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The origin and evolution of major histocompatibility complex (MHC).

主要组织相容性复合体（MHC）的起源和进化。

基本信息

批准号：
05044127
负责人：
TAKAHATA Naoyuki
金额：
$ 2.56万
依托单位：
The Graduate University for Advanced Studies
依托单位国家：
日本
项目类别：
Grant-in-Aid for international Scientific Research
财政年份：
1993
资助国家：
日本
起止时间：
1993 至 1994
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-05044127/
关键词：
Mhc T-cell repertoire Self-nonself discrimination Mhc restriction Diversity Adaptive evolution DNA sequences Natural selection データ解析

项目摘要

The major histocompatibility complex (Mhc) contains a family of genes whose products play crucial roles in self and nonself discrimination. Self is one's own peptides that bind to Mhc molecules and restrict the T-cell repertoire in the thymus, whereas nonself is processed peptides of foreign antigens that can be presented in the context of Mhc molecules and trigger the immune response. Since the immune system thus controlled by Mhc molecules affects the survival of individuals, the dual function of Mhc itself must be subjected to natural selection. This international scientific research program has focused on (1) DNA sequence analysis and population genetics theory on the origin and evolution of Mhc molecules and (2) the origin of mankind from a viewpoint of the Mhc diversity.(1) The origin and evolution of Mhc molecules : Although a number of attempts were made to isolate Mhc genes from jawless fishes and lower vertebrates, all were unsuccessful. This indicates that Mhc evolved at the … More early evolutionary stage of vertebrates. Since the vertebrate immune system involves Ig and T cell receptor genes, the molecular mechanism of genomic rearrangement was also acquired around the same time as the emergence of Mhc. We have argued why the immune system and the vertebrate evolution emerged in parallel in terms of the complexity of body and the number of offspring. Natural selection for Mhc genes is intimately related to the dual function of Mhc Molecules and selection is responsible for an extraordinary diversity of Mhc molecules within a species. We have estimated the intensity of natural selection operating on Mhc molecules, and based on this estimate, we plan to develop a conservation program for endangered species. The agent of natural selection is parasites : These and Mhc variants have been coevolving. Different parasites in different geographic regions are in part a cause of human Mhc (HLA) differentiation. Recent change in our society and improvement of environment suggest relaxation of natural selection for Mhc or loss of the diversity, thus posing a serious question on the defense system in the future mankind.(2) Diversity and local differentiation of human Mhc (HLA). Local differentiation of HLA is a reflection of local selection owing to different parasites as well as migration routes in the past. Conversely, the current HLA distribution allows us to infer migration routes of our ancestors. We have proposed a method in searching for vanished migration routes with special reference to recombination fraction. This method allows us to estimate when and among which populations migrations occurred : The higher the recombination fraction, the more recent migration event.Finally we have studied the origin of self-incompatibility in plants because the theoretical basis is similar to that for Mhc. We have pointed out that the emergence of selfincompatibility system coincided with the emergence of flowering plants, and will further investigate why. Less

主要组织相容性复合体（Mhc）包含一个基因家族，其产物在自我和非自我识别中起关键作用。自体是一个人自己的肽，它与Mhc分子结合并限制胸腺中的T细胞库，而非自体是外源抗原的加工肽，可以在Mhc分子的背景下呈递并触发免疫应答。由于Mhc分子控制的免疫系统影响个体的生存，因此Mhc本身的双重功能必须受到自然选择的影响。该国际科学研究计划的重点是（1）关于Mhc分子起源和进化的DNA序列分析和群体遗传学理论，以及（2）从Mhc多样性的角度来看人类的起源。(1)Mhc分子的起源和进化：尽管人们曾多次尝试从无颌鱼类和低等脊椎动物中分离Mhc基因，但都没有成功。这表明Mhc是在 ...更多信息脊椎动物进化的早期阶段。由于脊椎动物的免疫系统涉及IG和T细胞受体基因，基因组重排的分子机制也在Mhc出现的同时获得。我们已经讨论了为什么免疫系统和脊椎动物的进化是平行出现的，从身体的复杂性和后代的数量来看。Mhc基因的自然选择与Mhc分子的双重功能密切相关，选择是一个物种内Mhc分子异常多样性的原因。我们已经估计了Mhc分子的自然选择强度，并根据这一估计，我们计划制定一个濒危物种的保护计划。自然选择的代理人是寄生虫：这些和Mhc变体一直在共同进化。不同地理区域的不同寄生虫是人类MHC（HLA）分化的部分原因。近年来，随着社会的变化和环境的改善，对MHC的自然选择趋于缓和或多样性的丧失，对未来人类的防御系统提出了严峻的问题。(2)人类MHC（HLA）的多样性和局部分化。HLA的局部分化反映了由于不同的寄生虫以及过去的迁移路线而导致的局部选择。相反，目前的HLA分布使我们能够推断我们祖先的迁移路线。提出了一种利用复合分数寻找消失迁移路线的方法。这种方法使我们能够估计何时以及在哪些种群之间发生了迁移：重组分数越高，迁移事件越近。最后，我们研究了植物自交不亲和性的起源，因为理论基础与Mhc相似。我们已经指出自交不亲和系统的出现与有花植物的出现是同时发生的，并将进一步研究其原因。少