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PLoS Genet. 2014 Oct 16;10(10):e1004681. doi: 10.1371/journal.pgen.1004681. eCollection 2014 Oct.

Selection on a variant associated with improved viral clearance drives local, adaptive pseudogenization of interferon lambda 4 (IFNL4).

Author information

1
Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.
2
Department of Integrative Biology, University of California Berkeley, Berkeley, California, United States of America.
3
Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, United States of America.
4
School of Natural Sciences, University of California Merced, Merced, California, United States of America.
5
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.

Erratum in

  • PLoS Genet. 2014 Nov;10(11):e1004882.

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.

PMID:
25329461
PMCID:
PMC4199494
DOI:
10.1371/journal.pgen.1004681
[Indexed for MEDLINE]
Free PMC Article
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