Patterns of background nucleotide substitution in the human lineage

背景替换的模式和比率的知识对于识别和分析是必不可少的 人类基因组中的功能序列。如果知道这一点，就应该有可能确定 比较两个或多个基因组的功能序列。这样的序列将脱颖而出，因为 根据估计的比率，变化显著小于或显著大于预期 背景替换。尽管这一点很重要，但背景替换的模式很差 为人所知。背景替换率在人类基因组中是否有所不同，以及 这些比率在人类血统中的进化仍然存在争议。主要的困难在于找出 在没有功能约束的情况下进化的序列，以及在给定给定的 哺乳动物DNA中普遍存在依赖于邻居的CpG到TPG/CPA的快速转换。高潮 该过程的速率和对邻居的依赖使替换的所有推论实质上复杂化， 即使是非CpG位点的单核苷酸替换。该项目将利用一个新的最大 可同时推断CpG到TPG/CPA转化率和TPG/CPA转化率的似然方法 单核苷酸替代率大大超过了单纯的饱和点。此方法将是 应用于人类和其他生物体内丰富的可转座元件的死拷贝序列 过去2-3亿年间储存的哺乳动物基因组。这一分析将提供重要的新的 有关哺乳动物基因组中替代模式进化的信息，将创造出精细的尺度 (1-5 MBP)人类和其他哺乳动物基因组的替换模式和速率的基因组图， 并将研究哺乳动物背景替代模式的基因组决定因素。

Knowledge of the patterns and rates of background substitution is essential for the identification and analysis of functional sequences in the human genome. Provided this knowledge it should be possible to identify functional sequences in comparison of two or more genomes. Such sequences will stand out as those that have changed either significantly less or significantly more than expected under the estimated rates of background substitution. Despite this central importance, patterns of background substitution are poorly known. Questions of whether rates of background substitution vary across the human genome and whether these rates have been evolving in the human lineage remain controversial. Major difficulties lie in identifying sequences that evolve under no functional constraint and also in devising methods of inferences given the existence of a rapid neighbor-dependent CpG to TpG/CpA transition prevalent in mammalian DNA. The high rate and the neighbor-dependence of this process substantially complicate all inferences of substitution, even those of single-nucleotide substitutions at non-CpG sites. This project will utilize a new maximum likelihood method capable of simultaneous inference of the rates of CpG to TpG/CpA transition and of the rates of single-nucleotide substitution significantly beyond the point of naive saturation. This method will be applied to the abundant sequences of dead copies of transposable elements in the human and other mammalian genomes deposited over the last 200-300 million years. This analysis will provide essential new information regarding the evolution of patterns of substitution in mammalian genomes, will create fine-scale (1-5 Mbp) genomic maps of substitution patterns and rates of the human and other mammalian genomes, and will investigate genomic determinants of background substitution patterns in mammals.