Homozygous loss-of-function variants in European cosmopolitan and isolate populations

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.

Translational plasticity facilitates the accumulation of nonsense genetic variants in the human population

“…Consistent with the apparently mild purifying selection acting on common loss-offunction variants, a recent study of five European populations reported that no homozygous lossof-function variants within these populations were associated with detectable phenotypic deviance (Kaiser et al 2015). This report is consistent with expectations based on a gene disruption screen in zebrafish, which found that only 6% of randomly induced nonsense or splice site mutations yielded an embryonic phenotype (Kettleborough et al 2013).…”

“…Second, loss-offunction variants may disrupt coding DNA yet not completely disable their (essential) host genes' functions. Consistent with this hypothesis, previous studies noted that many loss-offunction variants do not affect all isoforms of their parent genes, and furthermore that loss-offunction variants are enriched near the 3' ends of coding sequences (MacArthur et al 2012;Liu and Lin 2015;Kaiser et al 2015). These observations suggest that some loss-of-function variants may not completely destroy the coding potential of their host genes, potentially explaining why those variants are well-tolerated.…”

“…Sequence analyses reported in previous studies suggest that both alternative splicing and protein truncation may contribute to the robust protein production from genes containing nonsense variants that we observed (Figure 1C-E). Approximately one-third of previously studied nonsense variants are isoform-specific (MacArthur et al 2012;Kaiser et al 2015); minor coding isoforms are enriched for nonsense variants relative to major isoforms (Liu and Lin 2015); nonsense variants preferentially occur at the 3' ends of their host CDSs (MacArthur et al 2012;Sulem et al 2015). We therefore set out to systematically identify molecular mechanisms that enabled protein production from genes containing nonsense variants.…”

Settling the score: variant prioritization and Mendelian disease

“…Moreover, in loci such as the ABO blood group gene 43 , a significant proportion of the human population has inherited at least one frameshifting variant. In many cases, even though these highly damaging alleles destroy protein function, they seem to have little (if any) impact on health, even when homozygous 44 . Obviously, other approaches beyond sequence conservation are needed for prioritization of stop codons and frameshifts.…”

New insights on the pharmacogenomics of antidepressant response from the GENDEP and STAR*D studies: rare variant analysis and high-density imputation

“…The gene-level meta-analysis did not show any consistent finding. Indeed the olfactory receptor family 4 subfamily K member 2 (OR4K2) gene reached the significance threshold ( Supplementary Table 6) but the effect of rare alleles on symptom improvement had opposite direction between GENDEP and STAR*D. Olfactory receptor genes have been shown to be over-represented among homozygous loss of function (HLOF) genes and segregating polymorphisms of functional and nonfunctional copies of olfactory genes are common (66). The olfactory receptor family is the most polymorphic family of genes in humans after the major histocompatibility complex and the phenotypic consequences of such genetic variability are not completely clear but likely not dramatic given their large diffusion (67).…”