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Originally published as Genetics Published Articles Ahead of Print on May 15, 2006.

Genetics, Vol. 173, 1555-1570, July 2006, Copyright © 2006
doi:10.1534/genetics.106.057034

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Rapid Evolution of Major Histocompatibility Complex Class I Genes in Primates Generates New Disease Alleles in Humans via Hitchhiking Diversity

Takashi Shiina*,1, Masao Ota{dagger},1, Sayoko Shimizu*, Yoshihiko Katsuyama{ddagger}, Nami Hashimoto*, Miwa Takasu§, Tatsuya Anzai*, Jerzy K. Kulski*,**, Eri Kikkawa*, Taeko Naruse*, Natsuki Kimura*, Kazuyo Yanagiya*, Atsushi Watanabe*, Kazuyoshi Hosomichi*, Sakae Kohara{dagger}{dagger}, Chie Iwamoto{ddagger}{ddagger}, Yumi Umehara{ddagger}{ddagger}, Alice Meyer§§, Valérie Wanner§§, Kazumi Sano*,§§, Cécile Macquin§§, Kazuho Ikeo{ddagger}{ddagger}, Katsushi Tokunaga§, Takashi Gojobori{ddagger}{ddagger}, Hidetoshi Inoko* and Seiamak Bahram§§,2

* Department of Basic Medical Science and Molecular Medicine, Tokai University School of Medicine, Isehara, Kanagawa 259-1143, Japan, {dagger} Department of Legal Medicine, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan, {ddagger} Department of Pharmacy, Shinshu University Hospital, Matsumoto, Nagano 390-8621, Japan, § Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan, ** Centre for Bioinformatics and Biological Computing, Murdoch University, Murdoch, Western Australia 6150, Australia, {dagger}{dagger} Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Kainan, Wakayama 642-0017, Japan, {ddagger}{ddagger} Center for Information Biology and DNA Data Bank of Japan, National Institute of Genetics, Research Organization of Information and Systems, Mishima, Shizuoka 411-8540, Japan and §§ Human Molecular Immunogenetics, Centre de Recherche d'Immunologie et d'Hématologie, Faculté de Médecine, 67085 Strasbourg, France

2 Corresponding author: Human Molecular Immunogenetics, Centre de Recherche d'Immunologie et d'Hématologie, Faculté de Médecine, 4 rue Kirschleger, 67085 Strasbourg, France.
E-mail: siamak{at}hemato-ulp.u-strasbg.fr

A plausible explanation for many MHC-linked diseases is lacking. Sequencing of the MHC class I region (coding units or full contigs) in several human and nonhuman primate haplotypes allowed an analysis of single nucleotide variations (SNV) across this entire segment. This diversity was not evenly distributed. It was rather concentrated within two gene-rich clusters. These were each centered, but importantly not limited to, the antigen-presenting HLA-A and HLA-B/-C loci. Rapid evolution of MHC-I alleles, as evidenced by an unusually high number of haplotype-specific (hs) and hypervariable (hv) (which could not be traced to a single species or haplotype) SNVs within the classical MHC-I, seems to have not only hitchhiked alleles within nearby genes, but also hitchhiked deleterious mutations in these same unrelated loci. The overrepresentation of a fraction of these hvSNV (hv1SNV) along with hsSNV, as compared to those that appear to have been maintained throughout primate evolution (trans-species diversity; tsSNV; included within hv2SNV) tends to establish that the majority of the MHC polymorphism is de novo (species specific). This is most likely reminiscent of the fact that these hsSNV and hv1SNV have been selected in adaptation to the constantly evolving microbial antigenic repertoire.




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