Common Homozygosity for Predicted Loss-Of-Function Variants Reveals Both Redundant and Advantageous Effects of Dispensable Human Genes
Common homozygosity for predicted loss-of-function variants reveals both redundant and advantageous effects of dispensable human genes Antonio Rausella,b,1,2, Yufei Luoa,b,1, Marie Lopezc, Yoann Seeleuthnerb,d, Franck Rapaporte, Antoine Faviera,b, Peter D. Stensonf, David N. Cooperf, Etienne Patinc, Jean-Laurent Casanovab,d,e,g,h,2, Lluis Quintana-Murcic,i, and Laurent Abelb,d,e,2 aClinical Bioinformatics Laboratory, INSERM UMR1163, Necker Hospital for Sick Children, 75015 Paris, France; bUniversity of Paris, Imagine Institute, 75015 Paris, France; cHuman Evolutionary Genetics Unit, Institut Pasteur, UMR2000, CNRS, Paris 75015, France; dLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Necker Hospital for Sick Children, 75015 Paris, France; eSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065; fInstitute of Medical Genetics, School of Medicine, Cardiff University, CF14 4XN Cardiff, United Kingdom; gHoward Hughes Medical Institute, New York, NY 10065; hPediatric Hematology and Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France; and iHuman Genomics and Evolution, Collège de France, Paris 75005, France Contributed by Jean-Laurent Casanova, January 10, 2020 (sent for review October 24, 2019; reviewed by Philippe Froguel, John M. Greally, and Lennart Hammarström). Humans homozygous or hemizygous for variants predicted to in-frame insertions−deletions (indels), missense variants, splice cause a loss of function (LoF) of the corresponding protein do not region variants not affecting the essential splice regions, and even necessarily present with overt clinical phenotypes. We report here synonymous or deep intronic mutations, that may actually be LoF 190 autosomal genes with 207 predicted LoF variants, for which but cannot be systematically identified as such in silico.
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