SELECTIVE MECHANISMS MAINTAINING H 2 POLYMORPHISMS

维持 H 2 多态性的选择性机制

• 批准号: 6179565
• 负责人: Wayne K. Potts
• 金额: $ 26.02万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-01-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6179565
• 关键词: alleles; animal mortality; biochemical evolution; cellular pathology; gene complementation; genetic models; genetic polymorphism; genetic susceptibility; genotype; host organism interaction; immunity; immunogenetics; inbreeding; infection; laboratory mouse; major histocompatibility complex; molecular pathology; pathologic process; polymerase chain reaction; statistics /biometry

DESCRIPTION: (Adapted from investigator's abstract) Major histocompatibility complex (MHC) genes control immunological self/nonself recognition and are the most diverse genes known in vertebrates. Despite the central importance of MHC genes to tissue rejection, tumor surveillance, and susceptibility to infectious and autoimmune diseases, the biological significance of MHC diversity is still not understood. Many MHC alleles predispose their bearers to infectious and autoimmue diseases, so what maintains these 'bad genes' in human and animal populations? Here they propose to test the three leading explanations for MHC genetic polymorphisms. (1) MHC diversity can be maintained by selection if MHC heterozygotes are more resistant to infectious diseases. Although there is no evidence for this hypothesis from many experiments testing single infectious agents, the stronger prediction is that heterozygotes should have an advantage during infections by multiple pathogens. The investigators will test this hypothesis by coinfecting MHC-congenic mice with 11 pair-wise combinations of infectious agents that show reciprocal MHC resistance/susceptibility profiles, and compare the resistance of homozygotes and heterozygotes. In addition to measuring pathogen loads, they will assess individual health, vigor, survival, and reproductive success of the coinfected mice in semi-natural enclosures. Preliminary coinfection studies with Salmonella and Theiler's virus have revealed an advantage to heterozygotes as they have an 80% lower (combined) pathogen load than homozygotes. (2) MHC polymorphisms may be the result of rapidly evolving pathogens adapting to MHC-dependent immune recognition, thereby generating selection for rare or new alleles (frequency-dependent selection). The central assumption of this hypothesis asserts that pathogens can evade MHC-dependent immune recognition of their hosts. They will test this assumption by passaging infectious agents through a series of three different MHC congenic strains of mice. Passages will continue for hundreds of pathogen generations to allow time for MHC evasion. Pathogen adaptation to host MHC alleles will be tested by comparing the reproductive output, virulence and related characters of post-and pre passage pathogens. Pathogen evasion of MHC-dependent immunity will be tested for four different infectious agents. The investigators will also test the ability of mouse hepatitis to adapt to different MHC alleles since this is the only pathogen shown to escape MHC-dependent immunity in a natural system. (3) MHC mating preferences may drive MHC-diversity as a mechanism to reduce inbreeding. This assumes that inbreeding is costly, yet no study has experimentally quantified the fitness costs of inbreeding depression for any vertebrate. They have found a 65% decline in fitness for progeny from full-sibling matings when in competition with outbred individuals. They propose to continue their inbreeding studies to determine the fitness consequences of lower levels of inbreeding, which are relevant to medical genetics. These experiments will enable them to determine the nature of selection maintaining MHC diversity. Furthermore, they will continue the integration of the fields of immunology, infectious diseases, ecology, behavior and evolutionary biology.

描述：(改编自调查人员摘要)主要组织相容性 复合体(MHC)基因控制免疫自我/非自我识别，是 脊椎动物中已知的最多样化的基因。尽管MHC的核心重要性 基因与组织排斥反应、肿瘤监测和感染性易感性 和自身免疫性疾病，MHC多样性的生物学意义仍然是 我不明白。许多MHC等位基因使其携带者容易感染和 自体免疫性疾病，那么是什么维持了人类和动物的这些“坏基因”？ 人口？在这里，他们提议测试对MHC的三种主要解释 遗传多态。(1)MHC的多样性可以通过选择保持 杂合子对传染病的抵抗力更强。虽然没有 这一假说的证据来自许多测试单一感染性的实验 代理人，更有力的预测是杂合子应该有优势 在被多种病原体感染期间。调查人员将对此进行测试 通过11对组合感染MHC同源基因小鼠的假说 感染病原体表现出对MHC的相互耐药/敏感性特征， 比较纯合子和杂合子的抗性。除了……之外 通过测量病原体载量，他们将评估个体的健康、活力、存活率、 以及在半自然围栏中混合感染的小鼠的繁殖成功。 与沙门氏菌和泰勒氏病毒混合感染的初步研究 显示出对杂合子的优势，因为他们有80%的低(加在一起) 病原菌载量高于纯合子。(2)MHC基因多态可能是由 快速进化的病原体适应MHC依赖的免疫识别， 从而产生对稀有或新等位基因(取决于频率)的选择 选择)。这一假说的中心假设断言病原体 可以逃避其宿主对MHC依赖的免疫识别。他们将对此进行测试 假设通过一系列不同的三种不同的传染病 MHC同源品系小鼠。数百种病原体的传代将继续 世世代代为MHC的逃避留出时间。病原菌对宿主MHC的适应 等位基因将通过比较繁殖产量、毒力和 传代后和传代前病原体的相关特征。病原菌逃逸 将对四种不同的感染源进行MHC依赖免疫测试。这个 研究人员还将测试小鼠肝炎适应能力 不同的MHC等位基因，因为这是唯一逃脱的病原体 自然系统中的MHC依赖免疫。(3)MHC交配偏好可 推动MHC多样性作为减少近亲繁殖的一种机制。这是假设 近亲交配的成本很高，但还没有研究从实验上量化这种适合度 对于任何脊椎动物来说，近亲繁殖的成本都很低。他们发现了65%的 在比赛中完全兄弟姐妹交配的后代适合度下降 与远亲交配的个体。他们建议继续他们的近亲交配研究 确定较低水平近亲交配的适合性后果，即 与医学遗传学相关的。这些实验将使他们能够确定 选择的本质维持了MHC的多样性。此外，他们还会 继续整合免疫学、传染病、 生态学、行为学和进化生物学。