Science 13 December 2013:
Vol. 342 no. 6164 pp. 1367-1372

Exonic Transcription Factor Binding Directs Codon Choice and Affects Protein Evolution

Andrew B. Stergachis, Eric Haugen, Anthony Shafer, Wenqing Fu, Benjamin Vernot, Alex Reynolds, Anthony Raubitschek, Steven Ziegler, Emily M. LeProust, Joshua M. Akey, John A. Stamatoyannopoulos | 2 Comments

Transcription factor binding within protein-coding regions of DNA constrains how the protein can evolve. [Also see Perspective by Weatheritt and Babu]

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Interesting work, but the authors appear to downplay previous findings with the following statements:

"Pervasive dual encoding of amino acid and regulatory information appears to be a fundamental feature of genome evolution. (...) [Codon biases linked to translation efficiency and mRNA stability] explain only a small fraction of observed codon preferences in mammalian genomes (7–11)".

In 2002, Majewski and Ott (cited in ref. 8) showed that there is a gradual depletion of SNPs near ends of exons, very roughly a 75% drop in frequency relative to the center, and attributed this signal to sequences that regulate splicing. In 2004, David Haussler and colleagues (PMID: 14992493) reported a spike in human-mouse conservation near ends of constitutive exons, and broader conservation within alternatively spliced exons, specifically at the end(s) subject to alternative splicing.

Thus "[p]ervasive dual encoding of amino acid and regulatory information appears" to have been reported previously.

Submitted on Wed, 12/18/2013 - 04:07

Is the intrinsic flexibility attributed to exploitation by natural selection epigenetically-effected by nutrient uptake? If so, natural selection for nutrients via seemingly futile cycles of themodynamically constrained protein biosynthesis and degradation might enable transcription factor binding that is limited by non-random nutrient-dependent changes in base pairs. The changes in based pairs would be accompanied by alternative splicings and amino acid substitutions in cells that stochastically express genes, which are most beneficial to species-specific cell types in different tissues.

The metabolism of nutrients to species-specific pheromones that control the physiology of reproduction could then epigenetically control transcription and gene expression from the top down via reproduction. We might then expect to see seemingly futile cycles of thermodynamically controlled nutrient-dependent protein biosynthesis and degradation result in conservation of genes associated with increased fitness in one ecological niche that might not be conserved in an organism that was competing for survival in the same ecological niche.

Clearly, the organism that was most capable of nutrient acquisition, which enabled the thermodynamics of its intercellular signaling to result in better organism-level thermoregulation, would establish its social niche among equally successful conspecifics that adapted to their ecological niche and proliferated more rapidly.

Symbiotic relationships might then result from cooperation among heterospecifics in situations where the failure to cooperate with other organisms and live from a different nutrient source would mean death to a unicellular organism or to a multicellular vertebrate. However, organisms that managed to somehow acquire more than an appropriate share of nutrients would be subjected to conserved molecular mechanisms for species diversification that suddenly were no longer adaptive.

Nutrient stress linked to thermal stress via abundance, but not by starvation or social stress, would then be the most likely cause of mutations that are not eliminated by the finely-tuned molecular mechanisms of adaptation to the epigenetic landscape that occur via its incorporation into the physical landscape of DNA in the organized genomes of species from microbes to man.

I welcome comments from anyone who thinks this theory might benefit progress, since I cannot properly evaluate my own model.

Submitted on Fri, 12/13/2013 - 14:46