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内容記述 |
Major histocompatibility complex (MHC) genes code for glycoproteins that can trigger the so- called acquired immune system by presenting non-self peptides to T cells. MHC class I genes evolved with rapid gene duplications and turnover. Indeed, comparative studies of marsupial and eutherian MHC class I genes have shown that the two mammalian subclasses express MHC class I genes of different evolutionary lineages. Furthermore, orthologous relationships have not been established among MHC class I genes of different mammalian orders, such as rodents, primates and so on. Until now, this also holds true even within primates, and New World monkeys (NWMs) occupy a critical phylogenetic position in elucidating the evolutionary process of MHC class I genes in primates. Although there have been many studies about primate MHC evolution, almost all studies have concentrated on humans, apes and Old World monkeys. These studies have revealed some orthologous relationships, but not with NWMs. To reconstruct the evolutionary history of primate MHC class I genes, it is imperative to examine NWMs.<br /> In outer to understand the evolutionary dynamics of primate MHC class I genes, the orthologous relationships of various MHC genes, particularly B and G related or group B and G genes, were examined in three species of NWMs. The 5' flanking region of class I genes was used in the analysis because this region contains a number of phylogenetically informative insertion elements and numerous nucleotide substitutions. From three subfamilies of Aotinae, Cebinae and Atelinae, the 5' flanking regions of 18 class I genes were obtained and phylogenetically examined in terms of their Alu/LINE insertion elements and nucleotide substitutions. Two pairs of genes from Aotinae and Atelinae are clearly orthologous to the HLA-E and -F genes. Among the remaining 14 genes, eight belong to a distinct group B, together with HLA-B and -C, but not with other HLA class I genes. These eight NWM genes are grouped into four, which are designated as NWM-Bl, -B2, -B3 and -B4. Of these, NWM-B2 is orthologous to HLA- B/C. Orthologous relationships of NWM-Bl, -B2 and -B3 are present between different families of Cebidae and Atelidae, which is in sharp contrast to the genus-spectfic gene organization within subfamily Callitrichinae. The other six genes belong to a distinct group G. However, a monophyletic clade of these six NWM genes is almost equally related to HLA-A, -J, -G or -K, and there is no strong support for their orthologous relationship to HLA-G. It is argued that class I genes in simian primates are extensively duplicated in their common ancestral lineage, and that their subsequent evolution in descendant species has been facilitated mainly by the independent loss of genes. <br /> Following on the above, DNA sequence data from HLA class I genes were analyzed, including pseudogenes, to estimate the time when previously functional HLA genes became pseudogenes. The functional cnstraint at nonsynonymous sites must have been relaxed since a HLA gene became a pseudogene. Using this change in functional constraint, I estimated the time of HLA pseudogenizaion. Four HLA pseudogenes (HLA-H, -J, -K and -L) were compared with functional HLA genes belonging to the most closely related groups (HLA-A, -G, -G and -B). The HLA dysfunctioning times were estimated as 1.3-6.6, 14.7-33.2, 36.6-45.9 and 46.2-46.6 million years (myr) ago for HLA-H, -J, -K and -L, respectively It is suggested that there have always been six to eight functional HLA genes at any given time during the past 50 myr. <br /> Finally, in order to explore the evolutionary trends of classical or nonclassical class I genes, I examined the HLA promoter region and peptide binding region (PBR), and discuss the functional changes of MHC class I genes in NWMs. The regulatory elements in HLA classical class I genes seem to be fairly well conserved On the other hand, nonclassical class I genes display nucleotide sequence variations when compared to sequences of classical class I gene promoters. Promoter sequence analysis of MHC genes of Aotus trivirgatus shows that Aotr-B1 and -B2 have nonclassical-like characteristics, and Aotr-B3, -G1 and - G2 have classical-like characteristics. Aotr-B1 lacks X2 and a TATA box, and Aotr-B2 lacks almost all transcription binding sites. In Aotr-G1 and -G2, all binding sites that are observed in classical class I genes are intact, whereas Aotr-B3 lacks only a TATA box. A phylogenetic analysis of PBRs supports the above characteristics. Consequently, it is suggested that there is no obvious relationship between the groups defined by phylogenetic analyses and the division of classical and nonclassical class I genes. |
要旨・審査要旨 / Abstract, Screening Result (288.9 kB)
