Quantitative assessment of relationship between sequence similarity and function similarity

Background: Comparative sequence analysis is considered as the first step towards annotating new proteins in genome annotation. However, sequence comparison may lead to creation and propagation of function assignment errors. Thus, it is important to perform a thorough analysis for the quality of sequence-based function assignment using large-scale data in a systematic way. Results: We present an analysis of the relationship between sequence similarity and function similarity for the proteins in four model organisms, i. e., Arabidopsis thaliana, Saccharomyces cerevisiae, Caenorrhabditis elegans, and Drosophila melanogaster. Using a measure of functional similarity based on the three categories of Gene Ontology (GO) classifications (biological process, molecular function, and cellular component), we quantified the correlation between functional similarity and sequence similarity measured by sequence identity or statistical significance of the alignment and compared such a correlation against randomly chosen protein pairs. Conclusion: Various sequence-function relationships were identified from BLAST versus PSI-BLAST, sequence identity versus Expectation Value, GO indices versus semantic similarity approaches, and within genome versus between genome comparisons, for the three GO categories. Our study provides a benchmark to estimate the confidence in assignment of functions purely based on sequence similarity.