Orthologous TFs have different functions and regulate different genes.

October 19, 2007

A recent PLoS Comp. Bio paper by Price, Dehal and Arkin (2007) looked at the evolution of transcription factors — focusing on the ability of bi-directional blast hits (BBH) to predict orthology. Their findings (in brief):

  1. BBHs of TFs from distantly related bacteria are usually not evolutionary orthologs.
  2. False orthologs typically respond to different signals and regulate different genes.
  3. True evolutionary orthologs typically have (nearly) conserved function.
  4. Regulatory networks evolve more rapidly than previously thought, as even closely in closely related species specific predictions are incorrect.

Anyone who has followed the literature on gene duplication evolution, the orthology inference problem, or TF binding/motif evolution should not be surprised by their findings. Predicting the associations of a particular TF with targets might not even be inferrable in detail (even in closely related sequences) if the “neutral binding” / “neutral turnover” model is true.

M. Eisen’s work in the twelve Drosophilia species emphasizes this point as well — since the two points he raised at the recent RECOMB meeting on Regulatory Genomics were that (1) most binding may be neutral and (2) distant enhancers with very different patterns of binding events can still drive correct patterning in Drosophilia. I am reminded of G. Wray who stated (in his Jan 2005 Symposium on Complex Life Histories in Marine Bathic Invertebrates) that the “picture of cis-regulatory sequence evolution that is emerging is one of dynamic change at the level of sequence comparison, coupled with long-term conservation of expression profiles.”

Price, M.N., Dehal, P.S., Arkin, A.P. (2007). Orthologous Transcription Factors in Bacteria Have Different Functions and Regulate Different Genes. PLoS Computational Biology, 3(9), e175. DOI: 10.1371/journal.pcbi.0030175


One Response to “Orthologous TFs have different functions and regulate different genes.”

  1. I think the same will be true for some types of protein-protein interactions (low specificity, transient ones). I like these ideas of large nearly-neutral spaces for interactions but it complicates the computational predictions. It not only matters if the interactions if biophysical possible but among these we still have to define the biological relevant ones. Conservation alone of the interaction might not be a good criteria since what is typically conserved in the function of group of interactions (i.e. am expression pattern or a signaling pathway response).

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