High mutation rates limit evolutionary adaptation in Escherichia coli

Abstract

Mutation is fundamental to evolution, because it generates the genetic variation on which selection can act. In nature, genetic changes often increase the mutation rate in systems that range from viruses and bacteria to human tumors. Such an increase promotes the accumulation of frequent deleterious or neutral alleles, but it can also increase the chances that a population acquires rare beneficial alleles. Here, we study how up to 100-fold increases in Escherichia coli’s genomic mutation rate affect adaptive evolution. To do so, we evolved multiple replicate populations of asexual E. coli strains engineered to have four different mutation rates for 3000 generations in the laboratory. We measured the ability of evolved populations to grow in their original environment and in more than 90 novel chemical environments. In addition, we subjected the populations to whole genome population sequencing. Although populations with higher mutation rates accumulated greater genetic diversity, this diversity conveyed benefits only for modestly increased mutation rates, where populations adapted faster and also thrived better than their ancestors in some novel environments. In contrast, some populations at the highest mutation rates showed reduced adaptation during evolution, and failed to thrive in all of the 90 alternative environments. In addition, they experienced a dramatic decrease in mutation rate. Our work demonstrates that the mutation rate changes the global balance between deleterious and beneficial mutational effects on fitness. In contrast to most theoretical models, our experiments suggest that this tipping point already occurs at the modest mutation rates that are found in the wild.

Low mutational load and high mutation rate variation in gut commensal bacteria

“…This indicates that multiple mutators emerged either simultaneously or sequentially and that nonmutator clones coexisted with both strong hypermutators (mutation rates up to 1,200-fold higher than the ancestral) and with intermediate hypermutators (10-to 100-fold increases in mutation rate). Coexistence between clones differing in mutation rate by less than 70-fold has been previously observed [42][43][44][45]. However, to the best of our knowledge, our results represent the first observation of long-term coexistence (>1,000 generations, i.e., >54 days) of clones differing in mutation rate by around 1,000-fold in the gut.…”

“…TCG) and measured their mutation rates. We generated approximately 20 clones carrying the DnaQ L145P allele, as dnaQ hypermutators can exhibit high mutation rate variation, possibly because of the rapid emergence of suppressors [42,51]. The dnaQ clones indeed showed a very high mutation rate, reaching 3,000-fold increases for both nalidixic acid and rifampicin ( Fig 2C).…”

High Genomic Diversity and Heterogenous Origins of Pathogenic and Antibiotic-Resistant Escherichia coli in Household Settings Represent a Challenge to Reducing Transmission in Low-Income Settings

“…However, mutation rate estimates hold several uncertainties. For example, laboratory conditions may not resemble generation times in nature (40,41) or disregard factors such as differential mutation rates among strains, selection, recombination, and mutational bias (41,42). Furthermore, little is known on how environmental factors, ecological niches, or different host species affect the rates of accumulation of diversity (39,43).…”

Dynamic Emergence of Mismatch Repair Deficiency Facilitates Rapid Evolution of Ceftazidime-Avibactam Resistance in Pseudomonas aeruginosa Acute Infection

“…KEYWORDS Pseudomonas aeruginosa, antimicrobial agents, bacterial evolution, ceftazidime-avibactam, host-pathogen interactions, hypermutator, microbial genomics, mismatch repair I n general, the maintenance of high-fidelity DNA replication and the reduction of spontaneous mutation rates are beneficial to organisms. Previous work has demonstrated that even moderately elevated mutational rates may be substantially deleterious and that exceeding certain threshold mutational rates results in the irrecoverable loss of essential wild-type sequences and population collapse (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). Replication fidelity in bacteria is maintained by elaborate machinery that includes the proofreading exonucleases in replicative DNA polymerases and an array of DNA repair proteins broadly organized into homologous DNA recombination, base and nucleotide excision repair pathways, and methyl-directed mismatch repair (MMR) (11)(12)(13).…”