現在のHLAの多様性は過去数百万年からそれ以上にわたりアフリカという環境の中でヒトが出会った細菌やウイルス（パソジェン） との共進化の結果できあがってきました。しかし、現生人類の集団はHLAの歴史に比較すると非常に短時間の間に、アフリカから全世界へ 生息環境を拡大させていきました。その過程で、アフリカでは出会うことのない地域特異的なウイルスや細菌に遭遇し、それらの新たな パソジェンにも適応していったことは想像に難くありません。長い時間をかけて作り上げられてきた多様性と、短時間で適応する必要があった 地域の特性という異なる進化学的な力のもとで、どのようにして現在のHLAの多様性が形成されてきたかを結合ペプチドの変化という観点から 明らかにしていこうと考えています。また、病因ペプチドの起源等、免疫関連疾患の進化学的意義を明らかにしたいと考えています。
The current human leukocyte antigen (HLA) diversity arose through the co-evolution of humans and pathogens (bacteria or viruses) in Africa over several million years before the exodus of modern humans from Africa. However, within the context of HLA evolutionary history, the subsequent period over which modern human populations migrated from Africa to other regions of the world was very short. It also likely that as these ancestral human populations colonized new areas, they would have encountered viruses and bacteria that did not exist in Africa, and that they would have adapted to these novel pathogens. Taken together, these two periods (within African and out of Africa) in the evolutionary history of humans have manifested as differences in the extent of HLA diversity or the mode of HLA evolution: specifically, one pattern of diversity arose over an extended period within Africa, while the other arose in the regions out of Africa, when humans needed to adapt to novel pathogens in a short period. In this study, we elucidated how the extant HLA diversity has evolved under these disparate different evolutionary forces focusing on the HLA peptide binding region. In addition, we also consider the evolutionary aspects of immune diseases.
ヒトのMHC（HLA）分子は、感染症への耐性に重要なことから多くの研究が行われてきました。過去20年間に、データベースのHLAアリル の塩基配列数が飛躍的に増え、それらをもとにHLA loci,HLA-A,-B,-C,-DRB1,-DQB1,and-DPB1について自然選択の強度の再推定を行い、 過去のデータの推定値との違いについて検討しています。さらにこの解析からHLA-DRB1遺伝子のPBRに興味深い進化パターンを発見しました。 機能アリルの数ペアはPBRにおいてアミノ酸置換がない一方、多くの非同義置換の蓄積がみられました。 そこで、PBRの非同義サイトにおけるアミノ酸置換パターン、特にペプチド結合ポケットを構成するアミノ酸を詳細に調べました。その結果、 アリル系統が異なるアリル間で、結合ポケットのアミノ酸サイトにおいて多重置換を起こしているように見えました。つまりそれは、何らかの機能的 制約で、それらのサイトでは使用できつアミノ酸残基が制限されていることを示唆しています。
To date, HLA has been extensively studied because of its importance in the immune response against pathogen infection. During the past two decades, the number of reported HLA alleles has increased significantly and a large number of nucleotide sequences for these regions have been made available in genetic databases. We therefore re-estimated several population parameters related to HLA evolution based on currently available sequences at six polymorphic HLA loci; HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1. The parameters estimated in the present analysis were compared with previous estimates that were based on fewer nucleotide sequences. The estimates are roughly the same as previously estimated ones. We found, however, an interesting evolutionary pattern in the nucleotide substitutions at peptide binding region (PBR) of the HLA-DRB1 genes. Several pairs of functional alleles showed no amino acid substitutions in the PBR, but substantial substitutions at other neutral sites (non-PBR sites). To resolve this problem, we conducted detailed examinations of amino acid substitution patterns at PBR nonsynonymous sites, particularly sites associated with peptide binding pockets. The results revealed that multiple substitutions appeared to occur at peptide binding pockets of different allelic lineages. These findings suggest that the number of amino acid residues are limited due to functional constraints
LAU Q., YASUKOCHI Y., SATTA Y. 2015 A limit to the divergent allele advantage model supported by variable pathogen recognition across HLA-DRB1 allele lineages. Tissue Antigens 86:343-352
YASUKOCHI Y., SATTA Y. 2014 A human-specific allelic group of the MHC DRB1 gene in primates. Journal of physiological anthropology 33:14
YASUKOCHI Y., SATTA Y. 2014 Nonsynonymous substitution rate heterogeneity in the peptide-binding region among different HLA-DRB1 lineages in humans. G3 4:1217-1226
YASUKOCHI, Y., and Y. SATTA, 2013
Current perspectives on the intensity of natural selection of MHC loci. Immunogenetics 65(6): 479-483