@article {Bartha010611, author = {Istvan Bartha and Antonio Rausell and Paul J McLaren and Manuel Tardaguila and Pejman Mohammadi and Jacques Fellay and Amalio Telenti}, title = {Heterozygous gene truncation delineates the human haploinsufficient genome}, elocation-id = {010611}, year = {2014}, doi = {10.1101/010611}, publisher = {Cold Spring Harbor Laboratory}, abstract = {Sequencing projects have identified large numbers of rare stop gain and frameshift variants in the human genome. Because most of these are observed in the heterozygous state, they test the genome{\textquoteright}s tolerance to dominant loss of function. We analyzed the distribution of truncating variants in 16818 protein coding autosomal genes from the exomes of 11546 individuals. We observed 45044 truncating variants affecting 12735 genes, against an expectation of observing 13612 genes under a model of neutral evolution. Extrapolating this to a larger human population, we estimate that 8-9\% of genes would not tolerate heterozygous truncation. The study of dominant loss of function variants delineates the essential genome, and underscores the functional importance of haploinsufficiency.}, URL = {https://www.biorxiv.org/content/early/2014/10/23/010611}, eprint = {https://www.biorxiv.org/content/early/2014/10/23/010611.full.pdf}, journal = {bioRxiv} }