Ontogeny and Phylogeny of the MHC

MHC 的个体发育和系统发育

基本信息

批准号：
6892391
负责人：
Martin F Flajnik
金额：
$ 37.93万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
1989
资助国家：
美国
起止时间：
1989-04-01 至 2009-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): In the past several years, there have been several entire vertebrate genomes sequenced, specifically those of human, mouse, and bony fish (e.g. the pufferfish). In the vertebrate tree, the cartilaginous fish (elasmobranchs including the sharks, skates, and rays) and amphibians are at important phylogenetic junctures, but these animals have not been well studied at the genetic level. Cartilaginous fish are at the base of the jawed vertebrate tree and are the oldest vertebrates to have an adaptive immune system based on the presence of immunoglobulins, T cell receptors, and the major histocompatibility complex (MHC). Amphibians, the first land vertebrates, have been one of the favored non-mammalian models for the study of the adaptive immune system (especially the frog Xenopus, a well known model for developmental biologists). Our analyses of nurse shark and Xenopus MHCs have shown that unlike the bony fish, but like humans, class I, class II, and class III genes are all present in their MHC; thus, representative animals from these vertebrate classes seemingly more accurately represent the hypothetical ancestral vertebrate MHC than the better studied bony fish (e.g. zebrafish). However, unlike humans, there are deep lineages of genes involved in the production (immunoproteasome), transport (TAP1/2), and display (classical class I proteins) of peptides in the MHC class I pathway, at least in Xenopus and probably also in shark. These genes are tightly linked in a true 'class I region,' which likely reflects the situation in the primordial MHC. In Xenopus as well, there is a series of polyploid individuals ranging from 2n-12n, which no doubt arose by genome-wide duplication events (allopolyploidization); the genes of the adaptive immune system become diploidized in the polyploids, presumably to maintain an optimal number of expressed MHC molecules. In order to study the evolution of MHC genetics and the apparent functional consequences of gene organization on the immune system our specific aims are: 1) To compile comparative maps of the MHC in representatives of all vertebrate classes, with an emphasis on nurse shark (cartilaginous fish or elasmobranch) and Xenopus (amphibian); 2) Examine the significance of Xenopus ancient biallelic class I region lineages, specifically by studying the specificity of immunoproteasome subunits, class I peptide-binding, TAP 1/2biochemistry and peptide transport, and in transgenic frogs; and 3) Study gene silencing in polyploid Xenopus: with the advent of genomic sequencing projects in Xenopus (especially the true diploid X. tropicalis), we will begin to analyze the modes of silencing in the tetraploids and eventually the higher order octo- and dodecaploid individuals.

描述（由申请人提供）：在过去的几年中，已经对整个脊椎动物基因组进行了测序，特别是人，小鼠和骨鱼的基因组（例如pufferfish）。在脊椎动物树中，软骨鱼（包括鲨鱼，溜冰鞋和射线在内的弹性分支）和两栖动物处于重要的系统发育结构处，但这些动物在遗传水平上尚未得到很好的研究。软骨鱼在颌脊椎动物树的底部，是最古老的脊椎动物，它具有基于免疫球蛋白，T细胞受体和主要的组织相容性复合物（MHC）的适应性免疫系统。两栖动物是第一批土地脊椎动物，一直是研究适应性免疫系统研究的最喜欢的非哺乳动物模型之一（尤其是青蛙Xenopus，这是一种著名的发育生物学家模型）。我们对护士鲨鱼和Xenopus MHC的分析表明，与骨鱼不同，但是像人类，I类，II类和III类基因一样，它们都存在于其MHC中。因此，这些脊椎动物类别的代表性动物似乎比研究得更好的骨鱼（例如斑马鱼）更准确地代表了假设的祖先脊椎动物MHC。但是，与人类不同，在MHC I类途径中的生产（免疫蛋白酶体），运输（TAP1/2）和显示（经典I类蛋白）中涉及基因的深层谱系，至少至少在Xenopus中，也可能在鲨鱼中。这些基因在真实的“ I类区域”中紧密相关，这可能反映了原始MHC的情况。在Xenopus中，还有一系列的多倍体个体，范围从2N-12N，毫无疑问，这是全基因组复制事件（杂多酶化）引起的。自适应免疫系统的基因在多倍体中二倍化，大概是为了维持最佳数量的表达MHC分子。为了研究MHC遗传学的演变以及基因组织对免疫系统的明显功能后果，我们的具体目的是：1）在所有脊椎动物类别的代表中编译MHC的比较图，重点是护士鲨鱼（Cartilaginous Fish或Elasmobranch）和Xenopus（Amphibian）（Amphibian）； 2）检查爪诺乱的古代双质I类区域谱系的重要性，特别是通过研究免疫蛋白酶体亚基，I类肽结合，TAP 1/2biochemistrion和肽转运的特异性，以及转基因青蛙；和3）研究多倍体异刺液中的基因沉默：随着xenopus基因组测序项目的出现（尤其是True Diploid X. Tropicalis），我们将开始分析四倍体中的沉默模式，并最终分析较高的OCTO OCTO-OCTO-OCTO和DODECAPLOID个体。