Patterns of Population Differentiation and Natural Selection on the Celiac Disease Background Risk Network

<div><p>Celiac disease is a common small intestinal inflammatory condition induced by wheat gluten and related proteins from rye and barley. Left untreated, the clinical presentation of CD can include failure to thrive, malnutrition, and distension in juveniles. The disease can additionally lead to vitamin deficiencies, anemia, and osteoporosis. Therefore, CD potentially negatively affected fitness in past populations utilizing wheat, barley, and rye. Previous analyses of CD risk variants have uncovered evidence for positive selection on some of these loci. These studies also suggest the possibility that risk for common autoimmune conditions such as CD may be the result of positive selection on immune related loci in the genome to fight infection. Under this evolutionary scenario, disease phenotypes may be a trade-off from positive selection on immunity. If this hypothesis is generally true, we can expect to find a signal of natural selection when we survey across the network of loci known to influence CD risk. This study examines the non-HLA autosomal network of gene loci associated with CD risk in Europe. We reject the null hypothesis of neutrality on this network of CD risk loci. Additionally, we can localize evidence of selection in time and space by adding information from the genome of the Tyrolean Iceman. While we can show significant differentiation between continental regions across the CD network, the pattern of evidence is not consistent with primarily recent (Holocene) selection across this network in Europe. Further localization of ancient selection on this network may illuminate the ecological pressures acting on the immune system during this critically interesting phase of our evolution.</p></div

Mean observed heterozygosity across CD GWAS SNPs from 1000 Genomes and Iceman.

<p>Histograms represent the distributions of observed average heterozygosities across 49 GWAS SNPs associated with CD in Europeans (Blue), East Asians (Red), Africans (Orange), and the Iceman (black arrow). This figure illustrates that the Iceman’s mean heterozygosity across CD associated loci is low compared to present-day Europeans.</p

Estimated effect of low coverage in the Iceman genome on mean heterozygosity at GWAS loci.

<p>Box plot illustrating the distribution of observed mean heterozygosity across 49 GWAS SNPs in present Europeans from the 1000 Genomes Project (Orange), the expected distribution of mean heterozygosity based on resampling from allele frequencies in Europe (Red), and the expected distribution of mean heterozygosity based on allele frequencies in Europe and random sampling of alleles according to the distribution of read coverage in the Iceman (Blue). Although there is a significant reduction in mean heterozygosity, the range of values is similar, suggesting that the observed reduction of heterozygosity in the Iceman compared to present Europeans is genuine.</p

Genome-wide high-F_ST ratio decay and non-HLA risk loci values.

<p>In each plot, the histogram represents the genome-wide distribution (11,000 samples) of the fraction of SNPs in each locus with F_ST higher than the 99% genome-wide upper boundary (black line) this distribution is plotted against the high- F_ST ratio for each CD risk locus bin in this analysis ordered from smallest to largest. Dots above the line represent loci with significantly elevated high- F_ST ratios (P<0.05). Raw data for CD regions is found in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0070564#pone.0070564.s001" target="_blank">Table S1</a>. a. within Africa, b. within East Asia, c. within Europe, d. between Europe/East Asia, e. between Africa/East Asia, f. between Africa/Europe.</p

Additional file 2: of Adaptively introgressed Neandertal haplotype at the OAS locus functionally impacts innate immune responses in humans

Supplementary tables. (XLSX 1030 kb

Additional file 1: of Adaptively introgressed Neandertal haplotype at the OAS locus functionally impacts innate immune responses in humans

Supplementary figures. (PDF 2303 kb