Evolutionary inferences from protein-coding genes

蛋白质编码基因的进化推论

• 批准号: 7093001
• 负责人: Jeffrey L. Thorne
• 金额: $ 14.73万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7093001
• 关键词: biochemical evolution; computer simulation; conformation; molecular biology information system; nucleic acid sequence; protein sequence

DESCRIPTION (provided by applicant): Protein tertiary structure changes slowly during evolution. Nucleotide substitution rates are expected to be low if they result in an amino acid replacement that disrupts protein structure. The effect of an amino acid replacement on tertiary structure is determined not only by the residues involved in the replacement but also by the residues that are spatially nearby the site that experiences the replacement. This relationship between protein structure and protein change induces an evolutionary dependence among the positions in the protein-coding genes. Unfortunately, widely used models for the evolution of protein-coding genes ignore this dependence. The research in this project will build upon a newly developed statistical technique for making evolutionary inferences from sequence pairs. This new technique incorporates dependence among codons due to pain/vise amino acid interactions that are imposed by the protein tertiary structure. The initial focus will be to extend this model-based approach to the analysis of more than two phylogenetically-related sequences. The resulting method will be a powerful tool for characterizing the impact of protein structure on protein evolution. The Pandit database of aligned protein-coding DMA sequences will be mined to assess which protein families evolve under the most and least influence of tertiary structure. Evidence of positive selection in this database will be identified and the issue of whether the strength of the relationship between protein structure and protein evolution varies among taxonomic groups will be addressed. To complement the empirical studies and to further evaluate the new methodology, simulations will be performed. In addition, the possibility of allowing protein tertiary structure to change over time will be explored. Ancestral sequence inference that accounts for covarying positions and the potential for applying ancestral sequence inference to vaccine design is another topic of interest. Although the emphasis of this project is evolutionary dependence among codons due to protein structure, the statistical approach is quite general and could be applied to diverse cases of evolutionary dependence where surrogates for sequence fitness can be measured or modeled.

描述（由申请人提供）：蛋白质三级结构在进化过程中变化缓慢。如果核苷酸取代导致破坏蛋白质结构的氨基酸取代，则核苷酸取代率预计较低。氨基酸置换对三级结构的影响不仅取决于置换中涉及的残基，而且还取决于在空间上靠近经历置换的位点的残基。蛋白质结构和蛋白质变化之间的这种关系导致了蛋白质编码基因中位置之间的进化依赖性。不幸的是，广泛使用的蛋白质编码基因进化模型忽略了这种依赖性。 本计画的研究将建立在一种新发展的统计技术上，以从序列对中进行演化推论。这种新技术结合了由于蛋白质三级结构所施加的pain/vise氨基酸相互作用而导致的密码子之间的依赖性。最初的重点将是将这种基于模型的方法扩展到两个以上的遗传相关序列的分析。由此产生的方法将是一个强大的工具，用于表征蛋白质结构对蛋白质进化的影响。Pandit数据库的比对蛋白质编码DMA序列将被挖掘，以评估哪些蛋白质家族在最大和最小的三级结构的影响下进化。在这个数据库中的积极选择的证据将被确定和蛋白质结构和蛋白质进化之间的关系的强度是否不同的分类群体之间的问题将得到解决。为了补充经验研究，并进一步评估新的方法，将进行模拟。此外，还将探索允许蛋白质三级结构随时间变化的可能性。祖先序列推断，占共变位置和应用祖先序列推断疫苗设计的潜力是另一个感兴趣的话题。虽然这个项目的重点是进化依赖的密码子之间的蛋白质结构，统计方法是相当普遍的，可以应用到不同的情况下，进化依赖的替代品序列健身可以测量或建模。