Genome-wide mutation models to decipher function

用于破译功能的全基因组突变模型

• 批准号: 8238861
• 负责人: DAVID D POLLOCK
• 金额: $ 26.75万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-13 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8238861
• 关键词: Affect; Amino Acids; DNA Sequence Rearrangement; DNA Transposable Elements; Data; Detection; Development; Didelphidae; Disease; Elements; Evolution; Gene Conversion; Genetic Recombination; Genome; Genomics; Genotype; Goals; Human; Human Genome; Knowledge; Lead; Methods; Mission; Modeling; Molecular; Molecular Structure; Mutation; Nature; Nucleotides; Open Reading Frames; Outcome; Pattern; Phenotype; Phylogenetic Analysis; Positioning Attribute; Principal Investigator; Process; Proteins; Public Health; Recording of previous events; Repetitive Sequence; Research; Role; Sampling; Sequence Analysis; Shapes; Site; Speed; Structure; Testing; Time; United States National Institutes of Health; Variant; Work; analytical method; base; comparative; comparative genomics; directed evolution; disease phenotype; fitness; genome-wide; genome-wide analysis; improved; mitochondrial genome; news; novel; predictive modeling; programs; tool; vertebrate genome

DESCRIPTION (provided by applicant): Complete vertebrate genomes are accumulating rapidly, and the pace of accumulation will only increase. This is excellent news, because the utility of comparative analysis depends heavily on the diversity of species sampling. There are, however, substantial challenges to exploiting the full potential of such extensive data: development of novel methods and analytical approaches is needed. We aim to develop and extend our capacity to analyze the dynamic evolutionary processes (across regions and through time) that have shaped extant genomes. We will achieve this goal using a Bayesian evolutionary analysis approach we recently developed that allows us many orders of magnitude speed advantage over competing approaches, and which scales well with model complexity and data size. Many of the studies we propose are based on biologically realistic paradigms that previously were impossible to consider or test because of computational limitations. We propose to comprehensively delineate the repetitive contents of a selected set of vertebrate genomes, including annotation of ancient elements from the "dark matter" of genomes (the currently unannotated portion). The transposable elements in this set of repeat sequences will be used to build the first complete genome-wide models of context-dependent substitution processes. We will consider contexts such as recombination, rearrangement, expression, and local nucleotide content, as well as unknown contexts, and analyze how the evolutionary processes influenced by these contexts have changed over time. These context- dependent substitution models will provide a powerful tool for identifying and annotating functional regions in interspecific comparisons of vertebrate genomes, and for differentiating and characterizing fitness-based effects in proteins. The core concept is that that if we better understand genome-wide patterns of background nucleotide substitution, then we will be able to more accurately identify genomic regions that are likely functional, and to understand how selection directs the evolution of proteins. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because it will develop new methods for understanding and interpreting vertebrate (and human) genomes, and for identifying genomic regions that are functionally important and thus relevant to phenotype and disease. The project is relevant to the NIH mission because it will provide methods for extracting information from comparative genomic data that will inform the structure and function of genomes, and how they relate to phenotypes of disease-related mutations in humans.

描述（申请人提供）：完整的脊椎动物基因组正在迅速积累，而且积累的速度只会加快。这是个好消息，因为比较分析的效用在很大程度上取决于物种采样的多样性。然而，充分利用如此广泛的数据的潜力面临着巨大的挑战：需要开发新的方法和分析方法。我们的目标是发展和扩展我们分析塑造现存基因组的动态进化过程（跨区域和跨时间）的能力。我们将使用我们最近开发的贝叶斯进化分析方法来实现这一目标，该方法使我们比竞争方法具有多个数量级的速度优势，并且可以很好地适应模型复杂性和数据大小。我们提出的许多研究都是基于生物学上的现实范式，由于计算限制，以前无法考虑或测试这些范式。我们建议全面描述一组选定的脊椎动物基因组的重复内容，包括对基因组“暗物质”中的古代元素（目前未注释的部分）进行注释。这组重复序列中的转座元件将用于构建第一个完整的依赖于上下文的替换过程的全基因组模型。我们将考虑重组、重排、表达和局部核苷酸含量等背景，以及未知背景，并分析受这些背景影响的进化过程如何随时间变化。这些上下文依赖的替代模型将提供一个强大的工具，用于识别和注释脊椎动物基因组种间比较中的功能区域，以及区分和表征蛋白质中基于适应性的效应。核心概念是，如果我们更好地了解背景核苷酸取代的全基因组模式，那么我们将能够更准确地识别可能具有功能的基因组区域，并了解选择如何指导蛋白质的进化。 公共健康相关性：拟议的研究与公共健康相关，因为它将开发新的方法来理解和解释脊椎动物（和人类）基因组，以及识别功能重要且与表型和疾病相关的基因组区域。该项目与 NIH 的使命相关，因为它将提供从比较基因组数据中提取信息的方法，这些信息将告知基因组的结构和功能，以及它们与人类疾病相关突变表型的关系。