  The utility of DNA sequence substrings (k-mers) in alignment-free
phylogenetic classification, including that of bacteria and viruses, is
increasingly recognized. However, its biological basis eludes many twenty-first
century practitioners. A path from the nineteenth century recognition of the
informational basis of heredity to the modern era can be discerned. Crick's DNA
"unpairing postulate" predicted that recombinational pairing of homologous DNAs
during meiosis would be mediated by short k-mers in the loops of stem-loop
structures extruded from classical duplex helices. The complementary "kissing"
duplex loops - like tRNA anticodon-codon k-mer duplexes - would seed a more
extensive pairing that would then extend until limited by lack of homology or
other factors. Indeed, this became the principle behind alignment-based methods
that assessed similarity by degree of DNA-DNA reassociation in vitro. These are
now seen as less sensitive than alignment-free methods that are closely
consistent, both theoretically and mechanistically, with chromosomal
anti-recombination models for the initiation of divergence into new species.
The analytical power of k-mer differences supports the theses that evolutionary
advance sometimes serves the needs of nucleic acids (genomes) rather than
proteins (genes), and that such differences have often played a role in early
speciation events.
