Evolutionary inferences from protein-coding genes

描述(申请人提供)：蛋白质三级结构在进化过程中变化缓慢。如果核苷酸替换导致氨基酸替换，从而扰乱蛋白质结构，那么核苷酸替换率预计会很低。氨基酸替换对三级结构的影响不仅取决于替换所涉及的残基，还取决于经历替换的位置附近的空间残基。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不同位置之间的进化依赖。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关系。 该项目的研究将建立在一种新开发的统计技术的基础上，用于从序列对进行进化推断。这项新技术结合了由于蛋白质三级结构强加的疼痛/虎氨基酸相互作用而导致的密码子之间的依赖。最初的重点将是将这种基于模型的方法扩展到分析两个以上的系统发育相关序列。由此产生的方法将是表征蛋白质结构对蛋白质进化的影响的有力工具。将挖掘Pandit数据库中的比对蛋白质编码DMA序列，以评估哪些蛋白质家族在三级结构的影响最大和最小的影响下进化。将确定该数据库中阳性选择的证据，并将讨论蛋白质结构和蛋白质进化之间的关系是否在不同分类组之间存在差异的问题。为了补充实证研究，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。另一个感兴趣的主题是祖先序列推断，它解释了共同变化的位置，以及将祖先序列推断应用于疫苗设计的可能性。虽然这个项目的重点是由于蛋白质结构而导致的密码子之间的进化依赖，但统计方法是相当普遍的，可以应用于各种进化依赖的情况，其中序列适应度的替代可以被测量或建模。

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.