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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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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.
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pone-0036205-g006: 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.

Mentions: Figure 6 provides a comprehensive view on the various aspects of these regions by displaying (a), traces of selective sweeps (b), the clustering of diseases-associated variants and (c) chromosomal rearrangements in the six vertebrate genomes for two of these regions, namely 3p21 and 5q31. An overview of the remaining clusters not discussed in detail here can be found in the supplementary material (Table S1). The gene cluster on chromosome 3p21 (Figure 6) has been associated with a variety of inflammatory diseases linked to the immune system and inflammation including inflammatory bowel disease and arteriosclerosis. The macrophage stimulating protein MST1R and the gluthatione peroxidase 1 (GPX1) have both been associated with CD in independent populations and are subject to positive selection in the mammalian lineage. The gene cluster on chromosome 5q31 (Figure 6) harbors several immune related genes, including the interleukins IL3, IL5 and the interferon regulator IRF1, which have been associated with Crohn’s disease in the European population.


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

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

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.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0036205-g006: 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.
Mentions: Figure 6 provides a comprehensive view on the various aspects of these regions by displaying (a), traces of selective sweeps (b), the clustering of diseases-associated variants and (c) chromosomal rearrangements in the six vertebrate genomes for two of these regions, namely 3p21 and 5q31. An overview of the remaining clusters not discussed in detail here can be found in the supplementary material (Table S1). The gene cluster on chromosome 3p21 (Figure 6) has been associated with a variety of inflammatory diseases linked to the immune system and inflammation including inflammatory bowel disease and arteriosclerosis. The macrophage stimulating protein MST1R and the gluthatione peroxidase 1 (GPX1) have both been associated with CD in independent populations and are subject to positive selection in the mammalian lineage. The gene cluster on chromosome 5q31 (Figure 6) harbors several immune related genes, including the interleukins IL3, IL5 and the interferon regulator IRF1, which have been associated with Crohn’s disease in the European population.

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