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Patterns of background nucleotide substitution in the human lineage

人类谱系中背景核苷酸取代的模式

基本信息

批准号：
7791280
负责人：
Dmitri Petrov
金额：
$ 19.47万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2011-03-31
项目状态：
已结题

项目摘要

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.

背景替代的模式和速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。如果有了这些知识，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，根据估计的比率，背景替换尽管有这种核心重要性，背景替代的模式却很差。知道的关于背景替换率是否在人类基因组中变化以及是否这些比率在人类谱系中一直在进化，仍然存在争议。主要困难在于确定在没有功能约束的情况下进化的序列，以及在给定的情况下设计推理方法，哺乳动物DNA中普遍存在快速的邻居依赖性CpG到TpG/CpA的转变。高该过程的速率和邻居依赖性实质上使所有的替代推断复杂化，甚至那些在非CpG位点的单核苷酸取代。该项目将利用新的最大值可能性方法能够同时推断CpG到TpG/CpA转换的速率和单核苷酸取代的速率显著超过幼稚饱和点。该方法将应用于人类和其他动物中大量的转座因子死亡拷贝的序列，哺乳动物的基因组在过去的2亿到3亿年里沉积下来。这一分析将提供重要的新关于哺乳动物基因组中替代模式进化的信息，将创造精细的 (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谱，并将研究哺乳动物背景替代模式的基因组决定因素。