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

• 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

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) 代表人类基因组中基因极其密集的区域，包含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，并将病原体衍生的抗原呈递给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 在针对当地病原体的免疫遗传适应中发挥着关键作用。该项目将研究 HLA 区域病原体介导的选择特征，重点关注不同水平人群的局部适应。在序列水平上，将探讨不同功能区域中单倍型和平衡选择特征之间潜在适应性结构变异的程度。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有利的高频等位基因的特征。在人群水平上，将分析当地 HLA 等位基因库的适应​​程度，并最终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可能仍在持续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，拟议的项目解决了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、人类群体内部和群体之间遗传多样性的维持以及选择制度的潜在变化在现代社会。获得的结果将有助于我们了解病原体抵抗力和免疫的个体差异，因此可能有助于新兴的个体化医学领域。

项目成果

Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases

HLA 基因座内广泛的非累加效应和相互作用效应可调节自身免疫性疾病的风险

• DOI: 10.1038/ng.3379
• 发表时间: 2015-09
• 期刊: Nature genetics
• 影响因子: 30.8
• 作者: Lenz TL;Deutsch AJ;Han B;Hu X;Okada Y;Eyre S;Knapp M;Zhernakova A;Huizinga TW;Abecasis G;Becker J;Boeckxstaens GE;Chen WM;Franke A;Gladman DD;Gockel I;Gutierrez-Achury J;Martin J;Nair RP;Nöthen MM;Onengut-Gumuscu S;Rahman P;Rantapää-Dahlqvist S;Stuart PE;Tsoi LC;van Heel DA;Worthington J;Wouters MM;Klareskog L;Elder JT;Gregersen PK;Schumacher J;Rich SS;Wijmenga C;Sunyaev SR;de Bakker PI;Raychaudhuri S
• 通讯作者: Raychaudhuri S

Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk

HLA-DQ 和 HLA-DR 分子中三个氨基酸位置的加性和相互作用效应会增加 1 型糖尿病风险

• DOI: 10.1038/ng.3353
• 发表时间: 2015-08
• 期刊: Nature Genetics
• 影响因子: 30.8
• 作者: Hu X;Deutsch AJ;Lenz TL;Onengut-Gumuscu S;Han B;Chen WM;Howson JM;Todd JA;de Bakker PI;Rich SS;Raychaudhuri S
• 通讯作者: Raychaudhuri S

Exploring local immunological adaptation of two stickleback ecotypes by experimental infection and transcriptome-wide digital gene expression analysis

通过实验感染和全转录组数字基因表达分析探索两种刺鱼生态型的局部免疫适应

• DOI: 10.1111/j.1365-294x.2012.05756.x
• 发表时间: 2013-02
• 期刊: Molecular Ecology
• 影响因子: 4.9
• 作者: Lenz TL;Eizaguirre C;Rotter B;Kalbe M;Milinski M
• 通讯作者: Milinski M