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首页> 外文期刊>BMC Genomics >A protein domain-centric approach for the comparative analysis of human and yeast phenotypically relevant mutations
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A protein domain-centric approach for the comparative analysis of human and yeast phenotypically relevant mutations

机译：以蛋白质域为中心的方法，用于人和酵母的表型相关突变的比较分析

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BackgroundThe body of disease mutations with known phenotypic relevance continues to increase and is expected to do so even faster with the advent of new experimental techniques such as whole-genome sequencing coupled with disease association studies. However, genomic association studies are limited by the molecular complexity of the phenotype being studied and the population size needed to have adequate statistical power. One way to circumvent this problem, which is critical for the study of rare diseases, is to study the molecular patterns emerging from functional studies of existing disease mutations. Current gene-centric analyses to study mutations in coding regions are limited by their inability to account for the functional modularity of the protein. Previous studies of the functional patterns of known human disease mutations have shown a significant tendency to cluster at protein domain positions, namely position-based domain hotspots of disease mutations. However, the limited number of known disease mutations remains the main factor hindering the advancement of mutation studies at a functional level. In this paper, we address this problem by incorporating mutations known to be disruptive of phenotypes in other species. Focusing on two evolutionarily distant organisms, human and yeast, we describe the first inter-species analysis of mutations of phenotypic relevance at the protein domain level.ResultsThe results of this analysis reveal that phenotypic mutations from yeast cluster at specific positions on protein domains, a characteristic previously revealed to be displayed by human disease mutations. We found over one hundred domain hotspots in yeast with approximately 50% in the exact same domain position as known human disease mutations.ConclusionsWe describe an analysis using protein domains as a framework for transferring functional information by studying domain hotspots in human and yeast and relating phenotypic changes in yeast to diseases in human. This first-of-a-kind study of phenotypically relevant yeast mutations in relation to human disease mutations demonstrates the utility of a multi-species analysis for advancing the understanding of the relationship between genetic mutations and phenotypic changes at the organismal level.
机译：背景技术具有已知表型相关性的疾病突变体继续增加，并且随着新的实验技术（例如全基因组测序以及疾病关联研究）的出现，预计突变速度会更快。但是，基因组关联研究受到所研究表型的分子复杂性和具有足够统计能力所需的种群规模的限制。解决这一对稀有疾病研究至关重要的问题的方法是研究现有疾病突变的功能研究中出现的分子模式。当前用于研究编码区突变的以基因为中心的分析受其无法解释蛋白质功能模块的限制。先前对已知人类疾病突变的功能模式的研究表明，聚集在蛋白质结构域位置（即疾病突变的基于位置的域热点）上的趋势很明显。但是，已知疾病突变的数量有限，仍然是阻碍在功能水平上进行突变研究的主要因素。在本文中，我们通过纳入已知可破坏其他物种表型的突变来解决此问题。我们着眼于两个进化距离较远的生物，即人类和酵母，我们首次对蛋白质结构域水平的表型相关突变进行了种间分析。结果分析结果表明，来自酵母簇的表型突变在蛋白质结构域的特定位置先前揭示的特征是人类疾病突变所显示。我们在酵母中发现了一百多个结构域热点，其中约50％与已知的人类疾病突变处于完全相同的结构域位置。结论我们通过研究人和酵母中的结构域热点以及相关的表型来描述使用蛋白质结构域作为框架来传递功能信息的分析酵母改变人类疾病。这项与人类疾病突变相关的与表型相关的酵母突变的首次研究证明了多物种分析在提高机体水平上遗传突变与表型变化之间的关系方面的实用性。

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