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）：对背景替代的模式和速率的了解对于人类基因组中功能序列的识别和分析至关重要。只要这些知识与两个或多个基因组相比，应该可以识别功能序列。这样的序列将脱颖而出，因为那些在估计的背景替代速率下变化的序列显着少或明显远远超过了预期的序列。尽管具有至关重要的重要性，但背景替代模式还是很众所周知的。背景替代率在人类基因组中是否有所不同，以及这些率是否在人类谱系中不断发展的问题仍然存在争议。主要的困难在于鉴定在无功能约束下进化的序列，并且鉴于存在于哺乳动物DNA中普遍存在的TPG/CPA转变的快速邻居依赖性CpG鉴于推论方法。该过程的高率和邻居依赖性基本上使所有替代的推断都变得复杂，即使是非CPG位点的单核苷酸取代的推断。该项目将利用一种能够同时推断CpG对TPG/CPA过渡的速率的新最大似然方法，以及单核苷酸取代的速率显着超出了天真饱和的点。该方法将应用于在过去的200 - 3亿年中人类和其他哺乳动物基因组中可转座元素的死亡副本的大量序列。该分析将提供有关哺乳动物基因组替代模式演变的基本新信息，将创建人类和其他哺乳动物基因组的替代模式和速率的细尺度（1-5 MBP）基因组图，并将研究哺乳动物中背景替代模式的基因组决定因素。