Genomic compliance with Chargaff's second parity rule may have originated non-adaptively, but stem-loops now function adaptively.

Of Chargaff's four rules on DNA base quantity, his second parity rule (PR-2) is the most contentious. Various biometricians (e.g., Sueoka, Lobry) regarded PR-2 compliance as a non-adaptive feature of modern genomes that could be modeled through interrelations among mutation rates. However, PR-2 compliance with stem-loop potential was considered adaptively relevant by biochemists familiar with analyses of nucleic acid structure (e.g., of Crick) and of meiotic recombination (e.g., of Kleckner). Meanwhile, other biometricians had shown that PR-2 complementarity extended beyond individual bases (1-mers) to oligonucleotides (k-mers), possibly reflecting "advantageous DNA structure" (Nussinov). An "introns early" hypothesis (Reanney, Forsdyke) had suggested a primordial nucleic acid world with recombination-mediated error-correction requiring genome-wide stem-loop potential to have evolved prior to localized intrusions of protein-encoding potential (exons). Thus, a primordial genome was equivalent to one long intron. Indeed, when assessed as the base order-dependent component (correcting for local influences of GC%), modern genes, especially when evolving rapidly under positive Darwinian selection, display high intronic stem-loop potential. This suggests forced migration from neighboring exons by competing protein-encoding potential. PR-2 compliance may have first arisen non-adaptively. Primary prototypic structures were later strengthened by their adaptive contribution to recombination. Thus, contentious views may actually be in harmony.