Resolving the Ortholog Conjecture: Orthologs Tend to Be Weakly, but Significantly, More Similar in Function than Paralogs

University of California Davis, United States of America
PLoS Computational Biology (Impact Factor: 4.62). 05/2012; 8(5):e1002514. DOI: 10.1371/journal.pcbi.1002514
Source: PubMed


The function of most proteins is not determined experimentally, but is extrapolated from homologs. According to the "ortholog conjecture", or standard model of phylogenomics, protein function changes rapidly after duplication, leading to paralogs with different functions, while orthologs retain the ancestral function. We report here that a comparison of experimentally supported functional annotations among homologs from 13 genomes mostly supports this model. We show that to analyze GO annotation effectively, several confounding factors need to be controlled: authorship bias, variation of GO term frequency among species, variation of background similarity among species pairs, and propagated annotation bias. After controlling for these biases, we observe that orthologs have generally more similar functional annotations than paralogs. This is especially strong for sub-cellular localization. We observe only a weak decrease in functional similarity with increasing sequence divergence. These findings hold over a large diversity of species; notably orthologs from model organisms such as E. coli, yeast or mouse have conserved function with human proteins.

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    • "Oneofthebenefitsofextensiveandaccuratepredictionoforthologsacrossplantspeciesistheabilityto projectfunctionalannotationbetweenpairsoforthologousgenesontheassumptionthatorthologues generallyretainfunctionbetweenspecies(Altenhoffetal.,2012 "
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    • "Several consequent studies suggested that GO annotations should be used to test the OC hypothesis with a great caution [30, 31] or even should not be used for this purpose [32]. A general consensus is that GO annotations are compatible with the OC hypothesis [30, 32], although Altenhoff and coworkers suggested that GO annotations are better compatible with the “uniform” model [31]. "
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    ABSTRACT: Ongoing debates about functional importance of gene duplications have been recently intensified by a heated discussion of the "ortholog conjecture" (OC). Under the OC, which is central to functional annotation of genomes, orthologous genes are functionally more similar than paralogous genes at the same level of sequence divergence. However, a recent study challenged the OC by reporting a greater functional similarity, in terms of gene ontology (GO) annotations and expression profiles, among within-species paralogs compared to orthologs. These findings were taken to indicate that functional similarity of homologous genes is primarily determined by the cellular context of the genes, rather than evolutionary history. Subsequent studies suggested that the OC appears to be generally valid when applied to mammalian evolution but the complete picture of evolution of gene expression also has to incorporate lineage-specific aspects of paralogy. The observed complexity of gene expression evolution after duplication can be explained through selection for gene dosage effect combined with the duplication-degeneration-complementation model. This paper discusses expression divergence of recent duplications occurring before functional divergence of proteins encoded by duplicate genes.
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    • "For each collected homeologous pair, an orthogroup was constructed consisting of the homeologous pair and their orthologs in other plant species, since orthology relationships provide the most accurate representation of the followed evolutionary history (Fawcett et al. 2009; Altenhoff et al. 2012; Gabaldon and Koonin 2013). We used Inparanoid (v4.1) (Ostlund et al. 2010) with default parameter settings to detect orthologs. "
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