title: Selection on a variant associated with improved viral clearance drives local, adaptive pseudogenization of interferon lambda 4 (IFNL4).
abstract: Interferon lambda 4 gene (IFNL4) encodes IFN-λ4, a new member of the IFN-λ family with antiviral activity. In humans IFNL4 open reading frame is truncated by a polymorphic frame-shift insertion that eliminates IFN-λ4 and turns IFNL4 into a polymorphic pseudogene. Functional IFN-λ4 has antiviral activity but the elimination of IFN-λ4 through pseudogenization is strongly associated with improved clearance of hepatitis C virus (HCV) infection. We show that functional IFN-λ4 is conserved and evolutionarily constrained in mammals and thus functionally relevant. However, the pseudogene has reached moderately high frequency in Africa, America, and Europe, and near fixation in East Asia. In fact, the pseudogenizing variant is among the 0.8% most differentiated SNPs between Africa and East Asia genome-wide. Its raise in frequency is associated with additional evidence of positive selection, which is strongest in East Asia, where this variant falls in the 0.5% tail of SNPs with strongest signatures of recent positive selection genome-wide. Using a new Approximate Bayesian Computation (ABC) approach we infer that the pseudogenizing allele appeared just before the out-of-Africa migration and was immediately targeted by moderate positive selection; selection subsequently strengthened in European and Asian populations resulting in the high frequency observed today. This provides evidence for a changing adaptive process that, by favoring IFN-λ4 inactivation, has shaped present-day phenotypic diversity and susceptibility to disease.
authors.affiliation: Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.
authors.forename: Felix M
authors.initials: FM
authors.lastname: Key
authors.affiliation: Department of Integrative Biology, University of California Berkeley, Berkeley, California, United States of America.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Peter
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, United States of America.
authors.forename: Megan Y
authors.initials: MY
authors.lastname: Dennis
authors.affiliation: School of Natural Sciences, University of California Merced, Merced, California, United States of America.
authors.forename: Emilia
authors.initials: E
authors.lastname: Huerta-Sánchez
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Prokunina-Olsson
authors.affiliation: Department of Integrative Biology, University of California Berkeley, Berkeley, California, United States of America.
authors.forename: Rasmus
authors.initials: R
authors.lastname: Nielsen
authors.affiliation: Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.
authors.forename: Aida M
authors.initials: AM
authors.lastname: Andrés
mesh_terms: D000349:Africa; D000818:Animals; D044466:Asian People / Q000235:genetics; D001483:Base Sequence; D001499:Bayes Theorem; D017124:Conserved Sequence; D005202:Asia, Eastern; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population; D015894:Genome, Human; D006239:Haplotypes; D006526:Hepatitis C / Q000235:genetics / Q000821:virology; D006801:Humans; D007378:Interleukins / Q000235:genetics* / Q000502:physiology; D008322:Mammals / Q000235:genetics; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D011544:Pseudogenes; D012641:Selection, Genetic; D044465:White People / Q000235:genetics; D000095022:Interferon Lambda
chemical_list: D007378:Interleukins; C579163:IFNL4 protein, human; D000095022:Interferon Lambda