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PLoS Comput Biol. 2015 Dec 7;11(12):e1004647. doi: 10.1371/journal.pcbi.1004647. eCollection 2015 Dec.

The Characteristics of Heterozygous Protein Truncating Variants in the Human Genome.

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SIB Swiss Institute of Bioinformatics, Lausanne and Basel, Switzerland.
School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Vital-IT group, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
Computational Biology Group, ETH Zurich, Zurich, Switzerland.
J. Craig Venter Institute, La Jolla, California, United States of America.


Sequencing projects have identified large numbers of rare stop-gain and frameshift variants in the human genome. As most of these are observed in the heterozygous state, they test a gene's tolerance to haploinsufficiency and dominant loss of function. We analyzed the distribution of truncating variants across 16,260 autosomal protein coding genes in 11,546 individuals. We observed 39,893 truncating variants affecting 12,062 genes, which significantly differed from an expectation of 12,916 genes under a model of neutral de novo mutation (p<10-4). Extrapolating this to increasing numbers of sequenced individuals, we estimate that 10.8% of human genes do not tolerate heterozygous truncating variants. An additional 10 to 15% of truncated genes may be rescued by incomplete penetrance or compensatory mutations, or because the truncating variants are of limited functional impact. The study of protein truncating variants delineates the essential genome and, more generally, identifies rare heterozygous variants as an unexplored source of diversity of phenotypic traits and diseases.

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