The Utility of Fisher's Geometric Model in Evolutionary Genetics.

The accumulation of data on the genomic bases of adaptation has triggered renewed interest in theoretical models of adaptation. Among these models, Fisher Geometric Model (FGM) has received a lot of attention over the last two decades. FGM is based on a continuous multidimensional phenotypic landscape, but it is for the emerging properties of individual mutation effects that it is mostly used. Despite an apparent simplicity and a limited number of parameters, FGM integrates a full model of mutation and epistatic interactions that allows the study of both beneficial and deleterious mutations, and subsequently the fate of evolving populations. In this review, I present the different properties of FGM and the qualitative and quantitative support they have received from experimental evolution data. I later discuss how to estimate the different parameters of the model and outline some future directions to connect FGM and the molecular determinants of adaptation.

MiniBioReactor Array (MBRA) in vitro gut model: a reliable system to study microbiota-dependent response to antibiotic treatment.

Background: Antimicrobial drugs are mostly studied for their impact on emergence of bacterial antibiotic resistance, but their impact on the gut microbiota is also of tremendous interest. In vitro gut models are important tools to study such complex drug-microbiota interactions in humans. Methods: The MiniBioReactor Array (MBRA) in vitro microbiota system; a single-stage continuous flow culture model, hosted in an anaerobic chamber; was used to evaluate the impact of three concentrations of a third-generation cephalosporin (ceftriaxone) on faecal microbiota from two healthy donors (treatment versus control: three replicates per condition). We conducted 16S microbiome profiling and analysed microbial richness, diversity and taxonomic changes. ß-Lactamase activities were evaluated and correlated with the effects observed in the MBRA in vitro system. Results: The MBRA preserved each donor's specificities, and differences between the donors were maintained through time. Before treatment, all faecal cultures belonging to the same donor were comparable in composition, richness, and diversity. Treatment with ceftriaxone was associated with a decrease in α-diversity, and an increase in ß-diversity index, in a concentration-dependent manner. The maximum effect on diversity was observed after 72 h of treatment. Importantly, one donor had a stronger microbiota ß-lactamase activity that was associated with a reduced impact of ceftriaxone on microbiota composition. Conclusions: MBRA can reliably mimic the intestinal microbiota and its modifications under antibiotic selective pressure. The impact of the treatment was donor- and concentration-dependent. We hypothesize these results could be explained, at least in part, by the differences in ß-lactamase activity of the microbiota itself. Our results support the relevance and promise of the MBRA system to study drug-microbiota interactions.

Costs and benefits of high mutation rates: adaptive evolution of bacteria in the mouse gut.

We have shown that bacterial mutation rates change during the experimental colonization of the mouse gut. A high mutation rate was initially beneficial because it allowed faster adaptation, but this benefit disappeared once adaptation was achieved. Mutator bacteria accumulated mutations that, although neutral in the mouse gut, are often deleterious in secondary environments. Consistently, the competitiveness of mutator bacteria is reduced during transmission to and re-colonization of similar hosts. The short-term advantages and long-term disadvantages of mutator bacteria could account for their frequency in nature.

Apparent mutational hotspots and long distance linkage disequilibrium resulting from a bottleneck.

Genome wide patterns of nucleotide diversity and recombination reveal considerable variation including hotspots. Some studies suggest that these patterns are primarily dictated by individual locus history related at a broader scale to the population demographic history. Because bottlenecks have occurred in the history of numerous species, we undertook a simulation approach to investigate their impact on the patterns of aggregation of polymorphic sites and linkage disequilibrium (LD). We developed a new index (Polymorphism Aggregation Index) to characterize this aggregation and showed that variation in the density of polymorphic sites results from an interplay between the bottleneck scenario and the recombination rate. Under particular conditions, aggregation is maximized and apparent mutation hotspots resulting in a 50-fold increase in polymorphic sites density can occur. In similar conditions, long distance LD can be detected.

Molecular epidemiology of penicillinase-producing Neisseria gonorrhoeae isolates in France.

OBJECTIVES: Characterizing the molecular epidemiology of antibiotic resistance is crucial for a better understanding of the evolution and spread of resistance in Neisseria gonorrhoeae. Here, we examine the molecular epidemiology of penicillinase-producing N. gonorrhoeae (PPNG) isolates in France. METHODS: We investigated 176 PPNG isolates collected between 2010 and 2012 by the National Reference Centre in France. Genotyping was performed using the NG-MAST technique, blaTEM genes were Sanger-sequenced, and plasmids were characterized by PCR-typing. RESULTS: We revealed the existence of four major clusters representing about one-third of PPNG circulating in France. These clusters were related to ST1479 (18/176, 10.2%), to ST1582 (15/176, 8.5%), to ST8922 (10/176, 5.6%), and to ST1285 (9/176, 5.1%). Wild-type TEM-1 was identified in 151 (151/176, 85.8%) PPNG isolates, and TEM-1 variants were mostly represented by the M182T mutation (14/176, 8%), followed by P14S/L (8/176, 4.5%), G228S (2/176, 1.1%), and Q269K (1/176, 0.6%). The blaTEM genes were carried by African (157/176, 89.2%), Asian (13/176, 7.4%), and Toronto/Rio (6/176, 3.4%) plasmids. The M182T variants were found in various genetic backgrounds, whereas the P14S variants were disseminated clonally. The G228S and Q269K variants belong to one of the four major clusters of PPNG, which suggests a recent de novo emergence of these mutations. CONCLUSIONS: Our results show that approximately one-third of the penicillinase-producing N. gonorrhoeae isolates in France belong to one of four major clusters and that the spread of the different TEM variants is associated with distinct patterns of molecular epidemiology.

Mutators, population size, adaptive landscape and the adaptation of asexual populations of bacteria.

Selection of mutator alleles, increasing the mutation rate up to 10, 000-fold, has been observed during in vitro experimental evolution. This spread is ascribed to the hitchhiking of mutator alleles with favorable mutations, as demonstrated by a theoretical model using selective parameters corresponding to such experiments. Observations of unexpectedly high frequencies of mutators in natural isolates suggest that the same phenomenon could occur in the wild. But it remains questionable whether realistic in natura parameter values could also result in selection of mutators. In particular, the main parameters of adaptation, the size of the adapting population and the height and steepness of the adaptive peak characterizing adaptation, are very variable in nature. By simulation approach, we studied the effect of these parameters on the selection of mutators in asexual populations, assuming additive fitness. We show that the larger the population size, the more likely the fixation of mutator alleles. At a large population size, at least four adaptive mutations are needed for mutator fixation; moreover, under stronger selection stronger mutators are selected. We propose a model based on multiple mutations to illustrate how second-order selection can optimize population fitness when few favorable mutations are required for adaptation.

From metabolism to polymorphism in bacterial populations: a theoretical study.

Stable polymorphisms are commonly observed in experimental bacterial populations grown in homogeneous media. Evidence is accumulating that metabolic interactions might be the main mechanism underlying the emergence and maintenance of such polymorphisms. To date, however, attempts to model the evolution of bacterial polymorphism have not considered metabolism as a possible component of polymorphism maintenance. Here, we propose a simulation approach to model the evolution of selected polymorphisms in a bacterial population. Using recent knowledge of the relationship between bacterial fitness and metabolism, we build a simple metabolic model and test the effect of resource competition on polymorphism. Without making an a priori hypothesis on fitness functions, we show that stable polymorphic situations could be observed under high nutrient competition, and we propose a functional, metabolism-based explanation to the debated issue of polymorphism maintenance.

Second-order selection in bacterial evolution: selection acting on mutation and recombination rates in the course of adaptation.

The increase in genetic variability of a population can be selected during adaptation, as demonstrated by the selection of mutator alleles. The dynamics of this phenomenon, named second-order selection, can result in an improved adaptability of bacteria through regulation of all facets of mutation and recombination processes.

Mutators and sex in bacteria: conflict between adaptive strategies.

Bacterial mutation rates can increase and produce genetic novelty, as shown by in vitro and in silico experiments. Despite the cost due to a heavy deleterious mutation load, mutator alleles, which increase the mutation rate, can spread in asexual populations during adaptation because they remain associated with the rare favorable mutations they generate. This indirect selection for a genetic system generating diversity (second-order selection) is expected to be highly sensitive to changes in the dynamics of adaptation. Here we show by a simulation approach that even rare genetic exchanges, such as bacterial conjugation or transformation, can dramatically reduce the selection of mutators. Moreover, drift or competition between the processes of mutation and recombination in the course of adaptation reveal how second-order selection is unable to optimize the rate of generation of novelty.

Evolutionary implications of the frequent horizontal transfer of mismatch repair genes.

Mutation and subsequent recombination events create genetic diversity, which is subjected to natural selection. Bacterial mismatch repair (MMR) deficient mutants, exhibiting high mutation and homologous recombination rates, are frequently found in natural populations. Therefore, we have explored the possibility that MMR deficiency emerging in nature has left some "imprint" in the sequence of bacterial genomes. Comparative molecular phylogeny of MMR genes from natural Escherichia coli isolates shows that, compared to housekeeping genes, individual functional MMR genes exhibit high sequence mosaicism derived from diverse phylogenetic lineages. This apparent horizontal gene transfer correlates with hyperrecombination phenotype of MMR-deficient mutators. The sequence mosaicism of MMR genes may be a hallmark of a mechanism of adaptive evolution that involves modulation of mutation and recombination rates by recurrent losses and reacquisitions of MMR gene functions.