Novel Methods for Characterizing Recombination and Selection

进化和选择是影响基因组变异模式的两种主要进化机制。推断历史重组模式的努力是疾病关联研究设计和分析的核心，识别选择目标的能力可能对生物医学研究具有重要意义。本申请的长期目标是定量表征重组和选择对基因组变异的影响。有效的算法和严格的数学技术将被开发用于人口基因组学的准确推断。这个应用程序的具体目标是：目标1：开发方法来评估蒙特卡罗方法的可能性计算的合并与重组。将开发确定性的、基于算法的方法来非常准确地计算可能性，为测试和微调蒙特卡罗方法来计算可能性打开了一扇新的机会之窗。对于中等规模的输入数据，新开发的工具将用于评估现有的蒙特卡罗方法。目标2：开发方法来表征历史交叉和基因转换重组。基于扩散近似的一般数学框架将被开发以获得精确的多位点条件抽样分布。使用这种方法，将开发一种可以联合估计交叉和基因转换率的方法。此外，现有的估计方法将被重新审视，并将作出具体的计算改进。目的3：研究多基因座自然选择的相互作用。在多个位点的选择的相互作用将进行分析研究，并通过相互作用的选择形成LD的结构将被表征。多位点选择下的固定概率也将被研究。相关性：了解人类基因组的变异模式是研究疾病风险和药物反应变异性的遗传基础的核心。本研究的目的是开发准确的方法来表征塑造基因组变异模式的各种进化机制。

Recombination and selection are two major evolutionary mechanisms that influence the pattern of variation in genomes. Efforts to deduce patterns of historical recombination are central to the design and analysis of disease association studies, and the ability to identify targets of selection may have important implications for biomedical research. The long-term objective of this application is to characterize quantitatively the effects of recombination and selection on genomic variation. Efficient algorithms and rigorous mathematical techniques will be developed for accurate inference in population genomics. The specific aims of this application are: Aim 1: Develop methods to assess Monte Carlo approaches to likelihood computations in the coalescent with recombination. Deterministic, algorithm-based methods will be developed to compute likelihoods very accurately, opening up a new window of opportunities for testing and fine-tuning Monte Carlo approaches to likelihood computation. For input data of moderate size, the newly developed tool will be used to evaluate existing Monte Carlo methods. Aim 2: Develop methods to characterize historical crossover and gene-conversion recombinations. A general mathematical framework based on diffusion approximation will be developed to obtain accurate multi-locus conditional sampling distributions. Using that approach, a method that can jointly estimate crossover and gene-conversion rates will be developed. Further, existing estimation methods will be revisited and specific computational improvements will be made. : Aim 3: Study the interaction of natural selection at multiple loci. The interaction of selection at multiple loci will be studied analytically and the structure of LD shaped by interacting selection will be characterized. Fixation probabilities under multi-locus selection will also be studied. ¿ Relevance: Understanding the pattern of variation in the human genome is central to the study of the genetic basis of disease risk and variability in drug response. The aim of this research is to develop accurate methods to characterize various evolutionary mechanisms that shape the pattern of genomic variation.