Molecular sex: The importance of base composition rather than homology when nucleic acids hybridize

On learning that nucleic acid hybridization had been achieved in a test tube, Huxley hailed the discovery of “molecular sex.” The description was apt, since sex involves recombination, which requires hybridization that, in turn, depends on a successful homology search. Conversely, when the homology search fails, recombination fails. In yeast, this failure has been attributed to “simple sequence divergence.” But sequence divergence does not impair nucleic acid hybridization simply. Most natural single-stranded nucleic acids are predisposed to adopt higher-order structures containing stem-loops. Tomizawa showed that the rate-limiting step in the hybridization of single-stranded sequences is an initial “kissing” exploration between complementary loops, which must first be appropriately extruded and aligned. Successful duplex formation requires successful synchronization of matching higher-ordered structures, which depends, not so much on the degree of similarity between their base sequences as on the closeness of their base compositions (GC%). In these terms, we can understand how the anti-recombinational effect of GC% differences supports the duplication both of genes within a genome and of genomes within a genus (speciation).