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Quantitative sequence-function relationships in proteins based on gene ontology.

ABSTRACT: BACKGROUND: The relationship between divergence of amino-acid sequence and divergence of function among homologous proteins is complex. The assumption that homologs share function--the basis of transfer of annotations in databases--must therefore be regarded with caution. Here, we present a quantitative study of sequence and function divergence, based on the Gene Ontology classification of function. We determined the relationship between sequence divergence and function divergence in 6828 protein families from the PFAM database. Within families there is a broad range of sequence similarity from very closely related proteins--for instance, orthologs in different mammals--to very distantly-related proteins at the limit of reliable recognition of homology. RESULTS: We correlated the divergence in sequences determined from pairwise alignments, and the divergence in function determined by path lengths in the Gene Ontology graph, taking into account the fact that many proteins have multiple functions. Our results show that, among homologous proteins, the proportion of divergent functions decreases dramatically above a threshold of sequence similarity at about 50% residue identity. For proteins with more than 50% residue identity, transfer of annotation between homologs will lead to an erroneous attribution with a totally dissimilar function in fewer than 6% of cases. This means that for very similar proteins (about 50 % identical residues) the chance of completely incorrect annotation is low; however, because of the phenomenon of recruitment, it is still non-zero. CONCLUSION: Our results describe general features of the evolution of protein function, and serve as a guide to the reliability of annotation transfer, based on the closeness of the relationship between a new protein and its nearest annotated relative.

SUBMITTER: Sangar V

PROVIDER: S-EPMC1976327 | biostudies-literature | 2007

REPOSITORIES: biostudies-literature

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Quantitative sequence-function relationships in proteins based on gene ontology.

Sangar Vineet V Blankenberg Daniel J DJ Altman Naomi N Lesk Arthur M AM

BMC bioinformatics 20070808

<h4>Background</h4>The relationship between divergence of amino-acid sequence and divergence of function among homologous proteins is complex. The assumption that homologs share function--the basis of transfer of annotations in databases--must therefore be regarded with caution. Here, we present a quantitative study of sequence and function divergence, based on the Gene Ontology classification of function. We determined the relationship between sequence divergence and function divergence in 6828 ...[more]

PMID: 17686158

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Project description:BACKGROUND: Gene Ontology (GO) annotation, which describes the function of genes and gene products across species, has recently been used to predict protein subcellular and subnuclear localization. Existing GO-based prediction methods for protein subcellular localization use the known accession numbers of query proteins to obtain their annotated GO terms. An accurate prediction method for predicting subcellular localization of novel proteins without known accession numbers, using only the input sequence, is worth developing. RESULTS: This study proposes an efficient sequence-based method (named ProLoc-GO) by mining informative GO terms for predicting protein subcellular localization. For each protein, BLAST is used to obtain a homology with a known accession number to the protein for retrieving the GO annotation. A large number n of all annotated GO terms that have ever appeared are then obtained from a large set of training proteins. A novel genetic algorithm based method (named GOmining) combined with a classifier of support vector machine (SVM) is proposed to simultaneously identify a small number m out of the n GO terms as input features to SVM, where m <<n. The m informative GO terms contain the essential GO terms annotating subcellular compartments such as GO:0005634 (Nucleus), GO:0005737 (Cytoplasm) and GO:0005856 (Cytoskeleton). Two existing data sets SCL12 (human protein with 12 locations) and SCL16 (Eukaryotic proteins with 16 locations) with <25% sequence identity are used to evaluate ProLoc-GO which has been implemented by using a single SVM classifier with the m = 44 and m = 60 informative GO terms, respectively. ProLoc-GO using input sequences yields test accuracies of 88.1% and 83.3% for SCL12 and SCL16, respectively, which are significantly better than the SVM-based methods, which achieve < 35% test accuracies using amino acid composition (AAC) with acid pairs and AAC with dipedtide composition. For comparison, ProLoc-GO using known accession numbers of query proteins yields test accuracies of 90.6% and 85.7%, which is also better than Hum-PLoc (85.0%) and Euk-OET-PLoc (83.7%) using ensemble classifiers with hybridization of GO terms and amphiphilic pseudo amino acid composition for SCL12 and SCL16, respectively. CONCLUSION: The growth of Gene Ontology in size and popularity has increased the effectiveness of GO-based features. GOmining can serve as a tool for selecting informative GO terms in solving sequence-based prediction problems. The prediction system using ProLoc-GO with input sequences of query proteins for protein subcellular localization has been implemented (see Availability).

Dataset Information

Quantitative sequence-function relationships in proteins based on gene ontology.

Publications

Quantitative sequence-function relationships in proteins based on gene ontology.

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