title: Human Knockout Carriers: Dead, Diseased, Healthy, or Improved?
abstract: Whole-genome and whole-exome sequence data from large numbers of individuals reveal that we all carry many variants predicted to inactivate genes (knockouts). This discovery raises questions about the phenotypic consequences of these knockouts and potentially allows us to study human gene function through the investigation of homozygous loss-of-function carriers. Here, we discuss strategies, recent results, and future prospects for large-scale human knockout studies. We examine their relevance to studying gene function, population genetics, and importantly, the implications for accurate clinical interpretations.
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Vagheesh M
authors.initials: VM
authors.lastname: Narasimhan
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Yali
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. Electronic address: cts@sanger.ac.uk.
authors.forename: Chris
authors.initials: C
authors.lastname: Tyler-Smith
mesh_terms: D019295:Computational Biology / Q000379:methods; D020868:Gene Silencing; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005828:Genetics, Population; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006579:Heterozygote; D006801:Humans; D010641:Phenotype; D012641:Selection, Genetic
keywords: clinical interpretation; gene function; loss-of-function variants