Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 65,152 bioRxiv papers from 288,686 authors.
Evaluating potential drug targets through human loss-of-function genetic variation
Eric V Minikel,
Hilary C Martin,
Beryl B Cummings,
Richard C Trembath,
David A van Heel,
Mark J. Daly,
Genome Aggregation Database Production Team,
Genome Aggregation Database Consortium,
Stuart L Schreiber,
Daniel G. MacArthur
Posted 28 Jan 2019
bioRxiv DOI: 10.1101/530881
Posted 28 Jan 2019
Naturally occurring human genetic variants predicted to cause loss of function of protein-coding genes provide an in vivo model of human gene inactivation that complements cell and model organism knockout studies. Here we investigate the application of human loss-of-function variants to assess genes as candidate drug targets, with three key findings. First, even essential genes, where loss-of-function variants are not tolerated, can be highly successful as targets of inhibitory drugs. Second, in most genes, loss-of-function variants are sufficiently rare that genotype-based ascertainment of homozygous or compound heterozygous "knockout" humans will await sample sizes ~1,000 times those available at present. Third, automated variant annotation and filtering are powerful, but manual curation remains critical for removing artifacts and making biological inferences, and is a prerequisite for recall-by-genotype efforts. Our results provide a roadmap for human "knockout" studies and should guide interpretation of loss-of-function variants in drug development.
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