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.

Guarding the frontiers: the biology of type III interferons

“…The tree is drawn to scale, with branch lengths measured in the number of substitutions per site. The IFNL4 gene became a liability during human evolution A report identified IFN-λ4 sequences in most mammalian species, with the notable exception of rodents 108 . Phylogenetic analyses (Fig.…”

“…This was confirmed by a bioinformatics analysis that found clear purifying selection acting on all nonhuman IFNL4 genes 108 . The frameshift mutation in human IFNL4 was introduced approximately 55,000 years ago, just before the 'Out of Africa' scenario, and was positively selected almost immediately 108 . This observation raises several interesting questions.…”

Activation of Type I and Type III Interferons in Chronic Hepatitis C

“…1). In fact, the IFNL4 gene, which is evolutionarily conserved in mammals, is recognized as turning into a polymorphic pseudogene in humans [47]. Pseudogenization is inferred to be targeted by a positive selection of various strengths rising in dimension from Africa to Europe and the New World and reaching near fixation in East Asia.…”

Gene–disease association with human IFNL locus polymorphisms extends beyond hepatitis C virus infections

“…14 The presence of the alternate allele (IFNL4-TT) renders IFNL4 a pseudogene and this allele is seen iñ 50% of the European population and in most of the east Asian population, but IFNL4 is a functional gene (IFNL4-ΔG allele) in majority (~95%) of the African population, 16 suggesting that human evolution has played an active role in elimination of a functional IFN-λ4 in the human species. 17 In fact, the pseudogene shows strong positive selection in human evolution, whereas the functional gene is conserved in other mammalian species except in mice and rats where the gene is completely absent. 17 In this article, I review the literature on genetic association studies that have shown the involvement of the HCV-GWAS SNPs in non-HCV disorders that involve both viral diseases and some non-infectious conditions.…”

“…17 In fact, the pseudogene shows strong positive selection in human evolution, whereas the functional gene is conserved in other mammalian species except in mice and rats where the gene is completely absent. 17 In this article, I review the literature on genetic association studies that have shown the involvement of the HCV-GWAS SNPs in non-HCV disorders that involve both viral diseases and some non-infectious conditions. I also update the progress on transcriptional studies of the IFNL4 gene and examine whether the functional IFN-λ4-generating SNP is sufficient to explain the molecular mechanism of causality in the diseases it is associated with, and whether the other IFNL locus SNPs (mainly the ones regulating IFN-λ3 expression) may have any functional roles to play in the observed phenotypes.…”