Suchergebnisse

PUBLISHED ; 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. ; We thank Takafumi Katsumura, Dr Yutaka Suzuki, and Dr Sumio Sugano in the Graduate School of Frontier Sciences, University of Tokyo, for his assistance of protein structure analysis and their technical assistance in DNA sequencing, respectively. We also thank three anonymous reviewers for many helpful comments and suggestions. S.N. was sup- ported by a Grant-in-Aid for the Japan Society for the Promotion of Science (JSPS) Research fellow (21-7453). L.K. was supported by the 7th Framework Programme of the European Union (grant HEALTH-PROT, contract number 229676). J.M.B. was supported by the Polish Ministry of Sci- ence and Higher Education (grant POIG.02.03.00-00-003/ 09). H.S. was supported by Priority Area ??Comparative Ge- nomics?? (20017021) from the Ministry of Education, Cul- ture, Sports, Science and Technology of Japan and by a Grant-in-Aid for Scientific Research (C) from JSPS (21590360). J.R.K. and K.K.K. were supported in part by GM057672. S.K. was supported by a Grant-in-Aid for Sci- entific Research (A) from JSPS (22247036). H.O. was sup- ported by a Grant-in-Aid for Scientific Research (B) from JSPS (21370108).

Abstract

Abstract
A tripartite structure for the genetic origin of Japanese populations states that present-day populations are descended from three main ancestors: (1) the indigenous Jomon hunter–gatherers; (2) a Northeast Asian component that arrived during the agrarian Yayoi period; and (3) a major influx of East Asian ancestry in the imperial Kofun period. However, the genetic heterogeneity observed in different regions of the Japanese archipelago highlights the need to assess the applicability and suitability of this model. Here, we analyse historic genomes from the southern Ryukyu Islands, which have unique cultural and historical backgrounds compared with other parts of Japan. Our analysis supports the tripartite structure as the best fit in this region, with significantly higher estimated proportions of Jomon ancestry than mainland Japanese. Unlike the main islands, where each continental ancestor was directly brought by immigrants from the continent, those who already possessed the tripartite ancestor migrated to the southern Ryukyu Islands and admixed with the prehistoric people around the eleventh century AD, coinciding with the emergence of the Gusuku period. These results reaffirm the tripartite model in the southernmost extremes of the Japanese archipelago and show variability in how the structure emerged in diverse geographic regions.