A Systematic Survey of Loss-of-Function Variants in Human Protein-Coding Genes

TLDR

Defective Gene Detective aims to identify disease‑causing genes, but loss‑of‑function variants frequently turn out to be sequencing errors rather than true genetic changes. The study sought to determine the true extent of loss‑of‑function genes in the human genome. Validation of 1000 Genomes and an additional European genome revealed that an average person carries about 100 genuine loss‑of‑function alleles, roughly 20 of which are homozygous, and that many disease‑associated genes are present in apparently healthy individuals, underscoring the need to refine clinical sequencing interpretation.

Abstract

Defective Gene Detective Identifying genes that give rise to diseases is one of the major goals of sequencing human genomes. However, putative loss-of-function genes, which are often some of the first identified targets of genome and exome sequencing, have often turned out to be sequencing errors rather than true genetic variants. In order to identify the true scope of loss-of-function genes within the human genome, MacArthur et al. (p. 823 ; see the Perspective by Quintana-Murci ) extensively validated the genomes from the 1000 Genomes Project, as well as an additional European individual, and found that the average person has about 100 true loss-of-function alleles of which approximately 20 have two copies within an individual. Because many known disease-causing genes were identified in “normal” individuals, the process of clinical sequencing needs to reassess how to identify likely causative alleles.