Abstract:
Background. Francis Crick’s central dogma provides a residue-by-residue mechanistic
explanation of the flow of genetic information in living systems. However, this principle
may not be sufficient for explaining how random mutations cause continuous variation
of quantitative highly polygenic complex traits. Chargaff’s second parity rule (CSPR),
also referred to as intrastrand DNA symmetry, defined as near-exact equalities G ≈ C
and A ≈ T within a single DNA strand, is a statistical property of cellular genomes.
The phenomenon of intrastrand DNA symmetry was discovered more than 50 years
ago; at present, it remains unclear what its biological role is, what the mechanisms are
that force cellular genomes to comply strictly with CSPR, and why genomes of certain
noncellular organisms have broken intrastrand DNA symmetry. The present work is
aimed at studying a possible link between intrastrand DNA symmetry and the origin
of genetic interactions in quantitative traits.
Methods. Computational analysis of single-nucleotide polymorphisms in human and
mouse populations and of nucleotide composition biases at different codon positions
in bacterial and human proteomes.
Results. The analysis of mutation spectra inferred from single-nucleotide polymorphisms observed in murine and human populations revealed near-exact equalities
of numbers of reverse complementary mutations, indicating that random genetic
variations obey CSPR. Furthermore, nucleotide compositions of coding sequences
proved to be statistically interwoven via CSPR because pyrimidine bias at the 3rd codon
position compensates purine bias at the 1st and 2nd positions.
Conclusions. According to Fisher’s infinitesimal model, we propose that accumulation
of reverse complementary mutations results in a continuous phenotypic variation
due to small additive effects of statistically interwoven genetic variations. Therefore,
additive genetic interactions can be inferred as a statistical entanglement of nucleotide
compositions of separate genetic loci. CSPR challenges the neutral theory of molecular
evolution—because all random mutations participate in variation of a trait—and
provides an alternative solution to Haldane’s dilemma by making a gene function
diffuse. We propose that CSPR is symmetry of Fisher’s infinitesimal model and that
genetic information can be transferred in an implicit contactless manner.
