SELECTIVE MECHANISMS MAINTAINING H 2 POLYMORPHISMS

维持 H 2 多态性的选择性机制

• 批准号: 6385717
• 负责人: Wayne K. Potts
• 金额: $ 26.89万
• 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/6385717
• 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：（改编自研究者摘要）主要组织相容性 复合体（MHC）基因控制着免疫学上的自我/非自我识别， 最多样化的基因。尽管MHC的核心重要性 基因对组织排斥、肿瘤监视和感染性 和自身免疫性疾病，MHC多样性的生物学意义仍然是 不理解。许多MHC等位基因使其携带者易患传染性和 自身免疫疾病，那么是什么在人类和动物中维持这些“坏基因”呢？ 人口？在这里，他们提出测试MHC的三个主要解释 遗传多态性(1)MHC多样性可以通过选择来维持， 杂合子对传染病的抵抗力更强。虽然没有 许多实验证明了这一假设， 代理人，更强的预测是，杂合子应该有优势 在多种病原体的感染中。调查人员将对此进行测试 通过用以下11种成对组合共感染MHC同源小鼠的假设 显示相互的MHC抗性/易感性特征的感染因子， 并对纯合子和杂合子的抗性进行比较。除了 通过测量病原体负荷，他们将评估个体的健康、活力、存活率， 和繁殖成功率的共同感染的小鼠在半自然的围栏。 沙门氏菌和泰勒病毒的初步共感染研究表明， 显示了杂合子的优势，因为它们具有80%的低（合并） 病原体负荷比纯合子。(2)MHC多态性可能是 快速进化的病原体适应MHC依赖性免疫识别， 从而产生对稀有或新等位基因的选择（频率依赖性 选择）。这一假说的核心假设是， 可以逃避宿主依赖MHC的免疫识别。他们会测试这个 假设通过一系列三种不同的 小鼠的MHC同源品系。数百种病原体将继续传代 以使MHC逃避有时间。病原体适应宿主MHC 将通过比较生殖输出、毒力和 传代前后病原菌的相关性状。病原逃避 将针对四种不同的感染因子检测MHC依赖性免疫力。的 研究人员还将测试小鼠肝炎适应 不同的MHC等位基因，因为这是唯一的病原体显示逃脱 自然系统中的MHC依赖性免疫。(3)MHC的交配偏好可能 驱动MHC多样性作为减少近亲繁殖的机制。这假设 近亲繁殖是昂贵的，但没有研究已经实验量化的健身 任何脊椎动物的近亲繁殖衰退的代价。他们发现65% 在竞争中，全同胞交配的后代适合度下降 远系繁殖的个体。他们建议继续进行近亲繁殖研究， 决定较低水平近亲繁殖的适应性后果， 与医学遗传学有关。这些实验将使他们能够确定 维持MHC多样性的自然选择。此外，他们将 继续整合免疫学，传染病， 生态学、行为学和进化生物学。