Abstract
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.
Highlights
Several studies have shown that evolutionarily constrained regions (ECRs) can pinpoint the position of residues that are relevant for the function of enzymes or other protein types and can even provide significant information to predict the effects of specific mutations[5,6,7,8,9,10,11]
The Aminode pipeline performs analyses based on two inputs: (i) The amino acid sequences of the protein homologs, and (ii) a phylogenetic tree that describes the evolutionary relationships of the inputted protein homologs
Users can retrieve the results from the pre-computed analysis of the human proteome cross-analyzed against 62 vertebrate proteomes available in Ensembl genome browser[17]
Summary
Constrained regions (ECRs) are a hallmark for sites of critical importance for a protein’s structure or function. 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. Several studies have shown that evolutionarily constrained regions (ECRs) can pinpoint the position of residues that are relevant for the function of enzymes or other protein types and can even provide significant information to predict the effects of specific mutations[5,6,7,8,9,10,11]. Relative rates are plotted as a function of their position along the protein alignment, and ECRs are identified as corresponding to the “valleys” in the plot[15] These procedures are time consuming and require skills in coding and bioinformatics. Includes a pre-computed analysis of the human proteome, and allows download of high-resolution graphs and computed data for immediate use
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