A classical experiment proposed in 1958 by Meselson and Stahl confirmed the semi-conservative mechanism of DNA replication in cellular organisms, according to which, after cell division, each daughter cell inherits a chromosome consisting of one parental chain (W or C) and one newly synthesized complementary chain (C' or W'). Since each DNA strand is replicated the same number of times after each cell division, it can be assumed that the W and C chains are equivalent as a result of a combination of cell division and a semi-conservative DNA replication mechanism. However, some non-cellular organisms, including single-stranded DNA and RNA viruses, do not conform to the concept of strand equivalence. A key feature of vertebrate mitochondrial genomes is the notable asymmetry in nucleotide composition between their two chains. This allows them to be separated during ultracentrifugation in an alkaline cesium chloride gradient into a heavy (H) chain that is rich in guanine and thymine, and a light (L) strand enriched in cytosine and adenine nucleotides. Despite extensive research, the exact mechanism of human mitochondrial DNA replication and its possible connection to this asymmetric composition remain unclear. In this paper, we propose a conceptual model for asymmetric inheritance of mitochondrial DNA strands to account for the strand-specific mutation asymmetry characteristic of vertebrate mtDNA.

Cellular organisms store heritable information in two forms, genetic and epigenetic, the latter being largely dependent on cytosine methylation (5mC). Chargaff’s Second Parity Rule (CSPR) describes the nucleotide composition of cellular genomes in terms of intra-strand DNA symmetry. However, it remains unknown whether DNA methylation patterns display intra-strand DNA symmetry. Computational analysis was conducted of the DNA methylation patterns observed in human cell lines and in tissue samples from healthy donors. Analysis of 5mC marks in mutually reverse-complementary pairs of short oligomers, containing CpG dinucleotide in the middle, revealed deviations from CSPR and methylation asymmetry that can be observed for two non-overlapping mirror groups defined by CpG methylation values. Deviations from CSPR, together with combinatorial probabilities of pattern distributions and computer simulations, highlight the non-random nature of methylation processes and enabled us to identify specific cell types as outliers. Further analysis revealed a compensatory methylation asymmetry that reduces deviations from intra-strand symmetry and implies the existence of strand-specific methylation during cell differentiation. Among six pairs of reverse-complementary tetranucleotides, four pairs with specific sequence motifs display pronounced methylation asymmetry. This mirror asymmetry may be associated with chromosome folding and the formation of a complex three-dimensional landscape.