Correction: Selection on a Variant Associated with Improved Viral Clearance Drives Local, Adaptive Pseudogenization of Interferon Lambda 4 (IFNL4)

Interferon lambda 4 gene (IFNL4) encodes IFN-l4, a new member of the IFN-l family with antiviral activity. In humans IFNL4 open reading frame is truncated by a polymorphic frame-shift insertion that eliminates IFN-l4 and turns IFNL4 into a polymorphic pseudogene. Functional IFN-l4 has antiviral activity but the elimination of IFN-l4 through pseudogenization is strongly associated with improved clearance of hepatitis C virus (HCV) infection. We show that functional IFN-l4 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-l4 inactivation, has shaped present-day phenotypic diversity and susceptibility to disease. Citation: Key FM, Peter B, Dennis MY, Huerta-Sánchez E, Tang W, et al. (2014) Selection on a Variant Associated with Improved Viral Clearance Drives Local, Adaptive Pseudogenization of Interferon Lambda 4 (IFNL4). PLoS Genet 10(10): e1004681. doi:10.1371/journal.pgen. 1004681 Editor: Jonathan K. Pritchard, Stanford University, United States of America Received April 9, 2014; Accepted August 18, 2014; Published October 16, 2014 This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All data is available from 1000 Genomes, ftp:// ftp.1000genomes. ebi.ac. uk/vol1/ftp/phase1/; GENCODE, http://pseudogene.org/psidr/; HapMap, http://hapmap.ncbi. nlm.nih. gov. Funding: FMK and AMA are funded by the Max Planck Society. MYD is supported by the National Institute of Neurological Disorder and Stroke of the U.S. National Institutes of Health (award K99NS083627). WT and LPO are supported by the Intramural Research Program of the NCI/NIH. RN and EHS are supported by research grants R01HG003229 (RN) and R01HG003229-08S2 (EHS) from the U.S. NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * Email: aida_andres@eva.mpg. de