EVOLUTION OF IMMUNE RECOGNITION AND EVASION

免疫识别和逃避的进化

• 批准号: 2022375
• 负责人: AUSTIN L. HUGHES
• 金额: $ 8.57万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-09-01 至 2001-03-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2022375
• 关键词: Anura; alleles; alternatives to animals in research; antibody receptor; biochemical evolution; gene duplication; gene expression; genetic polymorphism; genetic recombination; genetic regulatory element; glycoproteins; histocompatibility gene; host organism interaction; immunity; major histocompatibility complex; mathematical model; natural selections; nucleic acid sequence; statistics /biometry

The vertebrate immune system includes numerous proteins involved in the recognition and elimination of parasitic organisms. The general goals of this research are to understand the evolution of key molecular components of this system, especially the molecules encoded by the genes of the major histocompatibility complex (MHC), and to understand how immunogenic proteins of parasitic organisms have evolved under natural selection exerted by the host~s immune system. The MHC is a multi-gene family encoding cell-surface glycoproteins which play an important role in the immune system, binding foreign peptides and presenting them to T cells. Certain MHC loci are polymorphic in humans and other vertebrates, and our analyses of DNA sequence data have provided evidence that this polymorphism is maintained by positive selection favoring diversity in the peptide binding region of the MHC molecule and thus, presumably, favoring the ability to bind a variety of foreign peptides. Therefore the MHC provides an excellent system for studying the evolution of immune recognition and the role of infectious disease as an agent of natural selection. The methods involve statistical analysis of published DNA sequences, of which there are a large number for MHC genes of several mammalian species; for other immune system genes; and for the genes of parasites encoding immunogenic proteins. The purposes of these analyses are as follows: (1) to test the hypothesis that MHC polymorphism is maintained by overdominant selection (heterozygote advantage) relating to disease resistance; (2) to understand the relative roles of long-term persistence of polymorphism and of convergent evolution in contributing to MHC polymorphisms shared by different mammalian species; (3) to test the hypothesis that peptides presented by MHC molecules tend to be derived from highly conserved portions of generally conserved proteins); (4) to test the hypothesis that the vertebrate immune system has exerted selection on the proteins of parasitic organisms to evade recognition by the host; (5) to test the hypothesis that, in mammals, proteins expressed in the immune system evolve more rapidly than those expressed in other tissues; and (6) to understand the roles of gene duplication, interlocus recombination, and natural selection in the diversification of immune system gene families (including the MHC, complement components, the proteasome components, the chemokines, the C-type lectins, natural resistance associated macrophage proteins, and the protein tyrosine kinases).

脊椎动物免疫系统包括许多参与的蛋白质 寄生生物的识别和消除。 将军 这项研究的目标是了解关键分子的演变 该系统的组件，尤其是由 主要组织相容性复合物（MHC）的基因和至 了解寄生生物的免疫原性蛋白质如何具有 在宿主的免疫系统施加的自然选择下进化。 MHC是编码细胞表面糖蛋白的多基因家族 在免疫系统中起着重要作用，约束外国 肽并将其呈现给T细胞。 某些MHC基因座是 人类和其他脊椎动物的多态性，以及我们的分析 DNA序列数据提供了证据表明该多态性是 通过积极的选择有利于肽多样性的积极选择 MHC分子的结合区域，因此，大概有利于 结合各种外肽的能力。 因此MHC 提供了研究免疫进化的绝佳系统 识别和传染病作为自然毒剂的作用 选择。 该方法涉及对已发表DNA的统计分析 序列，其中的MHC基因数量很大 几种哺乳动物；用于其他免疫系统基因；和 编码免疫原性蛋白的寄生虫基因。 目的 这些分析如下：（1）测试MHC的假设 多态性通过过度选择（杂合子）维持 优势）与抗病性有关； （2）了解亲戚 多态性和收敛性长期持久性的作用 促进不同的MHC多态性的演变 哺乳动物物种； （3）检验肽呈现的假设 由MHC分子倾向于从高度保守的部分中得出 一般保守的蛋白质）； （4）检验以下假设 脊椎动物免疫系统已在蛋白质上进行选择 寄生生物以逃避宿主的认可； （5）测试 假设在免疫系统中表达的哺乳动物中 进化比其他组织中表达的进化更快。 （6）to 了解基因重复，间插入重组的作用和 免疫系统基因家族多样化的自然选择 （包括MHC，补体组件，蛋白酶体 成分，趋化因子，C型凝集素，自然电阻 相关的巨噬细胞蛋白和蛋白酪氨酸激酶）。