Mutation rate dynamics in a bacterial population reflect tension between adaptation and genetic load

Abstract

Mutations are the ultimate source of heritable variation for evolution. Understanding how mutation rates themselves evolve is thus essential for quantitatively understanding many evolutionary processes. According to theory, mutation rates should be minimized for well-adapted populations living in stable environments, whereas hypermutators may evolve if conditions change. However, the long-term fate of hypermutators is unknown. Using a phylogenomic approach, we found that an adapting Escherichia coli population that first evolved a mutT hypermutator phenotype was later invaded by two independent lineages with mutY mutations that reduced genome-wide mutation rates. Applying neutral theory to synonymous substitutions, we dated the emergence of these mutations and inferred that the mutT mutation increased the point-mutation rate by ∼150-fold, whereas the mutY mutations reduced the rate by ∼40-60%, with a corresponding decrease in the genetic load. Thus, the long-term fate of the hypermutators was governed by the selective advantage arising from a reduced mutation rate as the potential for further adaptation declined. experimental evolution | genomics | mutators | phylogenomics M utations are the ultimate source of heritable variation for evolution. Therefore, understanding how selection can change mutation rates is crucial for quantitatively describing evolutionary processes (1). More mutations are deleterious than beneficial (2), and organisms from bacteria to eukaryotes encode proofreading and repair enzymes that reduce mutation rates (3). If selection for beneficial mutations is weak relative to selection against deleterious mutations, then the rate of adaptation in asexual populations is maximized at some intermediate mutation rate (4). However, when populations encounter new environments, selection for beneficial mutations can be strong (5), and much higher mutation rates may evolve. Indeed, surveys of laboratory populations of microbes (6-10), clinical isolates of bacterial pathogens (11,12), and some types of eukaryotic tumors (13) have revealed a surprisingly high proportion of lineages that have evolved genetic defects in repair pathways. These hypermutators often have 10-to 100-fold increased mutation rates, and such elevated mutation rates can accelerate the progression of chronic diseases and the evolution of resistance to therapeutic agents.Hypermutable mutants can become established in asexual populations while they adapt to changed environments owing to their higher per capita probability of discovering rare beneficial mutations compared with nonmutators (14-18). Although hypermutable genotypes should produce beneficial mutations at a higher rate than their less mutable counterparts, they do not necessarily increase the rate of adaptation to a corresponding, or even measurable, degree. In large asexual populations, the waiting time for new beneficial mutations to occur may be short relative to the time required for a mutant to increase from one individual to fixation in the population, assuming the be...

The dynamics of molecular evolution over 60,000 generations

“…2 inset), consistent with evidence from sequenced clones 4 . In Ara–1, previous work has shown that this deceleration is driven by “antimutator” alleles that arise after the fixation of the initial mutator 20 . Our results suggest a similar process also occurs in other populations.…”

Experimental evolution and the dynamics of genomic mutation rate modifiers

“…Some very recent evidence for indirect selection favoring reduction of high mutation rates comes from the work of Wielgoss et al (2013), who showed that one of Lenski's long-term E. coli populations that had previously evolved a 150-fold elevated genomic mutation rate by fixing a defective mutT allele between 20 000 and 30 000 generations of propagation (Barrick et al, 2009) was subsequently invaded (by 40 000 generations) by two separate mutY mutations that reduced the mutation rate by 40-60%. Wielgoss et al estimated that the mutY mutations reduced the mutational load of the mutT background from 0.013 to 0.0073 and 0.0093, implying positive selection coefficients of B0.57% and B0.37% in favor of these mutations, respectively.…”

“…Very long-term evolution experiments such as that carried out by Lenski and collaborators for more than 50 000 generations in a constant abiotic environment present the best opportunity to study mutation rate modifier dynamics under conditions in which the deleterious load may outweigh the advantage of increased beneficial mutation supply rate (Wielgoss et al, 2013). Further studies in these experimental populations seem likely to provide additional important insights into the evolution of lower mutation rates and, potentially, the reversal of the phenotypic effects of mutators back to wild-type mutation rates in well-adapted populations.…”

“…Theoretical studies began exploring the population genetics of mutation rate modifier alleles in the 1960s, and significant theory papers on mutation rate evolution have appeared in every decade since (Kimura, 1967;Leigh, 1970Leigh, , 1973Ishii et al, 1989;Taddei et al, 1997;Johnson, 1999;Andre and Godelle, 2006;Gerrish et al, 2007;Lynch, 2008;Wylie et al, 2009;Desai and Fisher, 2011). Direct experimental work on the population genetics of mutation rate modifiers began in the 1970s (Gibson et al, 1970;Cox and Gibson, 1974) and has grown rapidly in recent years (Giraud et al, 2001;Notley-McRobb et al, 2002b;Thompson et al, 2006;Pal et al, 2007;Gentile et al, 2011;Raynes et al, 2011Raynes et al, , 2012Raynes et al, , 2014McDonald et al, 2012;Maharjan et al, 2013;Wielgoss et al, 2013). Here, we review advances in our understanding of mutation rate evolution that have been contributed by experimental studies.…”

Full Issue

“…35 While Shi'as constituted the majority of the Iraqi population like the other ethnicities, at the time they were not a single community. 36 In Northern Iraq, there were ethnic groups such as Turkmen, Kurds, Arabs, with a smaller population of Chaldo-Assyrian Christians, and a larger Sunni population. 37 However, Turkmen, Kurds, and Arabs were a blurred ethnic concept to those who presided in the area particularly because "an individual's or family's self-identity often stemmed from a combination of their preferred language and social status rather than their ancestry."…”