Implications of fidelity difference between the leading and the lagging strand of DNA for the acceleration of evolution

Abstract

Without exceptions, genomic DNA of living organisms is replicated using the leading and the lagging strand. In a conventional idea of mutagenesis accompanying DNA replication, mutations are thought to be introduced stochastically and evenly into the two daughter DNAs. Here, however, we hypothesized that the fidelity of the lagging strand is lower than that of the leading strand. Our simulations with a simplified model DNA clearly indicated that, even if mutation rates exceeded the so-called threshold values, an original genotype was guaranteed in the pedigree and, at the same time, the enlargement of diversity was attained with repeated generations. According to our lagging-strand-biased-mutagenesis model, mutator microorganisms were established in which mutations biased to the lagging strand were introduced by deleting the proofreading activity of DNA polymerase. These mutators ("disparity mutators") grew normally and had a quick and extraordinarily high adaptability against very severe circumstances. From the viewpoint of the fidelity difference between the leading and the lagging strand, the basic conditions for the acceleration of evolution are examined. The plausible molecular mechanism for the faster molecular clocks observed in birds and mammals is discussed, with special reference to the accelerated evolution in the past. Possible applications in different fields are also discussed.

Keywords: acceleration; biased-mutagenesis; evolution; leading/lagging strand; polymerase δ; proofreading; replicore.

FIGURE 1

The distribution of mutations according to the deterministic disparity model of a linear DNA is shown. A broad arrow indicates a template DNA strand, a thin arrow indicates a newly synthesized leading strand and a dashed thin arrow indicates a newly synthesized lagging strand. The black circle with a short bar crossing strands indicates a point mutation. Each number on the side of a black circle indicates a base substitution at a different site. The ori indicates the replication origin. Two mutations per a single replication are introduced exclusively in the lagging strand. Notice that for instance, in the family line of the genomes with the symbol mark (✪), the genotype is guaranteed forever.

FIGURE 2

The distribution of individuals with a given number of mutations in the tenth generation for the parity (A) and disparity (B) stochastic models is shown. The results of 12 trials of simulations are shown. For details see text. Adapted from Furusawa and Doi (1992).

FIGURE 3

A “hill-climbing problem” is resolved using the parity and disparity “neo-Darwinian genetic algorithm.” The genome of the genetic algorithm consists of 16 bit and replicates using the leading and lagging strands. In parity models mutations are introduced evenly in both strands (A,B), while in disparity models biased mutations are introduced in the lagging strand (C,D). The vertical and horizontal axes are the fitness score and the distance of peaks from the starting position, respectively. Black dots symbolize the position of individuals at the end of the experiment. The larger the dots are, the more individuals have accumulated at specific positions. For details see text.

FIGURE 4

Results of the simulation with the “neo-Darwinian genetic algorithm” in the diploid and sexual world are shown. (A) Disparity individuals with mutation rate (n) = 0.1. Green, no crossover; blue, crossover frequency (CF) = 0.2/chromosome; red, CF = 2.0; and black, asexual and diploid. (B) Disparity individuals n = 8.0. Green, no crossover: blue, CF = 0.2; red, CF = 2.0; and black, asexual. (C) Parity individuals n = 0.1. Green, no crossover; blue, CF = 0.2; red, CF = 2.0; and black, asexual. (D) Parity individual with various mutation rates. Black, n = 2.0 without crossover; magenta, n = 2.32 without crossover; cyan, n = 2.32 and CF = 2.0; red, n = 2.4 without crossover; and blue, n = 2.4 and CF = 2.0. Adapted from Wada et al. (1993); Copyright 1993, National Academy of Sciences, USA.

FIGURE 5

The mutant distribution in “quasi-species” as a function of the mean error rate (m) per genome. The genome has a binary base sequence of 50. c is the relative concentration of error-free polymerase. The sum of the relative stationary concentration of the wild-type sequence with zero-mutations (I₀), of all one-error mutants (I₁), of all two-error mutants (I₂), etc. are plotted. (A) c = 0 or the parity model; (B) c = 0.09; (C) c = 0.1; and (D) c = 0.3. Arrow indicates the error threshold. For details see text. Adapted from Aoki and Furusawa (2003); permitted to use this figure from APS Journal, ASP Copyright 2003.

FIGURE 6

The distribution of mutations according to the deterministic disparity model of a circular genome is shown. The ori is replication origin. DNA synthesis starts from the ori to opposite directions (short arrows). term, the position where the progress of DNA synthesis meets. (a) and (b), The left and right hemispheres of the genome, respectively. Broad circle indicates the template strand, and thin circle the newly synthesized strand. The thin circle with small arrow heads is the lagging strand. The black circle with a short bar crossing strands is a point mutation. Each number followed by a or b indicates a base substitution at different sites. Two biased mutations are introduced in the lagging strand in every replication. Notice that for instance, in the family line of the genomes with the symbol mark (✪), the genotype of the left hemisphere is guaranteed forever.