title: 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.
  
  
  RESULTS
  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.
authors.affiliation: Genetic Epidemiology of Vascular Disorders, Leibniz Institute for Arteriosclerosis Research (LIFA) at the University of Muenster, Muenster, Germany. christoph.preuss@lifa-muenster.de
authors.forename: Christoph
authors.initials: C
authors.lastname: Preuss
authors.forename: Mona
authors.initials: M
authors.lastname: Riemenschneider
authors.forename: David
authors.initials: D
authors.lastname: Wiedmann
authors.forename: Monika
authors.initials: M
authors.lastname: Stoll
mesh_terms: D000818:Animals; D003424:Crohn Disease / Q000235:genetics; D004194:Disease / Q000235:genetics*; D019143:Evolution, Molecular; D015321:Gene Rearrangement; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D005810:Multigene Family; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011995:Recombination, Genetic; D014714:Vertebrates / Q000235:genetics