Datasets used in this study

This is a compressed zip file of all the datasets used in this study grouped by analysis

Selection on a Variant Associated with Improved Viral Clearance Drives Local, Adaptive Pseudogenization of Interferon Lambda 4 (<i>IFNL4</i>)

<div><p>Interferon lambda 4 gene (<i>IFNL4</i>) encodes IFN-λ4, a new member of the IFN-λ family with antiviral activity. In humans <i>IFNL4</i> open reading frame is truncated by a polymorphic frame-shift insertion that eliminates IFN-λ4 and turns <i>IFNL4</i> 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.</p></div

(A) Graphical representation of the different models of selection tested in the ABC analysis (NTR - neutral, SDN - selection on a de novo mutation, and SSV - selection on standing variation).

<p>We simulated one ancestral population that splits at the out-of-Africa event (at 51,000 years ago) into the African (AFR) and the non-African (non-AFR) populations, which experience subsequent migration. The star indicates the appearance of the focal mutation. In the first case the neutral (black) mutation appeared and evolved under neutrality in both populations. In the SDN model the advantageous mutation (red) is immediately under positive selection with strength s_A, and time when selection started t_mut (the prior parameter space for t_mut is indicated by a green line); selection strength is allowed to change in the non-African population to s_NA. In the SSV model the neutral (black) mutation appeared and evolved under neutrality, becoming advantageous in the non-African population (red line) at time t_mut. Prior parameter spaces can be found in methods. (<b>B</b>) Posterior probabilities of the model choice for the different selection models under perfect additivity. (<b>C</b>) Posterior probabilities of the model choice for the different dominance models (and neutrality, NTR). For all models except NTR the posterior probability represent the sum for the SDN and SSV selection models. (<b>D</b>) Posterior probabilities of the model choice for the different selection models under the supra-additive model. In (<b>B</b>), (<b>C</b>), and (<b>D</b>), NTR has negligible posterior probability and is therefore not visible.</p

Derived allele frequency (DAF), LD to rs368234815, and signatures of selection (empirical P-values for F_ST and XP-EHH) for other relevant SNPs across the <i>IFNL</i>-locus.

<p>Derived allele frequency (DAF), LD to rs368234815, and signatures of selection (empirical P-values for F_ST and XP-EHH) for other relevant SNPs across the <i>IFNL</i>-locus.</p

Allele frequency of rs368234815 - ΔG allele (blue) and TT allele (green) for each population from the 1000 Genomes dataset.

<p>American populations of European and African origin (CEU, ASW) are placed near the geographic area of origin. For full population names see <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004681#s4" target="_blank">Methods</a>.</p

Phylogenetic tree showing the dN/dS ratio of each lineage analyzed.

<p>Phylogenetic tree showing the dN/dS ratio of each lineage analyzed.</p

F_ST values and for F_ST, XP-EHH, iHS and Fay and Wu's H (FW) the empirical P-values are shown for rs368234815 in every population.

<p>F_ST values and for F_ST, XP-EHH, iHS and Fay and Wu's H (FW) the empirical P-values are shown for rs368234815 in every population.</p