Crohn's disease risk alleles on the NOD2 locus have been maintained by natural selection on standing variation

Shigeki Nakagome, Shuhei Mano, Lukasz Kozlowski, Janusz M. Bujnicki, Hiroki Shibata, Yasuaki Fukumaki, Judith R. Kidd, Kenneth K. Kidd, Shoji Kawamura, Hiroki Oota

Research output: Contribution to journalArticle

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Abstract

Risk alleles for complex diseases are widely spread throughout human populations. However, little is known about the geographic distribution and frequencies of risk alleles, which may contribute to differences in disease susceptibility and prevalence among populations. Here, we focus on Crohn's disease (CD) as a model for the evolutionary study of complex disease alleles. Recent genome-wide association studies and classical linkage analyses have identified more than 70 susceptible genomic regions for CD in Europeans, but only a few have been confirmed in non-European populations. Our analysis of eight European-specific susceptibility genes using HapMap data shows that at the NOD2 locus the CD-risk alleles are linked with a haplotype specific to CEU at a frequency that is significantly higher compared with the entire genome. We subsequently examined nine global populations and found that the CD-risk alleles spread through hitchhiking with a high-frequency haplotype (H1) exclusive to Europeans. To examine the neutrality of NOD2, we performed phylogenetic network analyses, coalescent simulation, protein structural prediction, characterization of mutation patterns, and estimations of population growth and time to most recent common ancestor (TMRCA). We found that while H1 was significantly prevalent in European populations, the H1 TMRCA predated human migration out of Africa. H1 is likely to have undergone negative selection because 1) the root of H1 genealogy is defined by a preexisting amino acid substitution that causes serious conformational changes to the NOD2 protein, 2) the haplotype has almost become extinct in Africa, and 3) the haplotype has not been affected by the recent European expansion reflected in the other haplotypes. Nevertheless, H1 has survived in European populations, suggesting that the haplotype is advantageous to this group. We propose that several CD-risk alleles, which destabilize and disrupt the NOD2 protein, have been maintained by natural selection on standing variation because the deleterious haplotype of NOD2 is advantageous in diploid individuals due to heterozygote advantage and/or intergenic interactions.

Original languageEnglish
Pages (from-to)1569-1585
Number of pages17
JournalMolecular Biology and Evolution
Volume29
Issue number6
DOIs
Publication statusPublished - Jun 1 2012

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Crohn disease
Genetic Selection
natural selection
Crohn Disease
Haplotypes
haplotypes
allele
Alleles
alleles
loci
Population
common ancestry
ancestry
Human Migration
protein
HapMap Project
genome
Genealogy and Heraldry
Proteins
Genome-Wide Association Study

All Science Journal Classification (ASJC) codes

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics

Cite this

Crohn's disease risk alleles on the NOD2 locus have been maintained by natural selection on standing variation. / Nakagome, Shigeki; Mano, Shuhei; Kozlowski, Lukasz; Bujnicki, Janusz M.; Shibata, Hiroki; Fukumaki, Yasuaki; Kidd, Judith R.; Kidd, Kenneth K.; Kawamura, Shoji; Oota, Hiroki.

In: Molecular Biology and Evolution, Vol. 29, No. 6, 01.06.2012, p. 1569-1585.

Research output: Contribution to journalArticle

Nakagome, S, Mano, S, Kozlowski, L, Bujnicki, JM, Shibata, H, Fukumaki, Y, Kidd, JR, Kidd, KK, Kawamura, S & Oota, H 2012, 'Crohn's disease risk alleles on the NOD2 locus have been maintained by natural selection on standing variation', Molecular Biology and Evolution, vol. 29, no. 6, pp. 1569-1585. https://doi.org/10.1093/molbev/mss006
Nakagome, Shigeki ; Mano, Shuhei ; Kozlowski, Lukasz ; Bujnicki, Janusz M. ; Shibata, Hiroki ; Fukumaki, Yasuaki ; Kidd, Judith R. ; Kidd, Kenneth K. ; Kawamura, Shoji ; Oota, Hiroki. / Crohn's disease risk alleles on the NOD2 locus have been maintained by natural selection on standing variation. In: Molecular Biology and Evolution. 2012 ; Vol. 29, No. 6. pp. 1569-1585.
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