Evolutionary genomics of an optimal adaptive immune response

最佳适应性免疫反应的进化基因组学

• 批准号: 279645989
• 负责人: Professor Dr. Tobias Lenz
• 金额: --
• 依托单位: Department of Zoology
• 依托单位国家: 德国
• 项目类别: Independent Junior Research Groups
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/279645989?language=en
• 关键词: Evolutionary; genomics; optimal; adaptive; immune

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.

该项目研究了不同的进化因素和遗传机制，这些因素和遗传机制有助于安装最佳适应性免疫反应。脊椎动物适应性免疫系统允许对传染病和寄生虫的高度靶向免疫反应。但是，这种有针对性的反应需要多种复杂而复杂的机制，以最大程度地提高与入侵病原体作斗争的效率，同时最大程度地减少通过激活的免疫机械对自己组织的损害。这种平衡反映在主要组织相容性复合物（MHC）的异常复杂的基因组组织中，这是基因组中的一个区域，其中包含适应性免疫系统关键成分的遗传信息。在这里，我们使用分子，计算和理论方法来阐明有助于该复杂基因组区域进化的不同因素和机制，从而阐明了自适应免疫系统的演变。我们的方法包括对美国原住民人群的古代DNA样品的序列分析，人类MHC地区扩展单倍型的进化和功能评估，以及理论建模和模拟，以探索MHC复杂基因组组织复杂基因组组织进化的不同因素的相对贡献。此外，我们正在分析人类MHC分子的大型人类疾病队列中的基因型数据和抗原结合信息，以为MHC区域的遗传变异与许多自身免疫性疾病的遗传变异之间的牢固统计关联提供功能解释。将三跨粘结式粘背的经验序列数据结合在一起，作为脊椎动物模型系统和诱导的外周自我耐受性的理论模型，我们最终研究了可能已进化以防止自身免疫性的不同潜在潜在的MHC依赖机制。从该研究项目中获得的见解将进一步我们对人类进化的理解以及进化过程如何塑造脊椎动物基因组。此外，我们的结果将有助于进化医学的新兴领域，该领域结合了有关进化过程的知识和疾病易感性的个性化医疗预防和治疗中的个人遗传差异。

项目成果

HLA Heterozygote Advantage against HIV-1 Is Driven by Quantitative and Qualitative Differences in HLA Allele-Specific Peptide Presentation

• DOI: 10.1093/molbev/msz249
• 发表时间: 2020-03-01
• 期刊: MOLECULAR BIOLOGY AND EVOLUTION
• 影响因子: 10.7
• 作者: Arora, Jatin;Pierini, Federica;Lenz, Tobias L.
• 通讯作者: Lenz, Tobias L.

Genomewide Association Study of Severe Covid-19 with Respiratory Failure

• DOI: 10.1056/nejmoa2020283
• 发表时间: 2020-10-15
• 期刊: NEW ENGLAND JOURNAL OF MEDICINE
• 影响因子: 158.5
• 作者: Ellinghaus, David;Degenhardt, Frauke;Karlsen, Tom H.
• 通讯作者: Karlsen, Tom H.

HIV peptidome-wide association study reveals patient-specific epitope repertoires associated with HIV control

• DOI: 10.1073/pnas.1812548116
• 发表时间: 2019-01-15
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Arora, Jatin;McLare, Paul J.;Lenz, Tobias L.
• 通讯作者: Lenz, Tobias L.

Targeted analysis of polymorphic loci from low-coverage shotgun sequence data allows accurate genotyping of HLA genes in historical human populations

对低覆盖鸟枪序列数据的多态性位点进行针对性分析，可以对历史人群中的 HLA 基因进行准确的基因分型

• DOI: 10.1038/s41598-020-64312-w
• 期刊: Scientific Reports
• 影响因子: 4.6
• 作者: Pierini F;Nutsua M;Böhme L;Özer O;Bonczarowska J;Susat J;Franke A;Nebel A;Krause-Kyora B;Lenz TL
• 通讯作者: Lenz TL