Deep sequencing of 10,000 human genomes

TLDR

We report on the sequencing of 10,545 human genomes at 30–40× depth, emphasizing quality metrics and novel variant and sequence discovery. The study generated over 150 million single‑nucleotide variants across coding and noncoding regions by sequencing 10,545 genomes at 30–40× coverage. The data show that 84 % of each genome (including 91.5 % of exons and 95.2 % of known pathogenic sites) can be sequenced confidently, each genome contributes ~8,579 novel variants and 0.7 Mb of non‑reference sequence, and the resulting catalog enables high‑resolution intolerance profiling and demonstrates clinical‑grade quality.

Abstract

We report on the sequencing of 10,545 human genomes at 30×-40× coverage with an emphasis on quality metrics and novel variant and sequence discovery. We find that 84% of an individual human genome can be sequenced confidently. This high-confidence region includes 91.5% of exon sequence and 95.2% of known pathogenic variant positions. We present the distribution of over 150 million single-nucleotide variants in the coding and noncoding genome. Each newly sequenced genome contributes an average of 8,579 novel variants. In addition, each genome carries on average 0.7 Mb of sequence that is not found in the main build of the hg38 reference genome. The density of this catalog of variation allowed us to construct high-resolution profiles that define genomic sites that are highly intolerant of genetic variation. These results indicate that the data generated by deep genome sequencing is of the quality necessary for clinical use.