SELECTIVE MECHANISMS MAINTAINING H-2 POLYMORPHISMS

主要组织相容性1类和11类基因产物 MHC复合体将外源抗原呈递给T淋巴细胞， 因此是免疫反应的基本组成部分。 这些基因 也是已知的脊椎动物中最具多态性的基因座。 它有 人们普遍认为，这种前所未有的维护 遗传多样性是由于选择的力量所创造的 各种各样的病原体和寄生虫， 物种 然而，一个最关键的失败 预测，对特定传染病的易感性 应该与某些MHC等位基因相关，这造成了混乱。 各种各样的数据表明，这些多态性是 在自然种群中通过某种形式的强平衡来维持 选择. 虽然许多选择性机制已被假定 为了维持这些多态性， 在确定哪些机制方面取得了进展， 在自然种群中对MHC基因起作用。 我们提出 直接测量维持MHC的选择性机制， 通过分析圈养野生小鼠的适合度成分， 人口 这种总体水平方法允许测试 无法在实验室中测试的假设（例如， 频率相关假设），并将直接回答 MHC多态性如何影响适应性的基本问题 个人。 将检查以下健身组件。 MHC基因型对不同死亡率的影响 将测量繁殖成功率。 这些数据将允许 检验许多基于疾病的假设，如杂合子 优势和频率相关的选择。 择偶偏好 将通过观察确定外壳内的温度， 排除父子关系技术（例如基因指纹）。 交配偏好也将在实验室中进行测试，其中 将允许控制自然界中固有的混淆变量 社会制度。 有利于MHC杂合子的传递畸变 将通过检查提供信息的实验室配对进行测试， 在出生时就偏离了孟德尔的预期。 人口 遗传学模型表明，MHC多态性的维持 需要相对极端的选择水平， 生存或繁殖特征。 我们的无知， 这种选择模式是一个重大的差距，我们的理解如何 病原体和脊椎动物免疫系统相互作用。

Class 1 and 11 gene products of the major histocompatibility complex (MHC) present foreign antigens to T-lymphocytes and are thus essential components of the immune response. These genes are also the most polymorphic loci known for vertebrates. It has generally been assumed that the maintenance of this unprecedented genetic diversity is due to the selective forces created by the diverse group of pathogens and parasites that are endemic to each species. However, the failure of one of the most critical predictions, that susceptibility to specific infectious diseases should correlate with certain MHC alleles, has created confusion. A wide variety of data indicate that these polymorphisms are maintained in natural populations by some form of strong balancing selection. Although many selective mechanisms have been postulated to contribute to the maintenance of these polymorphisms, little progress has been made towards identifying which mechanisms actually operate on MHC genes in natural populations. We propose to measure directly the selective mechanisms that maintain MHC diversity by analyzing fitness components in a captive wild mouse population. This population level approach allows the testing of hypotheses that could never be tested in the laboratory (e.g. frequency dependent hypotheses) and will directly answer the fundamental question of how MHC polymorphisms affect the fitness of individuals. The following fitness components will be examined. The influence of MHC genotypes on differential mortality and reproductive success will be measured. These data will allow testing of numerous disease based hypotheses such as heterozygote advantage and frequency dependent selection. Mating preferences within the enclosure will be determined through observations and paternity exclusion techniques (e.g. genetic fingerprinting). Mating preferences will also be tested in the laboratory, which will allow control of confounding variables inherent in natural social systems. Transmission distortion favoring MHC heterozygotes will be tested by checking informative laboratory matings for deviations from Mendelian expectations at birth. Population genetics models indicate that the maintenance of MHC polymorphisms requires relatively extreme levels of selection, operating either on survival or reproductive traits. Our ignorance concerning the mode of this selection is a major gap in our understanding of how pathogens and the vertebrate immune system interact.