Common homozygosity for predicted loss-of-function variants reveals both redundant and advantageous effects of dispensable human genes. Antonio Rausell, Yufei Luo, Marie Lopez, Yoann Seeleuthner, Franck Rapaport, Antoine Favier, Peter Stenson, David Cooper, Etienne Patin, Jean-Laurent Casanova, et al. To cite this version: Antonio Rausell, Yufei Luo, Marie Lopez, Yoann Seeleuthner, Franck Rapaport, et al.. Common homozygosity for predicted loss-of-function variants reveals both redundant and advantageous effects of dispensable human genes.. Proceedings of the National Academy of Sciences of the United States of America , National Academy of Sciences, 2020, 117 (24), pp.13626-13636. 10.1073/pnas.1917993117. hal-03020429 HAL Id: hal-03020429 https://hal.archives-ouvertes.fr/hal-03020429 Submitted on 18 Dec 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. ArticleExpress Dear Author Please use this PDF proof to check the layout of your article. If you would like any changes to be made to the layout, you can leave instructions in the online proofing interface. Making your changes directly in the online proofing interface is the quickest, easiest way to correct and submit your proof. Please note that changes made to the article in the online proofing interface will be added to the article before publication, but are not reflected in this PDF proof. If you would prefer to submit your corrections by annotating the PDF proof, please download and submit an annotatable PDF proof by clicking here and you'll be redirected to our PDF Proofing system. Q:1; 2; 3; 4; 5 1 63 2 Common homozygosity for predicted loss-of-function 64 3 65 4 66 5 variants reveals both redundant and advantageous 67 6 68 7 effects of dispensable human genes 69 8 70 Antonio Rausella,b,1,2, Yufei Luoa,b,1, Marie Lopezc, Yoann Seeleuthnerb,d, Franck Rapaporte, Antoine Faviera,b, 9 71 Peter D. Stensonf, David N. Cooperf, Etienne Patinc, Jean-Laurent Casanovab,d,e,g,h,2, Lluis Quintana-Murcic,i, 10 72 and Laurent Abelb,d,e,2 11 73 12 aClinical Bioinformatics Laboratory, INSERM UMR1163, Necker Hospital for Sick Children, 75015 Paris, France; bImagine Institute, University of Paris, 75015 74 c d 13 Paris, France; Human Evolutionary Genetics Unit, Institut Pasteur, UMR2000, CNRS, Paris 75015, France; Laboratory of Human Genetics of Infectious 75 Diseases, Necker Branch, INSERM UMR1163, Necker Hospital for Sick Children, 75015 Paris, France; eSt. Giles Laboratory of Human Genetics of Infectious 14 Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065; fInstitute of Medical Genetics, School of Medicine, Cardiff University, CF14 76 15 4XN Cardiff, United Kingdom; gHoward Hughes Medical Institute, New York, NY 10065; hPediatric Hematology and Immunology Unit, Necker Hospital for 77 i 16 Sick Children, 75015 Paris, France; and Human Genomics and Evolution, Collège de France, Paris 75005, France 78 17 Contributed by Jean-Laurent Casanova, January 10, 2020 (sent for review October 24, 2019; reviewed by Philippe Froguel and Lennart Hammarström) 79 18 80 − 19 Humans homozygous or hemizygous for variants predicted to not predicted to be LoF, such as in-frame insertions deletions 81 cause a loss of function (LoF) of the corresponding protein do not (indels), missense variants, splice region variants affecting the 20 82 necessarily present with overt clinical phenotypes. We report here last nucleotides (nt) of exons, and even synonymous or deep 21 190 autosomal genes with 207 predicted LoF variants, for which intronic mutations, that may actually be LoF but cannot be sys- 22 the frequency of homozygous individuals exceeds 1% in at least tematically identified as such in silico. 23 one human population from five major ancestry groups. No such Many predicted LoF variants have nevertheless been con- 24 genes were identified on the X and Y chromosomes. Manual firmed experimentally, typically by demonstration of their asso- 25 curation revealed that 28 variants (15%) had been misannotated ciation with a clinical phenotype. Of the 229,161 variants Q:9 26 as LoF. Of the 179 remaining variants in 166 genes, only 11 alleles reported in the Human Gene Mutation Database (HGMD) (7), 27 in 11 genes had previously been confirmed experimentally to be as many as 99,027 predicted LoF alleles in 5,186 genes have been GENETICS 28 LoF. The set of 166 dispensable genes was enriched in olfactory found to be disease causing in association and/or functional 90 29 receptor genes (41 genes). The 41 dispensable olfactory receptor studies. For example, for the subset of 253 genes implicated in 91 genes displayed a relaxation of selective constraints similar to that 30 recessive forms of primary immunodeficiencies (8), 12,951 LoF 92 observed for other olfactory receptor genes. The 125 dispensable 31 variants are reported in HGMD. Conversely, a substantial pro- 93 nonolfactory receptor genes also displayed a relaxation of selec- portion of genes harboring biallelic null variants have no dis- 32 94 tive constraints consistent with greater redundancy. Sixty-two of cernible associated pathological phenotype, and several large- 33 95 these 125 genes were found to be dispensable in at least three scale sequencing surveys in adults from the general population 34 human populations, suggesting possible evolution toward pseu- 96 35 dogenes. Of the 179 LoF variants, 68 could be tested for two neu- Significance 97 36 trality statistics, and 8 displayed robust signals of positive 98 37 selection. These variants included a known FUT2 variant that con- 99 fers resistance to intestinal viruses, and an APOL3 variant involved Human genes homozygous for apparent loss of function (LoF) 38 variants are increasingly reported in a sizeable proportion of 100 39 in resistance to parasitic infections. Overall, the identification of 101 166 genes for which a sizeable proportion of humans are homo- individuals without overt clinical phenotypes. Here, we found 40 102 zygous for predicted LoF alleles reveals both redundancies and 166 genes with 179 predicted LoF variants for which the fre- 41 advantages of such deficiencies for human survival. quency of homozygous individuals exceeds 1% in at least one 103 42 of the populations present in databases ExAC and gnomAD. 104 These putatively dispensable genes showed relaxation of se- 43 redundancy | pseudogenization | loss of function | positive selection | 105 44 negative selection lective constraints, suggesting that a considerable proportion 106 45 of these genes may be undergoing pseudogenization. Eight of 107 46 these LoF variants displayed robust signals of positive selec- 108 Q:6 he human genome displays considerable DNA sequence di- tion, including two variants in genes involved in resistance to 47 Q:7 109 Q:8 Tversity at the population level. One of its most intriguing infectious diseases. The identification of dispensable genes will 48 features is the homozygosity or hemizygosity for variants of facilitate the identification of functions that are now re- 110 49 protein-coding genes predicted to be loss-of-function (LoF) dundant, or possibly even advantageous, for human survival. 111 50 found at various frequencies in different human populations 112 51 (1–3). An unknown proportion of these reported variants are not Author contributions: A.R., E.P., J.-L.C., L.Q.-M., and L.A. designed research; A.R., Y.L., 113 52 actually LoF, instead being hypomorphic or isomorphic, because M.L., and L.A. performed research; Y.L., M.L., Y.S., F.R., A.F., P.D.S., and D.N.C. contributed 114 new reagents/analytic tools; A.R., Y.L., M.L., Y.S., and F.R. analyzed data; and A.R., D.N.C., 53 of a reinitiation of translation, readthrough, or a redundant tail, E.P., J.-L.C., L.Q.-M., and L.A. wrote the paper. 115 resulting in lower, normal, or even higher than normal levels of 54 Reviewers: P.F., Imperial College London; and L.H., Karolinska Institutet. 116 protein function. Indeed, a bona fide nonsense allele, predicted 55 Competing interest statement: L.H. coauthored research papers with J.-L.C. in 2017 and 117 56 to be LoF, can actually be gain-of-function (hypermorphic), as with E.P., J.-L.C., L.Q.-M., and L.A. in 2018. 118 illustrated by IκBα mutations (4). Moreover, the LoF may apply 57 Published under the PNAS license. 119 selectively to one isoform or a subset of isoforms of a given gene, 1 58 A.R. and Y.L. contributed equally to this work. 120 but not others (e.g., if the exon carrying the premature stop is 2 59 To whom correspondence may be addressed. Email: [email protected], 121 spliced out for a specific set of alternative transcripts) (5). Fi- [email protected], or [email protected]. 60 nally, there are at least 400 discernible cell types in the human 122 61 This article contains supporting information online at https://www.pnas.org/lookup/suppl/ 123 body (6), and the mutant transcript may be expressed in only a doi:10.1073/pnas.1917993117/-/DCSupplemental. 62 limited number of tissues. Conversely, there are also mutations 124 www.pnas.org/cgi/doi/10.1073/pnas.1917993117 PNAS Latest Articles | 1of11 125 187 have reported human genes apparently tolerant to homozygous to the two databases, and are referred to hereafter as the set of Q:13 126 LoF variants (9–14).