Patterns of background nucleotide substitution in the human lineage

人类谱系中背景核苷酸取代的模式

• 批准号: 7077029
• 负责人: Dmitri Petrov
• 金额: $ 20.34万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/7077029
• 关键词: CpG islands; animal genetic material tag; animal population genetics; biochemical evolution; genetic mapping; genetic polymorphism; human genetic material tag; human population genetics; molecular biology information system; nucleic acid sequence; species difference

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：了解背景替代的模式和比率对于鉴定和分析人类基因组中的功能序列是必不可少的。有了这些知识，就有可能在两个或多个基因组的比较中鉴定功能序列。在估计的背景替代率下，这些序列的变化要么明显小于预期，要么明显大于预期。尽管具有这种核心重要性，但人们对背景替代的模式知之甚少。背景替代率是否在整个人类基因组中有所不同，以及这些比率是否在人类谱系中进化，这些问题仍然存在争议。主要的困难在于鉴定在没有功能限制的情况下进化的序列，以及在哺乳动物DNA中普遍存在的快速邻近依赖的CpG到TpG/CpA转换的情况下设计推断方法。这一过程的高速率和邻域依赖性极大地复杂化了所有取代的推断，甚至是非cpg位点的单核苷酸取代。该项目将利用一种新的最大似然方法，能够同时推断CpG到TpG/CpA转变的速率和单核苷酸取代的速率，大大超过初始饱和点。该方法将应用于过去2 -3亿年沉积在人类和其他哺乳动物基因组中的大量转座因子死亡拷贝序列。该分析将为哺乳动物基因组替代模式的进化提供重要的新信息，将创建人类和其他哺乳动物基因组替代模式和速率的精细（1-5 Mbp）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。