Evolutionary dynamics of co-segregating gene clusters associated with complex diseases

Abstract

Background: The distribution of human disease-associated mutations is not random across the human genome. Despite the fact that natural selection continually removes disease-associated mutations, an enrichment of these variants can be observed in regions of low recombination. There are a number of mechanisms by which such a clustering could occur, including genetic perturbations or demographic effects within different populations. Recent genome-wide association studies (GWAS) suggest that single nucleotide polymorphisms (SNPs) associated with complex disease traits are not randomly distributed throughout the genome, but tend to cluster in regions of low recombination.

Principal findings: Here we investigated whether deleterious mutations have accumulated in regions of low recombination due to the impact of recent positive selection and genetic hitchhiking. Using publicly available data on common complex diseases and population demography, we observed an enrichment of hitchhiked disease associations in conserved gene clusters subject to selection pressure. Evolutionary analysis revealed that these conserved gene clusters arose by multiple concerted rearrangements events across the vertebrate lineage. We observed distinct clustering of disease-associated SNPs in evolutionary rearranged regions of low recombination and high gene density, which harbor genes involved in immunity, that is, the interleukin cluster on 5q31 or RhoA on 3p21.

Conclusions: Our results suggest that multiple lineage specific rearrangements led to a physical clustering of functionally related and linked genes exhibiting an enrichment of susceptibility loci for complex traits. This implies that besides recent evolutionary adaptations other evolutionary dynamics have played a role in the formation of linked gene clusters associated with complex disease traits.

Figure 1. Enrichment of disease variants in regions of low recombination.

(A) Boxplots displaying local recombination rates for sliding windows of 500 kb harboring a different number of disease variants (0, 1–15,>15). (B) Ratio of windows showing an enrichment of disease variants (>15 disease variants) compared to windows without such a clustering (<15 disease variants) for different bins of local recombination rates.

Figure 2. Clustering of iHS signals in regions enriched with disease variants.

Boxplots highlighting (A) the distribution of mean iHS signals in regions enriched with disease variants (>15) compared to regions with a moderate number of disease associations (1–15) and (B) the ratio of strong iHS signals |iHS >2| for these regions.

Figure 3. iHS signal percentages for Crohn’s disease in the three HapMap populations.

Amounts of (A) iHS signals and (B) strong iHS signals are given as percentages out of all SNPs genome-wide (w.g.), SNPs associated with Crohn’s disease (assoc) or all SNPs in linkage disequilibrium of associated SNPs at r² > 0.8 (in LD) for the three HapMap populations (Blue: CEU, yellow: ASN, brown: YRI).

Figure 4. Plots of Crohn’s disease risk locus at chromosome 5q31.

(A) Map of the 5q31 risk locus containing –log(P) values of SNPs (CD SNPs), LD blocks defined by Proxy SNP with r² >0.8 as well as positions of SNPs considered iHS signals (light colour) or strong iHS signals (darker colour) for the three HapMap populations (blue: CEU, yellow: ASN, brown: YRI). (B) Reference allele frequencies of SNPs showing allele frequency differences in the 95^th percentile between at least two of three populations according to 1000 Genomes data. (C) Percentages of SNPs associated with Crohn’s disease, which are iHS signals (left) or show allele frequency difference in the 95^th percentile between populations (right).

Figure 5. Plots of Crohn’s disease risk locus at chromosome 3p21.

(A) Map of the 3p21 risk locus containing -log(P) values of SNPs, LD blocks defined by Proxy SNP with r² >0.8 as well as positions of SNPs considered iHS signals (light colour) or strong iHS signals (darker colour) for the three HapMap populations (CEU: blue, ASN: yellow, YRI: brown). (B) Reference allele frequencies of SNPs showing allele frequency differences in the 95^th percentile between at least two of three populations according to 1000 Genomes data. (C) Density plot of reference allele frequencies of SNPs associated with Crohn’s disease. Allele frequencies were retrieved from 1000 Genomes (CEU: blue, ASN: yellow, YRI: brown). (D) Percentages of SNPs associated with Crohn’s disease, which are iHS signals (left) or show allele frequency difference in the 95^th percentile between populations (right).

Figure 6. Overview of the co-segregating gene cluster on chromosome 3p21 and 5q31.

(A) Plot marking the extended haplotype homozygosity for the Asian population (3p21) and the European population (5q31) based on strong iHS signals (iHS >2.5) (B) Disease variant distribution (-log (P) values) for the co-segregating gene clusters in the human genome for the region on chromosome 3p21 (48–51 Mb) and 5q31 (130–133 Mb) and the local recombination rates. (C) Chromosomal rearrangements and organization of the co-segregating gene clusters in the different vertebrate lineages.