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Strong selection at synonymous sites conserves nucleic acid structure

Posted by forsdyke on 02 Jun 2013 at 15:29 GMT

An elegant paper! That geneticists both acknowledge strong selection at sites of synonymous mutations and call for re-evaluation of the role of such sites in disease, is most welcome. Base compositions of synonymous sites are generally reflective of the compositions of introns and flanking genome regions. In his “genome hypothesis”(1980), a founder of modern bioinformatic analysis, Richard Grantham, pointed to unknown pressures affecting the entire genome that would be expected to impact synonymous sites in genes [1]. Grantham’s quest for genome-wide function was supported by biophysicists and biochemists such as Akiyoshi Wada [2] and Georgio Bernardi [3], who identified genome-wide pressures and distinguished the “genome phenotype” from the conventional phenotype.

Lawrie et al. note that “a strong possibility remains that the function underlying the strong constraint at synonymous sites is related to mRNA structure.” But such structure can reflect a primary evolutionary pressure, not at the mRNA level, but at the genome level – be that genome DNA as in the fruit fly, or RNA as in viruses such as HIV-1. Indeed, despite the rich sophistication of its encoded proteins, it has long been known that conservation in HIV-1 acts primarily on RNA structure, which is greatly influenced by synonymous mutations [4-7]. If HIV-1 has an Achilles heel it relates to RNA structure, not protein function. Nevertheless, it is good that geneticists’ “collective biological intuition that synonymous sites had little functional or evolutionary importance” stands corrected, and that their evidence is now converging with that of non-geneticists.

[1]. Grantham R. (1980) Workings of the genetic code.Trends Biochem Sci 5: 327-331.
[2]. Wada A, Tachibana H, Gotoh O, Takanami M (1975) Long range homogeneity of physical stability in double-stranded DNA. Nature 263: 439-440.
[3]. Bernardi G, Bernardi G. (1986) Compositional constraints and genome evolution. J Mol Evol 24: 1-11.
[4] Forsdyke DR. (1995) Reciprocal relationship between stem-loop potential and substitution density in retroviral quasispecies under positive Darwinian selection. J Mol Evol 41: 1022-1037.
[5] Simon-Loriere E, Rossolillo P, Negroni M. (2011) RNA structure, genomic organization and selection of recombinant HIV. RNA Biol 8: 280-286.
[6] Zanini F, Neher RA (2013) Deleterious synonymous mutations hitchhike to high frequency in HIV-1 env evolution. arXiv:1303.0805v1 [q-bio.PE]
[7] Forsdyke DR. (2013) Role of HIV RNA structure in recombination and speciation: romping in purine A, keeps HTLV away. arXiv:1305.2132v1 [q-bio.GN]

No competing interests declared.

RE: Strong selection at synonymous sites conserves nucleic acid structure

dlawrie replied to forsdyke on 12 Jun 2013 at 06:00 GMT

Thank you for your comment! Selection on DNA structure is we something we considered to some extent. In the paper, we tested for selection pressure on nucleosome occupancy and indeed found a potential signal of purifying selection at nucleosome-bound positions. Further another paper published in PLoS Genetics at the same time as ours supports the notion that there is selection acting at the level of DNA structure in fruit flies [1]. However, one drawback to our test of selection is that we can only detect the differential in selective pressure between our test set of sites (in this case 4D synonymous sites) and our reference (short introns). Thus any force which equivalently affects our test and reference set of sites, as nucleosome-binding seems to do, will be undetected. (Note that short introns and 4D sites are roughly equally covered by nucleosomes.) This does not mean that there is no selection on DNA structure at the level of nucleosome binding, but this type of selection cannot explain the signature of strong constraint on 4D sites using short introns as the reference. There may also be selection acting on further levels of DNA structure and organization, but to explain our affect such a selective force would have to be acting differentially on synonymous sites versus short introns.

When defining our test and reference set by whether short intron sites are covered by nucleosomes or not, we do find a potential signal of selection. In testing for selection on DNA structure at other levels of organization, we would have to be careful about choosing which sites to use as a test set. The idea of selection to maintain DNA structure or organization of functional elements is an intriguing one and again, thank you for the comment! Any further suggestions or ideas on that front would be most welcome.

[1] Kenigsberg E, Tanay A (2013) Drosophila Functional Elements Are Embedded in Structurally Constrained Sequences. PLoS Genet 9(5): e1003512. doi:10.1371/journal.pgen.1003512

No competing interests declared.