Non-synonymous to synonymous substitutions suggest that orthologs tend to keep their functions, while paralogs are a source of functional novelty

Abstract

AbstractBackgroundOrthologs diverge after speciation events and paralogs after gene duplication. It is thus expected that orthologs would tend to keep their functions, while paralogs could be a source of new functions. Because protein functional divergence follows from non-synonymous substitutions, we performed an analysis based on the ratio of non-synonymous to synonymous substitutions (dN/dS) as proxy for functional divergence. We used four working definitions of orthology, including reciprocal best hits (RBH), among other definitions based on network analyses and clustering.ResultsThe results showed that orthologs, by all definitions tested, had values of dN/dS noticeably lower than those of paralogs, not only suggesting that orthologs keep their functions better, but also that paralogs are a readily source of functional novelty. The differences in dN/dS ratios remained favouring the functional stability of orthologs after eliminating gene comparisons with potential problems, such as genes having a high codon usage bias, low coverage of either of the aligned sequences, or sequences with very high similarities. The dN/dS ratios kept suggesting better functional stability of orthologs regardless of overall sequence divergence. Separating orthologs and paralogs into groups with similar overall substitution rates kept showing dN/dS differences favouring the functional stability of orthologs over that of paralogs.AvailabilityA couple of programs for obtaining orthologs and dN/dS values as tested in this manuscript are available at github: https://github.com/Computational-conSequences/SequenceTools.