Frantz Depaulis

Power of neutrality tests to detect bottlenecks and hitchhiking.

The power of several neutrality tests to reject a simple bottleneck model is examined in a coalescent framework. Several tests are considered including some relying on the frequency spectrum of mutations and some reflecting the linkage disequilibrium structure of the data. We evaluate the effect of the age and of the strength of the bottleneck, and their interaction. We contrast two qualitatively different bottleneck effects depending on their strength. In genealogical terms, during severe bottlenecks, all lineages coalesce leading to a star-like gene genealogy of the sample. Some time after the bottleneck, once new mutations have arisen, they tend to show an excess of rare variants and a slight excess of haplotypes. On the contrary, more moderate bottlenecks allow several lineages to survive the demographic crash, leading to a balanced genealogy with long internal branches. Soon after the event, data tend to show an excess of intermediate frequency variants and a deficit of haplotypes. We show that for moderate sequencing efforts, severe bottlenecks can be detected only after an intermediate time period has allowed for mutations to occur, preferably by frequency spectrum statistics. Moderate bottlenecks can be more easily detected for more recent events, especially using haplotype statistics. Finally, for a single locus, the bottleneck results closely approximate those of a simple hitchhiking model. The main difference concerns the frequency distribution of mutations and haplotypes after moderate perturbations. Hitchhiking increases the number of rare ancestral mutations and leads to a more predominant major haplotype class. Thus, despite a number of common features between the two processes, hitchhiking cannot be strictly modeled by bottlenecks.

From Grazing Resistance to Pathogenesis: The Coincidental Evolution of Virulence Factors

To many pathogenic bacteria, human hosts are an evolutionary dead end. This begs the question what evolutionary forces have shaped their virulence traits. Why are these bacteria so virulent? The coincidental evolution hypothesis suggests that such virulence factors result from adaptation to other ecological niches. In particular, virulence traits in bacteria might result from selective pressure exerted by protozoan predator. Thus, grazing resistance may be an evolutionarily exaptation for bacterial pathogenicity. This hypothesis was tested by subjecting a well characterized collection of 31 Escherichia coli strains (human commensal or extra-intestinal pathogenic) to grazing by the social haploid amoeba Dictyostelium discoideum. We then assessed how resistance to grazing correlates with some bacterial traits, such as the presence of virulence genes. Whatever the relative population size (bacteria/amoeba) for a non-pathogenic bacteria strain, D. discoideum was able to phagocytise, digest and grow. In contrast, a pathogenic bacterium strain killed D. discoideum above a certain bacteria/amoeba population size. A plating assay was then carried out using the E. coli collection faced to the grazing of D. discoideum. E. coli strains carrying virulence genes such as iroN, irp2, fyuA involved in iron uptake, belonging to the B2 phylogenetic group and being virulent in a mouse model of septicaemia were resistant to the grazing from D. discoideum. Experimental proof of the key role of the irp gene in the grazing resistance was evidenced with a mutant strain lacking this gene. Such determinant of virulence may well be originally selected and (or) further maintained for their role in natural habitat: resistance to digestion by free-living protozoa, rather than for virulence per se.

Human and Non-Human Primate Genomes Share Hotspots of Positive Selection

Among primates, genome-wide analysis of recent positive selection is currently limited to the human species because it requires extensive sampling of genotypic data from many individuals. The extent to which genes positively selected in human also present adaptive changes in other primates therefore remains unknown. This question is important because a gene that has been positively selected independently in the human and in other primate lineages may be less likely to be involved in human specific phenotypic changes such as dietary habits or cognitive abilities. To answer this question, we analysed heterozygous Single Nucleotide Polymorphisms (SNPs) in the genomes of single human, chimpanzee, orangutan, and macaque individuals using a new method aiming to identify selective sweeps genome-wide. We found an unexpectedly high number of orthologous genes exhibiting signatures of a selective sweep simultaneously in several primate species, suggesting the presence of hotspots of positive selection. A similar significant excess is evident when comparing genes positively selected during recent human evolution with genes subjected to positive selection in their coding sequence in other primate lineages and identified using a different test. These findings are further supported by comparing several published human genome scans for positive selection with our findings in non-human primate genomes. We thus provide extensive evidence that the co-occurrence of positive selection in humans and in other primates at the same genetic loci can be measured with only four species, an indication that it may be a widespread phenomenon. The identification of positive selection in humans alongside other primates is a powerful tool to outline those genes that were selected uniquely during recent human evolution.

Predation and Disturbance Interact to Shape Prey Species Diversity

Though predation, productivity (nutrient richness), spatial heterogeneity, and disturbance regimes are known to influence species diversity, interactions between these factors remain largely unknown. Predation has been shown to interact with productivity and with spatial heterogeneity, but few experimental studies have focused on how predation and disturbance interact to influence prey diversity. We used theory and experiments to investigate how these factors influence diversification of Pseudomonas fluorescens by manipulating both predation (presence or absence of Bdellovibrio bacteriovorus) and disturbance (frequency and intensity of disturbance). Our results show that in a homogeneous environment, predation is essential to promote prey species diversity. However, in most but not all treatments, elevated diversity was transitory, implying that the effect of predation on diversity was strongly influenced by disturbance. Both our experimental and theoretical results suggest that disturbance interacts with predation by modifying the interplay of resource and apparent competition among prey.

Using Classical Population Genetics Tools with Heterochroneous Data: Time Matters!

Background New polymorphism datasets from heterochroneous data have arisen thanks to recent advances in experimental and microbial molecular evolution, and the sequencing of ancient DNA (aDNA). However, classical tools for population genetics analyses do not take into account heterochrony between subsets, despite potential bias on neutrality and population structure tests. Here, we characterize the extent of such possible biases using serial coalescent simulations. Methodology/Principal Findings We first use a coalescent framework to generate datasets assuming no or different levels of heterochrony and contrast most classical population genetic statistics. We show that even weak levels of heterochrony (∼10% of the average depth of a standard population tree) affect the distribution of polymorphism substantially, leading to overestimate the level of polymorphism θ, to star like trees, with an excess of rare mutations and a deficit of linkage disequilibrium, which are the hallmark of e.g. population expansion (possibly after a drastic bottleneck). Substantial departures of the tests are detected in the opposite direction for more heterochroneous and equilibrated datasets, with balanced trees mimicking in particular population contraction, balancing selection, and population differentiation. We therefore introduce simple corrections to classical estimators of polymorphism and of the genetic distance between populations, in order to remove heterochrony-driven bias. Finally, we show that these effects do occur on real aDNA datasets, taking advantage of the currently available sequence data for Cave Bears (Ursus spelaeus), for which large mtDNA haplotypes have been reported over a substantial time period (22–130 thousand years ago (KYA)). Conclusions/Significance Considering serial sampling changed the conclusion of several tests, indicating that neglecting heterochrony could provide significant support for false past history of populations and inappropriate conservation decisions. We therefore argue for systematically considering heterochroneous models when analyzing heterochroneous samples covering a large time scale.

Combining contemporary and ancient DNA in population genetic and phylogeographical studies

The analysis of ancient DNA in a population genetic or phylogeographical framework is an emerging field, as traditional analytical tools were largely developed for the purpose of analysing data sampled from a single time point. Markov chain Monte Carlo approaches have been successfully developed for the analysis of heterochronous sequence data from closed panmictic populations. However, attributing genetic differences between temporal samples to mutational events between time points requires the consideration of other factors that may also result in genetic differentiation. Geographical effects are an obvious factor for species exhibiting geographical structuring of genetic variation. The departure from a closed panmictic model require researchers to either exploit software developed for the analysis of isochronous data, take advantage of simulation approaches using algorithms developed for heterochronous data, or explore approximate Bayesian computation. Here, we review statistical approaches employed and available software for the joint analysis of ancient and modern DNA, and where appropriate we suggest how these may be further developed.

Experimental Estimation of Mutation Rates in a Wheat Population With a Gene Genealogy Approach

Microsatellite markers are extensively used to evaluate genetic diversity in natural or experimental evolving populations. Their high degree of polymorphism reflects their high mutation rates. Estimates of the mutation rates are therefore necessary when characterizing diversity in populations. As a complement to the classical experimental designs, we propose to use experimental populations, where the initial state is entirely known and some intermediate states have been thoroughly surveyed, thus providing a short timescale estimation together with a large number of cumulated meioses. In this article, we derived four original gene genealogy-based methods to assess mutation rates with limited bias due to relevant model assumptions incorporating the initial state, the number of new alleles, and the genetic effective population size. We studied the evolution of genetic diversity at 21 microsatellite markers, after 15 generations in an experimental wheat population. Compared to the parents, 23 new alleles were found in generation 15 at 9 of the 21 loci studied. We provide evidence that they arose by mutation. Corresponding estimates of the mutation rates ranged from 0 to 4.97 × 10−3 per generation (i.e., year). Sequences of several alleles revealed that length polymorphism was only due to variation in the core of the microsatellite. Among different microsatellite characteristics, both the motif repeat number and an independent estimation of the Nei diversity were correlated with the novel diversity. Despite a reduced genetic effective size, global diversity at microsatellite markers increased in this population, suggesting that microsatellite diversity should be used with caution as an indicator in biodiversity conservation issues.

Selective sweep near the In(2L)t inversion breakpoint in an African population of Drosophila melanogaster.

Chromosomal inversions largely inhibit recombination and may be associated with selective forces, such as hitch-hiking effects: the effect of positive selection on linked loci. A West African population of Drosophila melanogaster showed a high frequency (0.61) of the In(2L)t inversion. Departure from neutrality statistically associated with the inversion polymorphism was previously recorded at Su(H), a locus distant from the proximal breakpoint of the inversion. These results were consistent with hitch-hiking effects with recombination. The present sequence polymorphism survey involves a 1 kb fragment of the Vha68-1 locus located closer to the proximal breakpoint of the inversion. It shows a significant deficit of polymorphism with respect to divergence when compared with other loci studied in the same population, thus suggesting selective effects. Only 11 polymorphic sites are present in a sample of 20 chromosomes and these sites present a significant excess of rare-frequency variants. The major haplotype shows an unexpectedly high frequency. Our estimate of the background selection effect is not sufficient to account for the observed reduction of polymorphism. Intraspecific variation is structured between inverted and standard chromosomes; there are no shared polymorphisms but also no fixed differences between them. This pattern, together with that found on other loci previously studied near this inversion breakpoint, suggests hitch-hiking effects enhanced by the inversion.

Detecting Selective Sweeps with Haplotype Tests

In this chapter, neutrality tests based on haplotype distribution are evaluated as a way of detecting selective sweeps. Several kinds of haplotype tests are reviewed, including haplotype number, haplotype diversity and haplotype partition tests. We focus on incomplete sweeps, where recombination between the selected locus and a given marker allows for several preexisting neutral lineages to survive the sweep and for some preexisting genetic variation to remain in a sample. Several problems are addressed, including the distinction between possible alternative hypotheses, the effect of sampling strategy, of conditioning the statistics on the population mutational parameter θ and/or the observed number of polymorphic sites S and, finally, the effect of intragenic recombination together with the choice of one- vs. two-tailed tests. Corresponding guidelines are proposed. To compare the power of haplotype tests and of other classical tests to detect selective sweeps, we use a simple selective sweep model with a deterministic approximation, allowing for genetic exchange between the selected locus and a given neutral marker. We conclude that there are ways of overcoming the difficulties in applying the tests, which are powerful means for revealing incomplete selective sweep effects.

Rapid and sustained autologous neutralizing response leading to early spontaneous recovery after HCV infection

After HCV infection, the association between the humoral response and viral sequence evolution remains unclear. We investigated the mechanisms leading to early HCV clearance and spontaneous recovery in two patients. The early evolution of the HCV envelope glycoproteins, and the infectivity spectrum of variants were explored using retroviral pseudoparticles bearing HCV envelopes. Ability of the autologous neutralizing response to control these variants was analyzed. For the first case, the maximum neutralizing activity was for serum collected between two and three months post ALT peak, this activity was still detectable after 30 months. For the second case, autologous neutralizing activity against the variant isolated at the ALT peak was detected in every serum collected between 4 days and 13 months after. The neutralizing response was sustained beyond the time at which the virus was cleared. This raise interesting questions about the role of such antibodies in case of re-exposure.