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Common homozygosity for predicted loss-of-function variants reveals both redundant and advantageous effects of dispensable human genes.

Authors :
Rausell, Antonio
Yufei Luo
Lopez, Marie
Seeleuthner, Yoann
Rapaport, Franck
Favier, Antoine
Stenson, Peter D.
Cooper, David N.
Patin, Etienne
Casanova, Jean-Laurent
Quintana-Murci, Lluis
Abel, Laurent
Source :
Proceedings of the National Academy of Sciences of the United States of America. 6/16/2020, Vol. 117 Issue 24, p13626-13636. 11p.
Publication Year :
2020

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 FUT2 variant that confers resistance to intestinal viruses, and an APOL3 variant involved in resistance to parasitic infections. Overall, the identification of 166 genes for which a sizeable proportion of humans are homozygous for predicted LoF alleles reveals both redundancies and advantages of such deficiencies for human survival. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00278424
Volume :
117
Issue :
24
Database :
Academic Search Index
Journal :
Proceedings of the National Academy of Sciences of the United States of America
Publication Type :
Academic Journal
Accession number :
143843988
Full Text :
https://doi.org/10.1073/pnas.1917993117