Generalised interrelations among mutation rates drive the genomic compliance of Chargaff's second parity rule

Abstract

Chargaff's second parity rule (PR-2), where the complementary base and k-mer contents are matching within the same strand of a double stranded DNA (dsDNA), is a phenomenon that invited many explanations. The strict compliance of nearly all nuclear dsDNA to PR-2 implies that the explanation should also be similarly adamant. In this work, we revisited the possibility of mutation rates driving PR-2 compliance. Starting from the assumption-free approach, we constructed kinetic equations for unconstrained simulations. The results were analysed for their PR-2 compliance by employing symbolic regression and machine learning techniques. We arrived to a generalised set of mutation rate interrelations in place in most species that allow for their full PR-2 compliance. Importantly, our constraints explain PR-2 in genomes out of the scope of the prior explanations based on the equilibration under mutation rates with simpler no-strand-bias constraints. We thus reinstate the role of mutation rates in PR-2 through its molecular core, now shown, under our formulation, to be tolerant to previously noted strand biases and incomplete compositional equilibration. We further investigate the time for any genome to reach PR-2, showing that it is generally earlier than the compositional equilibrium, and well within the age of life on Earth.

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

“…Nevertheless, in sufficiently long DNA segments, the parity is always restored due to alternation of DNA sequences with different signs of bias between Watson and Crick strands ( Rapoport & Trifonov, 2013 ). Several mechanisms have been proposed to explain the origin of CSPR: formation of stem-loop structures ( Forsdyke, 1995b ), a combination of a strand inversion and duplication ( Albrecht-Buehler, 2006 ), CSPR’s being a feature of the primordial genome ( Zhang & Huang, 2008 ), DNA free energy equilibrium ( Fariselli et al, 2021 ), and mutation rate interrelations ( Pflughaupt & Sahakyan, 2023 ). Previously, we introduced the concept of DNA strand equivalence and suggested that the broken intrastrand symmetry of vertebrate mitochondrial genomes is due to asymmetric DNA strand inheritance ( Matkarimov & Saparbaev, 2020 ).…”