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

Related in: MedlinePlus

Plots of Crohn’s disease risk locus at chromosome 5q31.(A) Map of the 5q31 risk locus containing –log(P) values of SNPs (CD SNPs), LD blocks defined by Proxy SNP with r2 >0.8 as well as positions of SNPs considered iHS signals (light colour) or strong iHS signals (darker colour) for the three HapMap populations (blue: CEU, yellow: ASN, brown: YRI). (B) Reference allele frequencies of SNPs showing allele frequency differences in the 95th percentile between at least two of three populations according to 1000 Genomes data. (C) Percentages of SNPs associated with Crohn’s disease, which are iHS signals (left) or show allele frequency difference in the 95th percentile between populations (right).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3351447&req=5

pone-0036205-g004: Plots of Crohn’s disease risk locus at chromosome 5q31.(A) Map of the 5q31 risk locus containing –log(P) values of SNPs (CD SNPs), LD blocks defined by Proxy SNP with r2 >0.8 as well as positions of SNPs considered iHS signals (light colour) or strong iHS signals (darker colour) for the three HapMap populations (blue: CEU, yellow: ASN, brown: YRI). (B) Reference allele frequencies of SNPs showing allele frequency differences in the 95th percentile between at least two of three populations according to 1000 Genomes data. (C) Percentages of SNPs associated with Crohn’s disease, which are iHS signals (left) or show allele frequency difference in the 95th percentile between populations (right).

Mentions: In order to test this hypothesis, we used 1000 Genome Pilot 1 data (www.1000genomes.org) and retrieved allele frequencies for the distinct populations. We found signs of population specific differences accompanied by genetic hitchhiking in the two regions exhibiting the most pronounced enrichment of deleterious SNPs. The first locus resides on chromosome 5q31, a region including genes such as SLC22A4, SLC22A5, IL3 and IRF. The LD block in Figure 4A shows a high iHS signal count in the CEU (8.7% of SNPs) and YRI (7.7% of SNPs) population. Figure 4B displays the selective sweep and the differences in allele frequencies around the IBD5 region, which has been recently associated with genetic hitchhiking in the European population [16]. Among the disease-associated SNPs, 49% in the CEU dataset and only 4% in the YRI dataset display signs of recent selection according to iHS signals (Figure 4C). This reflects differences in the spatial distribution of these signals, as most of the YRI iHS SNPs are clustered in a region without CD association near the gene FNIP1, while CEU signals are located in the vicinity of IL3 and SLC22A4. Regarding CD SNP allele frequencies, the European population is very different from the Asian population (56% of SNP with high allele frequency difference) and the African population (39%, see Figure 4C). Consistently, the index SNP risk allele rs12521668-T is very common in Europeans (0.48), while rare in the other populations (ASN: 0.02, YRI: 0.03). The allele rs1050152-T, which is a putative causal mutation in the SLC22A4 gene [17], shows similar allele frequencies (CEU: 0.39, ASN: 0.02, YRI: 0.03). This suggests that selection pressure acted on the European population and favored CD risk alleles. In the Yoruba population, the different environment was accompanied by different selection pressures, which shaped the neighboring FNIP1 gene. A possible cause of selective sweeps in the 5q31 region might be bacteria, as a recent study has linked this locus to Mycobacterium tuberculosis susceptibility [18]. As a study by Huff et al. pointed out that genetic hitchhiking might have also played a role in increasing CD risk by driving alleles of IRF1 to high frequency while selection pressures were acting on SLC22A4 due to changes in nutrition [16].


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

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

Plots of Crohn’s disease risk locus at chromosome 5q31.(A) Map of the 5q31 risk locus containing –log(P) values of SNPs (CD SNPs), LD blocks defined by Proxy SNP with r2 >0.8 as well as positions of SNPs considered iHS signals (light colour) or strong iHS signals (darker colour) for the three HapMap populations (blue: CEU, yellow: ASN, brown: YRI). (B) Reference allele frequencies of SNPs showing allele frequency differences in the 95th percentile between at least two of three populations according to 1000 Genomes data. (C) Percentages of SNPs associated with Crohn’s disease, which are iHS signals (left) or show allele frequency difference in the 95th percentile between populations (right).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0036205-g004: Plots of Crohn’s disease risk locus at chromosome 5q31.(A) Map of the 5q31 risk locus containing –log(P) values of SNPs (CD SNPs), LD blocks defined by Proxy SNP with r2 >0.8 as well as positions of SNPs considered iHS signals (light colour) or strong iHS signals (darker colour) for the three HapMap populations (blue: CEU, yellow: ASN, brown: YRI). (B) Reference allele frequencies of SNPs showing allele frequency differences in the 95th percentile between at least two of three populations according to 1000 Genomes data. (C) Percentages of SNPs associated with Crohn’s disease, which are iHS signals (left) or show allele frequency difference in the 95th percentile between populations (right).
Mentions: In order to test this hypothesis, we used 1000 Genome Pilot 1 data (www.1000genomes.org) and retrieved allele frequencies for the distinct populations. We found signs of population specific differences accompanied by genetic hitchhiking in the two regions exhibiting the most pronounced enrichment of deleterious SNPs. The first locus resides on chromosome 5q31, a region including genes such as SLC22A4, SLC22A5, IL3 and IRF. The LD block in Figure 4A shows a high iHS signal count in the CEU (8.7% of SNPs) and YRI (7.7% of SNPs) population. Figure 4B displays the selective sweep and the differences in allele frequencies around the IBD5 region, which has been recently associated with genetic hitchhiking in the European population [16]. Among the disease-associated SNPs, 49% in the CEU dataset and only 4% in the YRI dataset display signs of recent selection according to iHS signals (Figure 4C). This reflects differences in the spatial distribution of these signals, as most of the YRI iHS SNPs are clustered in a region without CD association near the gene FNIP1, while CEU signals are located in the vicinity of IL3 and SLC22A4. Regarding CD SNP allele frequencies, the European population is very different from the Asian population (56% of SNP with high allele frequency difference) and the African population (39%, see Figure 4C). Consistently, the index SNP risk allele rs12521668-T is very common in Europeans (0.48), while rare in the other populations (ASN: 0.02, YRI: 0.03). The allele rs1050152-T, which is a putative causal mutation in the SLC22A4 gene [17], shows similar allele frequencies (CEU: 0.39, ASN: 0.02, YRI: 0.03). This suggests that selection pressure acted on the European population and favored CD risk alleles. In the Yoruba population, the different environment was accompanied by different selection pressures, which shaped the neighboring FNIP1 gene. A possible cause of selective sweeps in the 5q31 region might be bacteria, as a recent study has linked this locus to Mycobacterium tuberculosis susceptibility [18]. As a study by Huff et al. pointed out that genetic hitchhiking might have also played a role in increasing CD risk by driving alleles of IRF1 to high frequency while selection pressures were acting on SLC22A4 due to changes in nutrition [16].

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