Evolutionary genomics of an optimal adaptive immune response

这个项目调查了不同的进化因素和遗传机制，有助于建立一个最佳的适应性免疫反应的微妙任务。脊椎动物的适应性免疫系统允许对传染性病原体和寄生虫发起高度靶向的免疫反应。然而，这种有针对性的反应需要一些复杂而复杂的机制，以最大限度地提高对抗入侵病原体的效率，同时通过激活的免疫机制将对自身组织的损害降到最低。这种平衡反映在主要组织相容性复合体（MHC）的异常复杂的基因组组织中，MHC是基因组中包含适应性免疫系统关键成分遗传信息的区域。在这里，我们使用分子，计算和理论方法来阐明促进这一复杂基因组区域进化的不同因素和机制，从而促进适应性免疫系统的进化。我们的研究方法包括对来自美洲土著人群的古代DNA样本进行序列分析，对人类MHC区域扩展单倍型进行进化和功能评估，以及理论建模和模拟，以探索不同因素对MHC复杂基因组组织进化的相对贡献。此外，我们正在分析来自大型人类疾病队列的基因型数据和人类MHC分子的抗原结合信息，以提供MHC区域遗传变异与许多自身免疫性疾病之间强统计关联的功能解释。结合三棘棘鱼作为脊椎动物模型系统的经验序列数据和诱导外周自我耐受的理论模型，我们最终研究了不同的潜在mhc依赖机制，这些机制可能已经进化到阻止自身免疫。从这项研究项目中获得的见解将进一步加深我们对人类进化以及进化过程如何塑造脊椎动物基因组的理解。此外，我们的研究结果将有助于新兴的进化医学领域，该领域将有关疾病易感性的进化过程和个体遗传差异的知识纳入个性化医疗预防和治疗中。

This project investigates the different evolutionary factors and genetic mechanisms that contribute to the delicate task of mounting an optimal adaptive immune response. The vertebrate adaptive immune system allows for initiating a highly targeted immune response against infectious pathogens and parasites. However, such a targeted response requires a number of complex and sophisticated mechanisms to maximize efficiency in fighting invading pathogens while at the same time minimize damage to own tissue through the activated immune machinery. This balance is reflected in the exceptionally complex genomic organisation of the major histocompatibility complex (MHC), a region in the genome that contains genetic information for key components of the adaptive immune system. Here we are using molecular, computational and theoretical approaches to elucidate the different factors and mechanisms that contribute to the evolution of this complex genomic region and thus the evolution of the adaptive immune system in general. Our approaches include the sequence analysis of ancient DNA samples from Native American populations, evolutionary and functional evaluation of extended haplotypes in the human MHC region, and theoretical modelling and simulations to explore the relative contribution of different factors for the evolution of the complex genomic organisation of the MHC. Furthermore, we are analysing genotype data from large human disease cohorts and antigen binding information for human MHC molecules to provide a functional explanation for the strong statistical association between genetic variation in the MHC region and many autoimmune diseases. Combining empirical sequence data from the three-spined stickleback as a vertebrate model system and theoretical models of induced peripheral self-tolerance, we eventually investigate different potential MHC-dependent mechanisms that may have evolved to prevent autoimmunity. The insights gained from this research project will further our understanding of human evolution and how evolutionary processes shape the vertebrate genome. Additionally, our results will contribute to the emerging field of evolutionary medicine, which incorporates the knowledge about evolutionary processes and individual genetic differences in disease predisposition into personalized medical prevention and therapy.