Limits...
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
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.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3351447&req=5

pone-0036205-g001: 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.

Mentions: After performing pairwise non parametric test statistics on our dataset, we found a significant difference in recombination rates between windows enriched for more than 15 disease variants compared to windows harboring only a limited number of disease variants (1–15) (Mann-Whitney-Wilcoxon test, P<0.01) (Figure 1A). However, we did not find evidence that windows which show an enrichment of disease variants are over-represented among regions of low recombination. The most pronounced enrichment of disease variants is observed for the bin with the smallest recombination rate (0–0.5 (cm/Mb)) as displayed in Figure 1B when comparing windows harboring more than 15 disease variants to windows containing less disease variants.


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

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

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.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0036205-g001: 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.
Mentions: After performing pairwise non parametric test statistics on our dataset, we found a significant difference in recombination rates between windows enriched for more than 15 disease variants compared to windows harboring only a limited number of disease variants (1–15) (Mann-Whitney-Wilcoxon test, P<0.01) (Figure 1A). However, we did not find evidence that windows which show an enrichment of disease variants are over-represented among regions of low recombination. The most pronounced enrichment of disease variants is observed for the bin with the smallest recombination rate (0–0.5 (cm/Mb)) as displayed in Figure 1B when comparing windows harboring more than 15 disease variants to windows containing less disease variants.

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