ArticleProceedings of the National Academy of Sciences of the United States of America2020
Common homozygosity for predicted loss-of-function variants reveals both redundant and advantageous effects of dispensable human genes.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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27 citing papers in PubMed, 41 citations in OpenAlex.
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- Protein-truncating variant in APOL3 increases chronic kidney disease risk in epistasis with APOL1 risk alleles.JCI insight · 2024Article
- Bayesian estimation of gene constraint from an evolutionary model with gene features.Nature genetics · 2024Article
- Bayesian estimation of gene constraint from an evolutionary model with gene features.bioRxiv : the preprint server for biology · 2024Article
- Burden of Mendelian disorders in a large Middle Eastern biobank.Genome medicine · 2024Article
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- Integrative analysis of risk factors for immune-related adverse events of checkpoint blockade therapy in cancer.Nature cancer · 2023Article
- Rare and population-specific functional variation across pig lines.Genetics, selection, evolution : GSE · 2022Article
- Integrative genetic and immune cell analysis of plasma proteins in healthy donors identifies novel associations involving primary immune deficiency genes.Genome medicine · 2022Article
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12 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Humans homozygous or hemizygous for variants predicted to cause a loss of function (LoF) of the corresponding protein do not necessarily present with overt clinical phenotypes. We report here 190 autosomal genes with 207 predicted LoF variants, for which the frequency of homozygous individuals exceeds 1% in at least one human population from five major ancestry groups. No such genes were identified on the X and Y chromosomes. Manual curation revealed that 28 variants (15%) had been misannotated as LoF. Of the 179 remaining variants in 166 genes, only 11 alleles in 11 genes had previously been confirmed experimentally to be LoF. The set of 166 dispensable genes was enriched in olfactory receptor genes (41 genes). The 41 dispensable olfactory receptor genes displayed a relaxation of selective constraints similar to that observed for other olfactory receptor genes. The 125 dispensable nonolfactory receptor genes also displayed a relaxation of selective constraints consistent with greater redundancy. Sixty-two of these 125 genes were found to be dispensable in at least three human populations, suggesting possible evolution toward pseudogenes. Of the 179 LoF variants, 68 could be tested for two neutrality statistics, and 8 displayed robust signals of positive selection. These latter variants included a known
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