Testing mechanisms of parasite-mediated selection on MHC genetic diversity

描述（由申请人提供）：本提案的长期目标是更好地了解宿主免疫系统如何由于寄生虫而进化。基因组适应性重要区域的遗传变异可能对自然种群的长期生存和活力至关重要。寄生虫介导的选择被认为是一种 维持主要组织相容性复合体遗传多样性的重要因素。该区域是脊椎动物免疫系统的高度可变的遗传组分，有助于对抗大型寄生虫感染（即绦虫、线虫、扁形虫和节肢动物）。虽然寄生虫经常被调用作为一个潜在的因素，介导的MHC多样性，相对较少的研究调查寄生虫介导的选择在自然群体中的机制。这些研究中有许多难以区分寄生虫介导的选择的三种假设：杂合子优势，稀有等位基因优势和波动选择。在某种程度上，这是由于这样一个事实，即为了区分杂合子和稀有等位基因优势，我们需要确定寄生虫物种与宿主杂合性和特异性MHC等位基因之间的关联。此外，它是至关重要的探索MHC和寄生虫之间的关联在时间和空间尺度上，因为否则的稀有等位基因优势和波动的选择假说是难以区分的。三个目标将 进一步了解寄生虫介导的选择机制：目的1将表征地中海壁虎（Hemidactylus turcicus）的MHC II类基因座。这些新的基因序列不仅将填补脊椎动物MHC进化中的系统发育空白，而且还将为可用于进一步研究宿主-寄生虫相互作用的新型模型系统提供遗传基础。目标2将检验当代选择作用于 MHC II类基因。这将是在广泛分布和本地丰富的动物模型中测试MHC基因选择的首批研究之一。目标3将通过评估多物种大型寄生虫感染的时空变化来测试寄生虫介导的选择。这一目标的结果将阐明哪些机制对壁虎MHC进化影响最大。实现我们的目标将有助于传染病的研究，提供一个明确的测试寄生虫如何影响适应性重要的遗传多样性在主机在空间和时间。这些知识将提供的观点的意义上的MHC的遗传变异的整体健康的自然人群。 公共卫生相关性：通过研究宿主-寄生虫在适应性重要基因组区域的相互作用，我们可以更好地了解寄生虫在宿主进化中的作用。该提案测试了几种寄生虫物种如何在免疫基因上保持遗传变异。遗传变异和寄生虫之间的关联对于自然种群的长期生存和活力至关重要。

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to better understand how host immune systems have and are currently evolving due to parasitism. Genetic variation at adaptively important regions of the genome may be essential to the long term survival and viability of natural populations. Parasite-mediated selection is thought to be an important factor maintaining genetic diversity at the major histocompatibility complex. This region is a highly variable, genetic component of the vertebrate immune system that helps combat macroparasite infections (i.e. cestodes, nematodes, flatworms, and arthropods). Though parasites are often invoked as a potential factor that mediates MHC diversity, relatively few studies have investigated the mechanisms of parasite-mediated selection in natural populations. Many of these studies have difficulty differentiating between the three hypotheses of parasite-mediated selection: heterozygote advantage, rare-allele advantage, and fluctuating selection. In part, this has been due to the fact that to discriminate between heterozygote and rare- allele advantage, we need to determine the association between parasite species and both the host heterozygosity and specific MHC alleles. Further, it is critical to explore the associations between MHC and parasites on both a temporal and spatial scales because otherwise the rare-allele advantage and fluctuating selection hypotheses are difficult to distinguish. Three aims will progress our understanding of the mechanisms of parasite-mediated selection: Aim 1 will characterize MHC class II loci in the Mediterranean gecko (Hemidactylus turcicus). These new gene sequences will not only fill phylogenetic gaps in vertebrate MHC evolution, but will also provide the genetic foundation for a novel model system that can be used to further investigate host-parasite interactions. Aim 2 will test the hypothesis that contemporary selection is acting on MHC class II genes. This will be one of the first studies to test for selection on MHC genes in a widely distributed and locally abundant animal model. Aim 3 will test for parasite-mediated selection by assessing the spatio-temporal variation in multi-species macroparasite infections. The results of this aim will clarify which mechanisms have had the most influence on gecko MHC evolution. Accomplishing our aims will contribute to infectious disease research by providing an explicit test of how parasites affect adaptively important genetic diversity in hosts over space and time. This knowledge will provide perspective on the significance of genetic variation at the MHC to the overall health of natural populations. PUBLIC HEALTH RELEVANCE: By investigating host-parasite interactions at adaptively important regions of the genome, we can better understand the role of parasites in host evolution. This proposal tests how several parasite species maintain genetic variation at immune genes. The association between genetic variation and parasites is essential for the long term survival and viability of natural populations.