Measuring immunogenetic diversity during the Pleistocene

绝大多数的遗传多样性研究都集中在现有的种群上。然而，结合古代DNA的种群遗传研究表明，对许多物种来说，当前的多样性和多样性分布甚至不能反映最近的过去。迄今为止，几乎所有使用古代DNA的种群遗传分析都依赖于线粒体DNA分析和测量多样性及其随时间的分布。我们建议研究两个物种从晚更新世到全新世（大约60000年的时间跨度）的核DNA多样性，以确定具有重要免疫学意义的核DNA位点的核DNA多样性。所选物种之间的主要对比是，长毛象（Mammuthus primigenius）已经灭绝，而麝牛（Ovibos moschatus）在大约1万年前的更新世末期灭绝中幸存下来，当时欧亚和美洲的大多数巨型动物（体重30公斤）都消失了。感兴趣的位点分别位于主要的组织相容性复合体（MHC）和toll样受体基因（TLRs）中，分别代表适应性免疫系统和先天免疫系统。这些基因的多样性对宿主抵御病原体至关重要。MHC多样性的变化与寄生虫负荷和对病毒感染的抵抗力等因素相关。在非灵长类动物中，TLR多样性的进化通常不太清楚，但与MHC多样性一样，TLR多样性与对传染病的抵抗力变异有关。先天免疫和适应性免疫基因多样性的减少与对病原体的易感性有关，如果采取极端措施，可能会导致物种减少。在对数百个样本进行分析后，长毛象和麝牛是线粒体DNA多样性最具特征的两个物种。我们建议对猛犸象和麝牛的MHC和TLR多样性进行表征，以研究线粒体多样性随时间和空间的变化。获得的数据集将代表已知线粒体多样性背景下的免疫遗传多样性的第一个长期进化分析，用于两个最大的古代DNA集合。我们期望确定这两个物种的TLR和MHC等位基因的进化速率、持久性和替换性，这将更好地理解这些基因座的进化动力学，这些基因座无法从现代DNA检测中获得。鉴于麝牛和猛犸象在特定时间点具有相同的人口统计模式，而在其他时间点则不同，这一比较将为阐明免疫遗传进化的一般原理提供背景，例如，证明相似的人口统计学变化是否会引发相似的进化免疫遗传趋势。

The vast majority of genetic diversity studies focus on currently existing populations. However, population genetic studies incorporating ancient DNA have demonstrated for many species that current diversity and diversity distribution does not reflect even the recent past. To date, almost all population genetic analysis using ancient DNA has relied on mitochondrial DNA analysis and on measuring diversity and its distribution over time. We propose to investigate nuclear DNA diversity in two species from the late Pleistocene through the Holocene (an approximate 60,000 year time span) for the nuclear DNA diversity of immunologically important nuclear DNA loci. The major contrast between the chosen species is that one, the woolly mammoth (Mammuthus primigenius) is extinct and the muskoxen (Ovibos moschatus) survived the end Pleistocene extinctions approximately 10,000 years ago which saw the disappearance of most of the Eurasian and American megafaunal (> 30 kg) species. The loci of interest are in the major histocompatibility complex (MHC) and Toll-Like-Receptor genes (TLRs) representing the adaptive and innate immune systems respectively. Diversity in these genes is crucial to host defence against pathogens. Variation in MHC diversity correlates with factors such as parasite load and resistance to viral infection. TLR diversity evolution is generally less well characterized in non-primates but like MHC diversity, is associated with variation in resistance to infectious disease. Reduced diversity in both the innate and adaptive immune genes is associated with susceptibility to pathogens which if taken to extremes could hypothetically result in species declines. The woolly mammoth and the muskox are two of the best characterized species for mitochondrial DNA diversity with hundreds of samples analyzed. We propose to characterize MHC and TLR diversity in mammoths and muskoxen previously characterized for mitochondrial diversity to examine changes over space and time. The data set obtained will represent the first long term evolutionary analysis of immunogenetic diversity in the context of known mitochondrial diversity for two of the largest collections of ancient DNA available. We expect to determine the rate of evolution, persistence and replacement of TLR and MHC alleles for both species which will provide a better understanding of the evolutionary dynamics of the loci that cannot be obtained from examination of modern DNA. Given that muskoxen and mammoths both share demographic patterns at given time points and diverge at others, the comparison will provide context for elucidating general principles of immunogenetic evolution e.g. demonstrate whether similar demographic changes elicit similar evolutionary immnogenetic trends.