Chargaff's second parity rule lies at the origin of additive genetic interactions in quantitative traits to make natural selection possible.

A major challenge of modern biology is to understand how random genetic variation causes phenotypic variation in quantitative traits. Chargaff's Second Parity Rule (CSPR) is a statistical property of cellular genomes defined as near exact equalities G-C and A-T within single DNA strand. Analysis of mutation spectra inferred from single nucleotide polymorphisms (SNPs) observed in human and mice populations reveals near exact equalities of the reverse complementary mutations, indicating that genetic variations obey CSPR. Furthermore, the nucleotide compositions of coding sequences are statistically interwoven via CSPR since pyrimidine bias at 3rd codon position compensates purine bias at 1st and 2nd positions. Due to this inter-dependence both synonymous and non-synonymous mutations are subject to natural selection. Based on the Fisher's infinitesimal model, we propose that accumulation of a sufficient number of the reverse complementary mutations results in a continuous trait variation due to small additive effects of statistically inter-linked genetic alterations. Therefore, additive genetic interactions can be inferred as the statistical entanglement of nucleotide compositions of different genetic loci. CSPR challenges the neutral theory of molecular evolution, because all random mutations participate in variation of the traits. The sequence of a gene is interwoven with many other loci in a genome, each of which making infinitely small contribution to a trait variation in contactless manner. ### Competing Interest Statement The authors have declared no competing interest.