On the Causes of Evolutionary Transition:Transversion Bias

Abstract

A pattern in which nucleotide transitions are favored several fold over transversions is common in molecular evolution. When this pattern occurs among amino acid replacements, explanations often invoke an effect of selection, on the grounds that transitions are more conservative in their effects on proteins. However, the underlying hypothesis of conservative transitions has never been tested directly. Here we assess support for this hypothesis using direct evidence: the fitness effects of mutations in actual proteins measured via individual or paired growth experiments. We assembled data from 8 published studies, ranging in size from 24 to 757 single-nucleotide mutations that change an amino acid. Every study has the statistical power to reveal significant effects of amino acid exchangeability, and most studies have the power to discern a binary conservative-vs-radical distinction. However, only one study suggests that transitions are significantly more conservative than transversions. In the combined set of 1,239 replacements (544 transitions, 695 transversions), the chance that a transition is more conservative than a transversion is 53 % (95 % confidence interval 50 to 56) compared with the null expectation of 50 %. We show that this effect is not large compared with that of most biochemical factors, and is not large enough to explain the several-fold bias observed in evolution. In short, the available data have the power to verify the "conservative transitions" hypothesis if true, but suggest instead that selection on proteins plays at best a minor role in the observed bias.

Detection of SNPs based on DNA specific-locus amplified fragment sequencing in Chinese fir (Cunninghamia lanceolata (Lamb.) Hook)

“…The most frequent SNPs occurred in C/T (34.3%) and A/T change represented the least type of variations (4.3%). Overall, the transition:transversion ratio (Ts/Tv) was 2.14, agreeing with common observations that nucleotide transitions are favored several-fold over transversions in molecular evolution (Stoltzfus & Norris, 2015). According to the population (n = 18) SNP frequencies, we grouped SNPs into three categories: rare SNPs (found in less than 6 clones), medium frequency SNPs (found in between 7-12 clones), and common SNPs (found in more than 12 clones).…”

Mutational biases influence parallel adaptation

“…One possibility is that transitions are systematically fitter than transversions. As noted earlier, laboratory studies do not show a substantial fitness advantage of transitions over transversions (Stoltzfus and Norris, 2016;Dai et al, 2016). However, these studies examine the entire distribution of fitness, and do not have the power to resolve di↵erences far in the right tail of rare beneficial mutations.…”

“…A ratio greater than 0.5 could also in principle be caused by a factor other than mutation, and in particular, if transition mutations tended to be more fit than transversion mutations, transitions might be over-represented due to their fitness e↵ects, rather than their elevated mutation rates. However, systematic fitness assays indicate that there is hardly any di↵erence in fitness e↵ects of transitions and transversions (Stoltzfus and Norris, 2016;Dai et al, 2016). We return to a variety of other alternative explanations for our observations in the Discussion.…”

Large-scalein silicomutagenesis experiments reveal optimization of genetic code and codon usage for protein mutational robustness

“…Transitions are substitutions that interchange purines (A↔G) or pyrimidines (C↔T), whereas transversions interchange purines and pyrimidines (C,T↔A,G). Transitions are known to be from 2 to 5 times more frequent than transversions [50,67], an observation called the transition:transversion bias. However, the origin of this bias is a longstanding problem in molecular evolution.…”

“…However, the origin of this bias is a longstanding problem in molecular evolution. Recently, the relationship between this bias and the fitness score was analyzed on a set of about 1,200 mutations, in which a probability of 53% was found for the transitions to be fitter than the transversions [67]. However, this tiny difference cannot justify the large bias observed in evolutionary investigations, and thus essentially discard a selection effect as main explanation.…”