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