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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.

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Related in: MedlinePlus

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).
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pone-0036205-g003: 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).

Mentions: To find traces of population specific signs of positive selection, iHS values were retrieved from the Caucasian Europeans/Utah (CEU), East Asians (ASN) and Yoruba/Ibidan (YRI) datasets [15]. iHS signals were retrieved for all SNPs associated with Crohn’s disease (CD) at p<1.0×10−4 in the meta-analysis [10] (see methods section). SNPs with /iHS/ >2 were defined as “iHS signals” while SNPs with /iHS/ >2.5 were defined as “strong iHS signals”. The genome-wide frequency of iHS signals for all SNPs resolves around 4% depending on the population and is lower compared to the disease-associated SNPs in the different populations resolving around 6%-11% as displayed in Figure 3A. The most striking deviation in iHS frequency was observed for the ASN dataset, in which 11.4% of SNPs associated with CD in the European population correspond with iHS signals exhibiting genome-wide significance. In the CEU population, 6.9% of SNPs within these regions fell into this category and 6.2% of the SNPs in the YRI dataset. Figure 3B highlights that when considering only iHS signals with a stringent threshold of >2.5, the same distribution of iHS signals can be observed for the distinct populations. The deviation in iHS signals between the three populations points towards population specific differences that account for the differences in disease allele frequencies between the populations.


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

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

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).
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Related In: Results  -  Collection

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

pone-0036205-g003: 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).
Mentions: To find traces of population specific signs of positive selection, iHS values were retrieved from the Caucasian Europeans/Utah (CEU), East Asians (ASN) and Yoruba/Ibidan (YRI) datasets [15]. iHS signals were retrieved for all SNPs associated with Crohn’s disease (CD) at p<1.0×10−4 in the meta-analysis [10] (see methods section). SNPs with /iHS/ >2 were defined as “iHS signals” while SNPs with /iHS/ >2.5 were defined as “strong iHS signals”. The genome-wide frequency of iHS signals for all SNPs resolves around 4% depending on the population and is lower compared to the disease-associated SNPs in the different populations resolving around 6%-11% as displayed in Figure 3A. The most striking deviation in iHS frequency was observed for the ASN dataset, in which 11.4% of SNPs associated with CD in the European population correspond with iHS signals exhibiting genome-wide significance. In the CEU population, 6.9% of SNPs within these regions fell into this category and 6.2% of the SNPs in the YRI dataset. Figure 3B highlights that when considering only iHS signals with a stringent threshold of >2.5, the same distribution of iHS signals can be observed for the distinct populations. The deviation in iHS signals between the three populations points towards population specific differences that account for the differences in disease allele frequencies between the populations.

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
Related in: MedlinePlus