LAUSR

Individuals who lack a functional copy of a gene — gene knockouts — can reveal the gene's role. Most knockout research has used model organisms, but now a comprehensive catalogue of human knockouts is in sight. See Letter p.235 Understanding the function of every human gene is one of the major goals in biomedicine and analysing phenotypes in individuals with loss of function mutations in a particular gene is one way to gain such insight. Sekar Kathiresan and colleagues systematically examined predicted loss-of-function mutations from sequencing data, making preliminary efforts to investigate their functional relevance through phenotypic association. They sequenced the exomes of 10,503 individuals living in Pakistan and participating in the PROMIS study. They identified 49,138 rare predicted loss-of-function mutations that are estimated to knock out 1,317 genes, each in at least one participant, and tested for association with a panel of 201 traits measured in blood samples. The authors demonstrate the usefulness of a reverse-genetics approach, which involves recruiting participants by genotype, and discuss a framework for a human knockout project.