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

Preuss C, Riemenschneider M, Wiedmann D, Stoll M - PLoS ONE (2012)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Genetic Epidemiology of Vascular Disorders, Leibniz Institute for Arteriosclerosis Research (LIFA) at the University of Muenster, Muenster, Germany. christoph.preuss@lifa-muenster.de

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.

Show MeSH
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.
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pone-0036205-g002: 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.

Mentions: Several neutral factors, including genetic drift, population size and demographic effects, can generate stretches of low recombination around closely linked loci enriched for disease variants within the human genome. Here, we were primarily interested in the impact of positive natural selection on the observed enrichment of disease variants in regions of low recombination. Therefore, we compared the distribution of signs of positive selection between the bins holding a different number of disease-associated SNPs using the integrated haplotype score developed by Voight et al. [15]. We observed a significant increase in integrated haplotype score (iHS) signals in the top 2.6% of all windows harboring more than 15 SNPs compared to windows without disease variants and windows containing 1 to 15 disease variants (Mann-Whitney-Wilcoxon test, P<0.05) (Figure 2A).


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

Preuss C, Riemenschneider M, Wiedmann D, Stoll M - PLoS ONE (2012)

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.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3351447&req=5

pone-0036205-g002: 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.
Mentions: Several neutral factors, including genetic drift, population size and demographic effects, can generate stretches of low recombination around closely linked loci enriched for disease variants within the human genome. Here, we were primarily interested in the impact of positive natural selection on the observed enrichment of disease variants in regions of low recombination. Therefore, we compared the distribution of signs of positive selection between the bins holding a different number of disease-associated SNPs using the integrated haplotype score developed by Voight et al. [15]. We observed a significant increase in integrated haplotype score (iHS) signals in the top 2.6% of all windows harboring more than 15 SNPs compared to windows without disease variants and windows containing 1 to 15 disease variants (Mann-Whitney-Wilcoxon test, P<0.05) (Figure 2A).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Genetic Epidemiology of Vascular Disorders, Leibniz Institute for Arteriosclerosis Research (LIFA) at the University of Muenster, Muenster, Germany. christoph.preuss@lifa-muenster.de

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.

Show MeSH