Department of Molecular and Human Genetics, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, 77030, USA.
Microsoft Corporation, 1 Microsoft Way, Redmond, WA, 98052, USA.
Sci Rep. 2018 Jan 22;8(1):1357. doi: 10.1038/s41598-018-19744-w.
Evolutionarily constrained regions (ECRs) are a hallmark for sites of critical importance for a protein's structure or function. ECRs can be inferred by comparing the amino acid sequences from multiple protein homologs in the context of the evolutionary relationships that link the analyzed proteins. The compilation and analysis of the datasets required to infer ECRs, however, are time consuming and require skills in coding and bioinformatics, which can limit the use of ECR analysis in the biomedical community. Here, we developed Aminode, a user-friendly webtool for the routine and rapid inference of ECRs. Aminode is pre-loaded with the results of the analysis of the whole human proteome compared with proteomes from 62 additional vertebrate species. Profiles of the relative rates of amino acid substitution and ECR maps of human proteins are available for immediate search and download on the Aminode website. Aminode can also be used for custom analyses of protein families of interest. Interestingly, mapping of known missense variants shows great enrichment of pathogenic variants and depletion of non-pathogenic variants in Aminode-generated ECRs, suggesting that ECR analysis may help evaluate the potential pathogenicity of variants of unknown significance. Aminode is freely available at http://www.aminode.org .
进化约束区域（ECRs）是蛋白质结构或功能关键部位的标志。通过比较分析蛋白质进化关系中多个蛋白质同源物的氨基酸序列，可以推断 ECRs。然而，编译和分析推断 ECRs 所需的数据集是一项耗时的任务，并且需要编码和生物信息学方面的技能，这可能会限制 ECR 分析在生物医学领域的应用。在这里，我们开发了 Aminode，这是一个用户友好的 Web 工具，用于常规和快速推断 ECRs。Aminode 预先加载了与来自 62 种其他脊椎动物物种的蛋白质组进行比较的整个人类蛋白质组分析结果。相对氨基酸替换率的概况和人类蛋白质的 ECR 图谱可在 Aminode 网站上立即搜索和下载。Aminode 还可用于自定义分析感兴趣的蛋白质家族。有趣的是，已知错义变异的映射显示 Aminode 生成的 ECRs 中致病性变异明显富集，而非致病性变异明显减少，这表明 ECR 分析可能有助于评估未知意义变异的潜在致病性。Aminode 可在 http://www.aminode.org 免费获取。
