The extent and impact of human genomic variation revealed by the Genome Aggregation Database, gnomAD, consortium

Each individual’s genome is unique. To reflect this diversity and to capture the extent of variation on an unprecedented scale, the Genome Aggregation Database (gnomAD) has aggregated 15,708 whole genomes and 125,748 exomes (the protein-coding part of the genome). Analyses of this rich resource have created a catalogue of the different types of variation present, and revealed their potential functional impact and how this information could help to identify disease-causing mutations and to prioritize potential drug targets.

The gnomAD flagship paper and several accompanying papers were published in Nature journals this week. Director of FIMM, Mark Daly, has contributed significantly to the work and was one of the senior authors of the flagship paper entitled “The mutational constraint spectrum quantified from variation in 141,456 humans”.

gnomAD includes exomes and genomes from European, Latino African and African American, South Asian, East Asian, Ashkenazi Jewish and other populations. The gnomAD team, led by Daniel MacArthur, consists of more than 100 scientists who have provided either data or analytical effort to the consortium, several of whom come from Finland. gnomAD is also the largest resource of Finnish exome and genome sequencing variation, with data from more than 12 500 Finns.

The flagship study focuses on loss-of-function variants, which completely disrupt the function of the gene product. More than 443 000 such variants were detected among the gnomAD participants. This information can also help disease gene discovery efforts, since a higher or lower than expected number of loss-of-function variants in a particular gene is a valuable indication of gene’s tolerance to disruptive mutations. The less tolerant the gene is, the more likely the damaging variant identified has an impact on the health of the individual.

Interestingly, for 1,815 genes, biallelic loss-of-function variants (both copies of a gene are inactive) were found in at least one individual, suggesting that humans can tolerate the loss of these gene products. The value of loss-of-function variants for the discovery and validation of drug targets was explored further in one of the accompanying papers, providing a roadmap for “human knockout” studies.

This work, only possible as a result of enormous collaboration and data sharing from researchers around the world, has created a resource of unsurpassed importance to both rare disease diagnostics as well as to understanding patterns of variation in common disease and population genetics.  It is gratifying to see how much the scientific community has made progress through such collaboration.

- Mark Daly


Read more:

gnomAD feature in Nature

Flagship paper

Press release from Broad Institute