scientific community working on genomics and genetics.