Evolutionary inferences from protein-coding genes

蛋白质编码基因的进化推论

• 批准号: 7470015
• 负责人: Jeffrey L. Thorne
• 金额: $ 14.25万
• 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 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7470015
• 关键词: Accounting; Address; Amino Acid Sequence; Amino Acids; Code; Codon Nucleotides; Compatible; Complement; Computer Simulation; DNA; Data Set; Databases; Dependence; Evolution; Genes; Genotype; Intuition; Measures; Methodology; Methods; Mining; Modeling; Modification; Molecular; Nucleotides; Pain; Peptide Sequence Determination; Phenotype; Positioning Attribute; Procedures; Protein Family; Proteins; RNA; Rate; Research; Research Personnel; Silicon Dioxide; Site; Solvents; Structure; Surveys; System; Techniques; Tertiary Protein Structure; Time; Trees; Vaccine Design; Variant; Viral; base; experience; fitness; improved; interest; neglect; protein structure; simulation; tool

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缓慢变化。如果核苷酸取代率导致氨基酸取代破坏蛋白质结构，则预计其取代率较低。氨基酸置换对三级结构的影响不仅取决于置换所涉及的残基，还取决于空间上靠近置换位点的残基。蛋白质结构和蛋白质变化之间的这种关系引起了蛋白质编码基因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。 该项目的研究将建立在一种新开发的统计技术的基础上，用于从序列对中进行进化推论。这项新技术结合了由于蛋白质三级结构所施加的疼痛/反式氨基酸相互作用而导致的密码子之间的依赖性。最初的重点是将这种基于模型的方法扩展到两个以上系统发育相关序列的分析。由此产生的方法将成为表征蛋白质结构对蛋白质进化影响的有力工具。将挖掘比对的蛋白质编码 DMA 序列的 Pandit 数据库，以评估哪些蛋白质家族在三级结构影响最大和最小的情况下进化。将确定该数据库中正向选择的证据，并将解决蛋白质结构与蛋白质进化之间的关系强度是否因分类群体而异的问题。为了补充实证研究并进一步评估新方法，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。解释共变位置的祖先序列推断以及将祖先序列推断应用于疫苗设计的潜力是另一个令人感兴趣的主题。尽管该项目的重点是由于蛋白质结构而导致密码子之间的进化依赖性，但统计方法非常通用，可以应用于进化依赖性的各种情况，其中可以测量或建模序列适应性的替代物。