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

Abstract

Genome sequencing studies indicate that all humans carry many genetic variants predicted to cause loss of function (LoF) of protein-coding genes, suggesting unexpected redundancy in the human genome. Here we apply stringent filters to 2,951 putative LoF variants obtained from 185 human genomes to determine their true prevalence and properties. We estimate that human genomes typically contain ~100 genuine LoF variants with ~20 genes completely inactivated. We identify rare and likely deleterious LoF alleles, including 26 known and 21 predicted severe disease-causing variants, as well as common LoF variants in non-essential genes. We describe functional and evolutionary differences between LoF-tolerant and recessive disease genes, and a method for using these differences to prioritize candidate genes found in clinical sequencing studies.

Individualized Iterative Phenotyping for Genome-wide Analysis of Loss-of-Function Mutations

“…A central position (i.e., not near the 3 0 or 5 0 end) of a variant in a gene has been suggested as an attribute that can be used to predict deleteriousness of a variant. 1 Although variants predicted to result in premature truncation close to the ends of the gene might be less likely to disrupt protein function sufficiently to cause disease, variants in BRCA1 and SGCE identified in this study in individuals with positive phenotypes fell within the first 5% of the open reading frame (ORF) and the identified pathogenic variant in PPARG is located at the very 3 0 end of the ORF.…”

“…1 Genome sequence analysis can generate up to 800 pLOF mutations in a single genome, which is much higher than the estimate of true loss-of-function variants, which are estimated to be present at a level closer to 100 variants per person. The large number of pLOF alleles is attributable to sequencing and annotation errors, gene redundancy, hypomorphic alleles, true LOF alleles for carrier states, and LOF mutations in genes that are sensitive to haploinsufficiency.…”

“…The large number of pLOF alleles is attributable to sequencing and annotation errors, gene redundancy, hypomorphic alleles, true LOF alleles for carrier states, and LOF mutations in genes that are sensitive to haploinsufficiency. 1,2 With the increasing use of next-generation sequencing technologies for predictive medicine, it is critical to be able to predict the consequences of pLOFs, especially in individuals without preexisting clinical diagnoses. Although many bioinformatic approaches have been developed to classify missense alterations, there are few tools available to assess pLOF variants.…”

Solving the molecular diagnostic testing conundrum for Mendelian disorders in the era of next-generation sequencing: single-gene, gene panel, or exome/genome sequencing

“…Recent large-scale sequencing and genotyping projects have revealed a surprisingly large number of lossof-function variants-which have traditionally been viewed in the context of severe Mendelian disease-in the genomes of apparently healthy individuals. 20 The newly released variant classification criteria (2014) by the American College of Medical Genetics and Genomics (ACMG) list functional studies as one of the most important components for variant classification. However, functional studies have to be carefully evaluated, especially when using a single viral or bacterial enzyme to study the functionally diverse human proteome.…”

Phenome-wide association studies (PheWASs) for functional variants

“…MacArthur et al 27 were one of the first to systematically survey loss-of-function variants for disease associations. Using the Wellcome Trust Case Control Consortium, 417 loss-of-function variants were associated with seven complex phenotypes in nearly 16 000 patients.…”