Using loss-of-function human mutations to evaluate drug targets

* IN BRIEF * 08 June 2020 By * Sarah Crunkhorn * Sarah Crunkhorn The identification of individuals with loss-of-function (LOF) variants in a gene of interest can provide information about

gene function and disease biology, as well as the potential safety and phenotypic effects of therapeutic targeting. With the aim of guiding the interpretation of human LOF variation in drug

development, Minikel et al. interrogated their Genome Aggregation Database (gnomAD) — a catalogue of 15,708 whole genomes and 125,748 exomes in 141,456 individuals, designed to capture the

extent of genetic variation among a large group of individuals — and reported their key findings. Through comparison of constraint in human drug targets, they discovered that even a highly

deleterious knockout phenotype may be compatible with a gene being a viable drug target. In addition, they report that given the rarity of LOF variants in most genes, identifying total

knockout individuals will require 1,000-fold larger sample sizes. Finally, by manually curating gnomAD data and the scientific literature for six genes associated with gain-of-function

neurodegenerative diseases, they demonstrated the value of manual curation of LOF variants in removing artefacts, assessing and interpreting the cumulative allele frequency of true LOF

variants, and revealing important error modes or disease biology. ACCESS OPTIONS Access Nature and 54 other Nature Portfolio journals Get Nature+, our best-value online-access subscription

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https://doi.org/10.1038/d41573-020-00104-1_ REFERENCES RELATED ARTICLES