GENETIC, EVOLUTIONARY, AND PHYLOGENETIC ANALYSIS OF HUMAN ALLELES

我们目前正在参与几个项目，旨在解决 重组、连锁不平衡和分子的模式 有趣的人类基因座的进化，特别是主要的 组织相容性复合体(MHC)区。这些的主要结果是 研究应该是提炼当前许多疾病的能力 与大的基因组区域的关联，如MHC，进入 构成疾病的一个或多个基因座。第一个问题涉及《第五号报告书》： Delta32等位基因，我们的实验室之前已经证明它与 对艾滋病的抗药性和延缓艾滋病。我们现在已经估计， 这个等位基因大约有4300年的历史，是高加索人独有的 以及与高加索人混杂在一起的人口。在这个过程中 我们开发了一种估计等位基因年龄的新方法。 此外，CCR5-delta32等位基因是我们的几个等位基因之一 这在很大程度上是高加索人独有的研究。这种“高加索人”的等位基因 非洲裔美国人人口中的种族隔离定义了地区 这将对通过混合连锁进行作图特别有用 不平衡(Z01 BC 05681-07 LGD)。 MHC的分子进化是一个悖论，关于 重组，因为有据可查的连锁不平衡 延伸到整个MHC表明重组水平降低， 然而，组成等位基因(如HLAB、DPB1)的系统发育分析 暗示广泛的等位基因间重组是主要的来源 等位基因多样性。这个项目的一个主要焦点是改进 现有的种群遗传和进化理论，特别是 关于对连锁不平衡模式的解释 在适度的重组水平下。这包括改进 现有的重组检测算法及其应用 MHC和其他基因座的等位基因序列。我们目前正在研究 HLAA、-B、-C和DPB1，计划解决DRB1、DQA1和DQB1。为 许多MHC基因座，等位基因的集合可以描述为一系列 不同图案的马赛克组合。从这个意义上说，每个等位基因 是一种单倍型，这使得连锁不平衡理论与 井。我们开始遇到的数据类型以 MHC(等位基因和单倍型频率，大量替代DNA 序列)，而这些将需要更多 以严谨的方法了解他们的自然历史。最直接的 挑战在于，对这种中等到长期的分析 变异体的单倍型体现了聚合理论、连锁 不平衡和系统发育。这些项目的一个基本目标是 研究是能够确定观察到的基因或等位基因 关联是真正起作用的(例如，与疾病相关的)，或者仅仅是 历史种群遗传或进化过程的结果。

We are currently involved in several projects intended to resolve patterns of recombination, linkage disequilibrium, and molecular evolution of interesting human loci, especially the major histocompatibility complex (MHC) region. A principal result of these studies should be the ability to refine many of the current disease associations with large genomic regions, such as the MHC, into the constituent disease locus or loci. The first of these concerns the CCR5- delta32 allele, which our lab has previously shown to be related both to AIDS resistance and postponement of AIDS. We have now estimated that this allele is approximately 4300 years old, and is unique to Caucasians and populations that have admixed with Caucasians. In the course of this work we developed a new method for estimating the age of alleles. Furthermore, the CCR5-delta32 allele is one of several alleles we are studying that is largely unique to Caucasians. Such "Caucasian" alleles that are segregating in the African-American population define regions that will be especially useful for mapping by admixture linkage disequilibrium (Z01 BC 05681-07 LGD). The molecular evolution of the MHC is something of a paradox regarding recombination, in that the well-documented linkage disequilibrium that extends across the entire MHC suggests a reduced level of recombination, yet phylogenetic analyses of constituent alleles (e.g., HLAB, DPB1) suggest extensive inter-allelic recombination as a major source of allelic diversity. A primary focus of this project is the improvement of existing population genetic and evolutionary theories, especially with regard to interpretation of patterns of linkage disequilibrium under moderate levels of recombination. This includes improvement of the existing algorithms for detecting recombination, and their application to allelic sequences from MHC and other loci. We are currently studying HLAA, -B, -C, and DPB1, with plans to address DRB1, DQA1, and DQB1. For many MHC loci, the collection of alleles can be described as a series of mosaic combinations of variable motifs. In this sense, each allele is a haplotype, which makes linkage disequilibrium theory relevant as well. We are starting to encounter the types of data exemplified by the MHC (allele and haplotype frequencies, large numbers of alternative DNA sequences) from other genomic regions, and these will require a more rigorous approach to understanding their natural history. The immediate challenge is that the analysis of such moderate to long range "haplotypes" of variants embodies coalescence theory, linkage disequilibrium, and phylogenetics. An underlying objective of these studies is to be able to determine whether observed genic or allelic associations are truly functional (e.g., disease related) or simply a consequence of historic population genetic or evolutionary processes.