Abstract
Homozygous loss of function (HLOF) variants provide a valuable window on gene function in humans, as well as an inventory of the human genes that are not essential for survival and reproduction. All humans carry at least a few HLOF variants, but the exact number of inactivated genes that can be tolerated is currently unknown—as are the phenotypic effects of losing function for most human genes. Here, we make use of 1432 whole exome sequences from five European populations to expand the catalogue of known human HLOF mutations; after stringent filtering of variants in our dataset, we identify a total of 173 HLOF mutations, 76 (44%) of which have not been observed previously. We find that population isolates are particularly well suited to surveys of novel HLOF genes because individuals in such populations carry extensive runs of homozygosity, which we show are enriched for novel, rare HLOF variants. Further, we make use of extensive phenotypic data to show that most HLOFs, ascertained in population-based samples, appear to have little detectable effect on the phenotype. On the contrary, we document several genes directly implicated in disease that seem to tolerate HLOF variants. Overall HLOF genes are enriched for olfactory receptor function and are expressed in testes more often than expected, consistent with reduced purifying selection and incipient pseudogenisation.
Highlights
The human genome contains more than 20 000 protein-coding genes, but it is currently unknown how many of these genes are essential for development, survival and reproduction, and how many genes are, to some degree, ‘dispensable’
Using exome sequences from 1432 individuals, we extend the known repertoire of human genes that are dispensable, i.e. genes that can carry homozygous loss of function variants in healthy individuals
We do find the isolate populations to be enriched for homozygous loss of function (LOF) variants of low frequency because rarer variants are relatively more likely to be brought into the homozygous state within the long runs of homozygosity (ROHs) present in these populations
Summary
The human genome contains more than 20 000 protein-coding genes, but it is currently unknown how many of these genes are essential for development, survival and reproduction, and how many genes are, to some degree, ‘dispensable’. All humans carry genetic variants predicted to cause loss of function (LOF) for a variety of protein-coding genes, i.e. they carry frameshift or premature stop codon mutations in the coding regions of genes, whole gene deletions, or splice site disruptions [1]. In addition it has been estimated that each human genome carries around 20 of these LOF variants in the homozygous state (HLOF), resulting in a naturally occurring ‘knockout’ of the gene concerned [2]. Compared with Mendelian disease variants, the phenotypic consequences of such HLOF variants may often be small, though HLOFs may have detectable effects upon more subtle phenotypes. Loss of gene function can have protective effects against disease, and such genes are of particular interest as novel therapeutic drug targets. HLOF at PCSK9 can lead to reduced levels of LDL cholesterol [3], HLOF at SLC30A8 is protective for type 2 diabetes [4] and a homozygous partial deletion of CCR5 protects against HIV infection [5,6]
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