The Characteristics of Heterozygous Protein Truncating Variants in the Human Genome

• DOI: 10.1371/journal.pcbi.1004647
• Publication Date: 2015-12-08T19:16:49Z
• Authors: István Bartha; Antonio Rausell; Paul J. McLaren; Pejman Mohammadi; Manuel Tardaguila; Nimisha Chaturvedi; Jacques Fellay; Amalio Telenti
• Keywords: Haploinsufficiency; Penetrance; Human genetics

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