Integrative computational framework for pattern mining in big -omics data: linking synonymous codon usage to protein biogenesis

大组学数据模式挖掘的综合计算框架：将同义密码子使用与蛋白质生物发生联系起来

基本信息

批准号：
9706238
负责人：
Patricia Louise Clark
金额：
$ 2.67万
依托单位：
UNIVERSITY OF NOTRE DAME
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2019-06-30
项目状态：
已结题

项目摘要

PROJECT SUMMARY Efficient production of functional proteins is arguably the most important function of a cell. Ribosomes synthesize proteins by decoding mRNA codons, and N-terminal portions of proteins can begin to fold even while synthesis is still underway. The genetic code is degenerate, meaning that most amino acids can be encoded by more than one codon. Because synonymous codon substitutions do not alter the amino acid sequence of the encoded protein, they have historically been regarded as “silent”. However, it is now known that some synonymous substitutions can disrupt the expression, folding, targeting and/or function of the encoded protein, although the precise mechanisms are poorly understood. Computational analyses have attempted to identify connections between the locations of synonymous codons and features of the encoded protein, but to date have yielded conflicting results, and there have been few attempts to experimentally test predictions made from these computational studies. Hence we currently lack a systematic understanding of the connections between synonymous codon usage and protein biogenesis. Establishing these connections would broadly transform our interpretation of synonymous codon substitutions, including single-nucleotide polymorphisms (SNPs) associated with human disease and synonymous substitutions in genome-wide association studies (GWAS). Establishing these connections would also enable the addition of coding sequence design as an integral aspect of the rational design of novel gene products (proteins). Thus, we aim to design an innovative integrative computational and experimental strategy with which to identify connections between codon usage patterns and protein biogenesis. We will search broadly for such connections, developing and applying several novel new approaches: (i) computational approaches to track, quantify and align synonymous codon usage patterns in homologous proteins, (ii) network approaches to map codon usage onto all levels of protein structure, and (iii) an innovative combination of broad and targeted experimental approaches to test the importance and specific effects of altering codon usage on protein biogenesis. Throughout the project, rigorous statistical methods will be applied to test the validity of identified connections, and cell-based experiments will be used to both test and refine hypotheses resulting from the computational analyses and develop new hypotheses that will feed back into the computational analyses. The goal of this project is to transform our understanding of the connections between synonymous codon usage and protein biogenesis. The endpoint for this project period is the development of a set of general principles for codon usage, including user-friendly open-source software to enable the biomedical community to analyze genes of interest for synonymous codon usage features likely to affect protein biogenesis. At the same time, our methodology will be generalizable, to allow the public to search for additional connections between sequence and/or network patterns and protein function, as well as for similar connections in other domains.

项目概要功能蛋白的有效生产可以说是核糖体最重要的功能。通过解码 mRNA 密码子来合成蛋白质，蛋白质的 N 端部分甚至可以开始折叠而合成仍在进行中，遗传密码是简并的，这意味着大多数氨基酸都可以被简并。因为同义密码子替换不会改变氨基酸。编码蛋白质的序列，它们历来被认为是“沉默的”，但现在已经知道了。一些同义替换可能会破坏基因的表达、折叠、靶向和/或功能编码的蛋白质，尽管计算分析对其精确机制知之甚少。试图确定同义密码子位置和编码特征之间的联系蛋白质，但迄今为止已经产生了相互矛盾的结果，并且几乎没有尝试进行实验测试因此，我们目前缺乏对这些计算研究的预测的系统了解。同义密码子使用和蛋白质生物发生之间的联系。将广泛改变我们对同义密码子替换的解释，包括单核苷酸与人类疾病相关的多态性 (SNP) 和全基因组同义替换关联研究（GWAS）也可以增加编码。序列设计作为新基因产物（蛋白质）合理设计的一个组成部分。因此，我们的目标是。设计一种创新的综合计算和实验策略来识别联系我们将广泛寻找密码子使用模式和蛋白质生物发生之间的联系，开发和应用几种新颖的新方法：（i）跟踪、量化和对齐同源蛋白质中的同义密码子使用模式，(ii) 映射密码子使用的网络方法蛋白质结构的各个层面，以及（iii）广泛和有针对性的实验的创新组合测试改变密码子使用对蛋白质生物发生的重要性和具体影响的方法。在整个项目中，将应用严格的统计方法来测试已识别连接的有效性，基于细胞的实验将用于测试和完善计算得出的假设分析并提出新的假设，这些假设将反馈到计算分析中。该项目旨在改变我们对同义密码子使用和蛋白质之间联系的理解该项目阶段的终点是制定一套密码子的一般原则。用途，包括用户友好的开源软件，使生物医学界能够分析基因对可能影响蛋白质生物合成的同义密码子使用特征的兴趣。方法将是可推广的，以允许公众寻找序列之间的其他联系和/或网络模式和蛋白质功能，以及其他领域中的类似连接。