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Variabilität des Haupthistokompatibilitätskomplexes auf verschiedenen Ebenen - Eine evolutionäre Perspektive

主要组织相容性复合物在不同水平上的变异性——进化的角度

基本信息

批准号：
194296481
负责人：
Professor Dr. Tobias Lenz
金额：
--
依托单位：
Department of Genetics
依托单位国家：
德国
项目类别：
Research Fellowships
财政年份：
2011
资助国家：
德国
起止时间：
2010-12-31 至 2013-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/194296481?language=en
关键词：
Variabilit des Haupthistokompatibilit tskomplexes auf

项目摘要

The human leukocyte antigen (HLA) represents an exceptionally gene-dense region in the human genome, containing some of the most polymorphic human genes known to date. These genes code for cell surface molecules that are key factors of the adaptive immune system and present pathogen-derived antigens to immune effector cells to initiate a pathogen-specific immune response. Due to the restricted allele-specific range of presented antigens, the HLA plays a key role in immunogenetic adaptation to local pathogens. This project will investigate signatures of pathogen-mediated selection in the HLA region with a focus on local adaptation in human populations at different levels. At the sequence level, the extent of potentially adaptive structural variation between haplotypes and signatures of balancing selection in different functional regions will be explored. At the allele/genotype level, allele-specific antigen-binding properties, non-random association of alleles and characteristics of potentially advantageous high-frequency alleles will be investigated. At the population level, the extent of adaptation in local HLA allele pools will be analyzed and eventually, the link between local signatures of selection and geographical differences in human epidemiology will be made to improve our understanding of potentially still ongoing immunogenetic adaptation in human populations. By bridging the fields of human genetics and evolutionary medicine, the proposed project addresses several fundamental aspects of human evolution, such as co-evolution between humans and their pathogens, maintenance of genetic diversity within and among human populations but also potential changes in the selection regime in modern societies. The acquired results will contribute to our understanding of individual differences in pathogen resistance and immunity, and therefore potentially contribute to the emerging field of individualized medicine.

人类白细胞抗原（HLA）代表了人类基因组中一个异常密集的基因区域，包含了迄今为止已知的一些最具多态性的人类基因。这些基因编码细胞表面分子，这些分子是适应性免疫系统的关键因素，并将病原体来源的抗原呈递到免疫效应细胞以启动病原体特异性免疫反应。由于呈递抗原的等位基因特异性范围有限，HLA在对局部病原体的免疫遗传适应中起着关键作用。该项目将研究HLA区域病原体介导选择的特征，重点研究不同水平人群的局部适应。在序列水平上，将探索单倍型之间潜在的适应性结构变异程度和不同功能区平衡选择的特征。在等位基因/基因型水平上，将研究等位基因特异性抗原结合特性、等位基因的非随机关联以及潜在优势高频等位基因的特征。在人群水平上，将分析当地HLA等位基因池的适应程度，最终，将建立当地选择特征与人类流行病学地理差异之间的联系，以提高我们对人类群体中潜在的仍在进行的免疫遗传适应的理解。通过连接人类遗传学和进化医学领域，拟议的项目涉及人类进化的几个基本方面，例如人类与其病原体之间的共同进化，维持人类种群内部和种群之间的遗传多样性，以及现代社会选择制度的潜在变化。获得的结果将有助于我们了解病原体耐药性和免疫力的个体差异，因此可能有助于个体化医学的新兴领域。