The Impact of Genetic Surfing on Neutral Genomic Diversity.

Range expansions have been common in the history of most species. Serial founder effects and subsequent population growth at expansion fronts typically lead to a loss of genomic diversity along the expansion axis. A frequent consequence is the phenomenon of "gene surfing," where variants located near the expanding front can reach high frequencies or even fix in newly colonized territories. Although gene surfing events have been characterized thoroughly for a specific locus, their effects on linked genomic regions and the overall patterns of genomic diversity have been little investigated. In this study, we simulated the evolution of whole genomes during several types of 1D and 2D range expansions differing by the extent of migration, founder events, and recombination rates. We focused on the characterization of local dips of diversity, or "troughs," taken as a proxy for surfing events. We find that, for a given recombination rate, once we consider the amount of diversity lost since the beginning of the expansion, it is possible to predict the initial evolution of trough density and their average width irrespective of the expansion condition. Furthermore, when recombination rates vary across the genome, we find that troughs are over-represented in regions of low recombination. Therefore, range expansions can leave local and global genomic signatures often interpreted as evidence of past selective events. Given the generality of our results, they could be used as a null model for species having gone through recent expansions, and thus be helpful to correctly interpret many evolutionary biology studies.

The role of spatial structure in multi-deme models of evolutionary rescue.

Genetic variation and population sizes are critical factors for successful adaptation to novel environmental conditions. Gene flow between sub-populations is a potent mechanism to provide such variation and can hence facilitate adaptation, for instance by increasing genetic variation or via the introduction of beneficial variants. On the other hand, if gene flow between different habitats is too strong, locally beneficial alleles may not be able to establish permanently. In the context of evolutionary rescue, intermediate levels of gene flow are therefore often optimal for maximizing a species chance for survival in metapopulations without spatial structure. To which extent and under which conditions gene flow facilitates or hinders evolutionary rescue in spatially structured populations remains unresolved. We address this question by studying the differences between evolutionary rescue in the island model and in the stepping stone model in a gradually deteriorating habitat. We show that evolutionary rescue is modulated by the rate of gene flow between different habitats, which in turn depends strongly on the spatial structure and the pattern of environmental deterioration. We use these insights to show that in many cases spatially structured models can be translated into a simpler island model using an appropriately scaled effective migration rate.

A genomic history of Aboriginal Australia.

The population history of Aboriginal Australians remains largely uncharacterized. Here we generate high-coverage genomes for 83 Aboriginal Australians (speakers of Pama-Nyungan languages) and 25 Papuans from the New Guinea Highlands. We find that Papuan and Aboriginal Australian ancestors diversified 25-40 thousand years ago (kya), suggesting pre-Holocene population structure in the ancient continent of Sahul (Australia, New Guinea and Tasmania). However, all of the studied Aboriginal Australians descend from a single founding population that differentiated ~10-32 kya. We infer a population expansion in northeast Australia during the Holocene epoch (past 10,000 years) associated with limited gene flow from this region to the rest of Australia, consistent with the spread of the Pama-Nyungan languages. We estimate that Aboriginal Australians and Papuans diverged from Eurasians 51-72 kya, following a single out-of-Africa dispersal, and subsequently admixed with archaic populations. Finally, we report evidence of selection in Aboriginal Australians potentially associated with living in the desert.

Slightly deleterious genomic variants and transcriptome perturbations in Down syndrome embryonic selection.

The majority of aneuploid fetuses are spontaneously miscarried. Nevertheless, some aneuploid individuals survive despite the strong genetic insult. Here, we investigate if the survival probability of aneuploid fetuses is affected by the genome-wide burden of slightly deleterious variants. We analyzed two cohorts of live-born Down syndrome individuals (388 genotyped samples and 16 fibroblast transcriptomes) and observed a deficit of slightly deleterious variants on Chromosome 21 and decreased transcriptome-wide variation in the expression level of highly constrained genes. We interpret these results as signatures of embryonic selection, and propose a genetic handicap model whereby an individual bearing an extremely severe deleterious variant (such as aneuploidy) could escape embryonic lethality if the genome-wide burden of slightly deleterious variants is sufficiently low. This approach can be used to study the composition and effect of the numerous slightly deleterious variants in humans and model organisms.

Mutation load dynamics during environmentally-driven range shifts.

The fitness of spatially expanding species has been shown to decrease over time and space, but specialist species tracking their changing environment and shifting their range accordingly have been little studied. We use individual-based simulations and analytical modeling to compare the impact of range expansions and range shifts on genetic diversity and fitness loss, as well as the ability to recover fitness after either a shift or expansion. We find that the speed of a shift has a strong impact on fitness evolution. Fastest shifts show the strongest fitness loss per generation, but intermediate shift speeds lead to the strongest fitness loss per geographic distance. Range shifting species lose fitness more slowly through time than expanding species, however, their fitness measured at equal geographic distances from the source of expansion can be considerably lower. These counter-intuitive results arise from the combination of time over which selection acts and mutations enter the system. Range shifts also exhibit reduced fitness recovery after a geographic shift and may result in extinction, whereas range expansions can persist from the core of the species range. The complexity of range expansions and range shifts highlights the potential for severe consequences of environmental change on species survival.

Dissection of the mutation accumulation process during bacterial range expansions.

BACKGROUND: Recent experimental work has shown that the evolutionary dynamics of bacteria expanding across space can differ dramatically from what we expect under well-mixed conditions. During spatial expansion, deleterious mutations can accumulate due to inefficient selection on the expansion front, potentially interfering with and modifying adaptive evolutionary processes. RESULTS: We used whole genome sequencing to follow the genomic evolution of 10 mutator Escherichia coli lines during 39 days ( ~ 1650 generations) of a spatial expansion, which allowed us to gain a temporal perspective on the interaction of adaptive and non-adaptive evolutionary processes during range expansions. We used elastic net regression to infer the positive or negative effects of mutations on colony growth. The colony size, measured after three day of growth, decreased at the end of the experiment in all 10 lines, and mutations accumulated at a nearly constant rate over the whole experiment. We find evidence that beneficial mutations accumulate primarily at an early stage of the experiment, leading to a non-linear change of colony size over time. Indeed, the rate of colony size expansion remains almost constant at the beginning of the experiment and then decreases after ~ 12 days of evolution. We also find that beneficial mutations are enriched in genes encoding transport proteins, and genes coding for the membrane structure, whereas deleterious mutations show no enrichment for any biological process. CONCLUSIONS: Our experiment shows that beneficial mutations target specific biological functions mostly involved in inter or extra membrane processes, whereas deleterious mutations are randomly distributed over the whole genome. It thus appears that the interaction between genetic drift and the availability or depletion of beneficial mutations determines the change in fitness of bacterial populations during range expansion.

Mutational and Selective Processes Involved in Evolution during Bacterial Range Expansions.

Bacterial populations have been shown to accumulate deleterious mutations during spatial expansions that overall decrease their fitness and ability to grow. However, it is unclear if and how they can respond to selection in face of this mutation load. We examine here if artificial selection can counteract the negative effects of range expansions. We examined the molecular evolution of 20 mutator lines selected for fast expansions (SEL) and compared them to 20 other mutator lines freely expanding without artificial selection (CONTROL). We find that the colony size of all 20 SEL lines have increased relative to the ancestral lines, unlike CONTROL lines, showing that enough beneficial mutations are produced during spatial expansions to counteract the negative effect of expansion load. Importantly, SEL and CONTROL lines have similar numbers of mutations indicating that they evolved for the same number of generations and that increased fitness is not due to a purging of deleterious mutations. We find that loss of function mutations better explain the increased colony size of SEL lines than nonsynonymous mutations or a combination of the two. Interestingly, most loss of function mutations are found in simple sequence repeats (SSRs) located in genes involved in gene regulation and gene expression. We postulate that such potentially reversible mutations could play a major role in the rapid adaptation of bacteria to changing environmental conditions by shutting down expensive genes and adjusting gene expression.

Evolution of Dispersal Can Rescue Populations from Expansion Load.

Understanding the causes and consequences of range expansions or range shifts has a long history in evolutionary biology. Recent theoretical, experimental, and empirical work has identified two particularly interesting phenomena in the context of species range expansions: (i) gene surfing and the relaxation of natural selection and (ii) spatial sorting. The former can lead to an accumulation of deleterious mutations at range edges, causing an expansion load and slowing down expansion. The latter can create gradients in dispersal-related traits along the expansion axis and cause an acceleration of expansion. We present a theoretical framework that treats spatial sorting and gene surfing as spatial versions of natural selection and genetic drift, respectively. This model allows us to analytically study how gene surfing and spatial sorting interact and derive the probability of fixation of pleiotropic mutations at the expansion front. We use our results to predict the coevolution of mean fitness and dispersal rates, taking into account the effects of random genetic drift, natural selection, and spatial sorting, as well as correlations between fitness- and dispersal-related traits. We identify a "rescue effect" of spatial sorting, where the evolution of higher dispersal rates at the leading edge rescues the population from incurring expansion load.

Range Expansion Theories Could Shed Light on the Spatial Structure of Intra-tumour Heterogeneity.

Many theoretical studies of range expansions focus on the dynamics of species' ranges or on causes and consequences of biological invasions. The similarities between biological range expansions and the dynamics of tumour growth have recently become more obvious, highlighting that tumours can be viewed as a population of abnormal cells expanding its range in the body of its host. Here, we discuss the potential of recent theoretical developments in the context of range expansions to shed light on intra-tumour heterogeneity, and to develop novel computational and statistical methods for studying the increasingly available genomic and phenotypic data from tumour cells. We review two spatial eco-evolutionary processes that could lead to a better understanding of the spatial structure of intra-tumour heterogeneity during the development of solid tumours: (1) the increase in dispersal abilities and (2) the accumulation of deleterious mutations at the front of expanding range edges. We first summarize theoretical and empirical evidences for each of these two phenomena and illustrate the eco-evolutionary dynamics of these processes using mathematical models. Secondly, we review evidences that these phenomena could also occur during the spatial expansion of a tumour within hosts. Finally, we discuss promising avenues for future research with the aim of synthesizing insights from clinical and theoretical studies of tumour development and evolutionary biology.

Distance from sub-Saharan Africa predicts mutational load in diverse human genomes.

The Out-of-Africa (OOA) dispersal ∼ 50,000 y ago is characterized by a series of founder events as modern humans expanded into multiple continents. Population genetics theory predicts an increase of mutational load in populations undergoing serial founder effects during range expansions. To test this hypothesis, we have sequenced full genomes and high-coverage exomes from seven geographically divergent human populations from Namibia, Congo, Algeria, Pakistan, Cambodia, Siberia, and Mexico. We find that individual genomes vary modestly in the overall number of predicted deleterious alleles. We show via spatially explicit simulations that the observed distribution of deleterious allele frequencies is consistent with the OOA dispersal, particularly under a model where deleterious mutations are recessive. We conclude that there is a strong signal of purifying selection at conserved genomic positions within Africa, but that many predicted deleterious mutations have evolved as if they were neutral during the expansion out of Africa. Under a model where selection is inversely related to dominance, we show that OOA populations are likely to have a higher mutation load due to increased allele frequencies of nearly neutral variants that are recessive or partially recessive.

Expansion load and the evolutionary dynamics of a species range.

Expanding populations incur a mutation burden, the so-called expansion load. Using a mixture of individual-based simulations and analytical modeling, we study the expansion load process in models where population growth depends on the population's fitness (i.e., hard selection). We show that expansion load can severely slow down expansions and limit a species' range, even in the absence of environmental variation. We also study the effect of recombination on the dynamics of a species range and on the evolution of mean fitness on the wave front. If recombination is strong, mean fitness on front approaches an equilibrium value at which the effects of fixed mutations cancel each other out. The equilibrium rate at which new demes are colonized is similar to the rate at which beneficial mutations spread through the core. Without recombination, the dynamics is more complex, and beneficial mutations from the core of the range can invade the front of the expansion, which results in irregular and episodic expansion. Although the rate of adaptation is generally higher in recombining organisms, the mean fitness on the front may be larger in the absence of recombination because high-fitness individuals from the core have a higher chance to invade the front. Our findings have important consequences for the evolutionary dynamics of species ranges as well as on the role and the evolution of recombination during range expansions.

Expansion load: recessive mutations and the role of standing genetic variation.

Expanding populations incur a mutation burden - the so-called expansion load. Previous studies of expansion load have focused on codominant mutations. An important consequence of this assumption is that expansion load stems exclusively from the accumulation of new mutations occurring in individuals living at the wave front. Using individual-based simulations, we study here the dynamics of standing genetic variation at the front of expansions, and its consequences on mean fitness if mutations are recessive. We find that deleterious genetic diversity is quickly lost at the front of the expansion, but the loss of deleterious mutations at some loci is compensated by an increase of their frequencies at other loci. The frequency of deleterious homozygotes therefore increases along the expansion axis, whereas the average number of deleterious mutations per individual remains nearly constant across the species range. This reveals two important differences to codominant models: (i) mean fitness at the front of the expansion drops much faster if mutations are recessive, and (ii) mutation load can increase during the expansion even if the total number of deleterious mutations per individual remains constant. We use our model to make predictions about the shape of the site frequency spectrum at the front of range expansion, and about correlations between heterozygosity and fitness in different parts of the species range. Importantly, these predictions provide opportunities to empirically validate our theoretical results. We discuss our findings in the light of recent results on the distribution of deleterious genetic variation across human populations and link them to empirical results on the correlation of heterozygosity and fitness found in many natural range expansions.

Scoary2: rapid association of phenotypic multi-omics data with microbial pan-genomes.

Unraveling bacterial gene function drives progress in various areas, such as food production, pharmacology, and ecology. While omics technologies capture high-dimensional phenotypic data, linking them to genomic data is challenging, leaving 40-60% of bacterial genes undescribed. To address this bottleneck, we introduce Scoary2, an ultra-fast microbial genome-wide association studies (mGWAS) software. With its data exploration app and improved performance, Scoary2 is the first tool to enable the study of large phenotypic datasets using mGWAS. As proof of concept, we explore the metabolome of yogurts, each produced with a different Propionibacterium reichii strain and discover two genes affecting carnitine metabolism.

Demographic history and genomic consequences of 10,000 generations of isolation in a wild mammal.

Increased human activities caused the isolation of populations in many species-often associated with genetic depletion and negative fitness effects. The effects of isolation are predicted by theory, but long-term data from natural populations are scarce. We show, with full genome sequences, that common voles (Microtus arvalis) in the Orkney archipelago have remained genetically isolated from conspecifics in continental Europe since their introduction by humans over 5,000 years ago. Modern Orkney vole populations are genetically highly differentiated from continental conspecifics as a result of genetic drift processes. Colonization likely started on the biggest Orkney island and vole populations on smaller islands were gradually split off, without signs of secondary admixture. Despite having large modern population sizes, Orkney voles are genetically depauperate and successive introductions to smaller islands resulted in further reduction of genetic diversity. We detected high levels of fixation of predicted deleterious variation compared with continental populations, particularly on smaller islands, yet the fitness effects realized in nature are unknown. Simulations showed that predominantly mildly deleterious mutations were fixed in populations, while highly deleterious mutations were purged early in the history of the Orkney population. Relaxation of selection overall due to benign environmental conditions on the islands and the effects of soft selection may have contributed to the repeated, successful establishment of Orkney voles despite potential fitness loss. Furthermore, the specific life history of these small mammals, resulting in relatively large population sizes, has probably been important for their long-term persistence in full isolation.

The efficacy of selection may increase or decrease with selfing depending upon the recombination environment.

Much theory has focused on how a population's selfing rate affects the ability of natural selection to remove deleterious mutations from a population. However, most such theory has focused on mutations of a given dominance and fitness effect in isolation. It remains unclear how selfing affects the purging of deleterious mutations in a genome-wide context where mutations with different selection and dominance coefficients co-segregate. Here, we use individual-based forward simulations and analytical models to investigate how mutation, selection and recombination interact with selfing rate to shape genome-wide patterns of mutation accumulation and fitness. In addition to recovering previously described results for how selfing affects the efficacy of selection against mutations of a given dominance class, we find that the interaction of purifying selection against mutations of different dominance classes changes with selfing and recombination rates. In particular, when recombination is low and recessive deleterious mutations are common, outcrossing populations transition from purifying selection to pseudo-overdominance, dramatically reducing the efficacy of selection. At these parameter combinations, the efficacy of selection remains low until populations hit a threshold selfing rate, above which it increases. In contrast, selection is more effective in outcrossing than (partial) selfing populations when recombination rates are moderate to high and recessive deleterious mutations are rare.

Randomized Controlled Trial of Thresholds for Drain Removal After Anatomic Lung Resection.

BACKGROUND: The criteria for chest drain removal after lung resections remain vague and rely on personal experience instead of evidence. Because pleural fluid resorption is proportional to body weight, a weight-related approach seems reasonable. We examined the feasibility of a weight-adjusted fluid output threshold concerning postoperative respiratory complications and the occurrence of symptomatic pleural effusion after chest drain removal. Our secondary objectives were the hospital length of stay and pain levels before and after chest drain removal. METHODS: This was a single-center randomized controlled trial including 337 patients planned for open or thoracoscopic anatomical lung resections. Patients were randomly assigned postoperatively into 2 groups. The chest drain was removed in the study group according to a fluid output threshold calculated by the 5 mL × body weight (in kg)/24 hours formula. In the control group, our previous traditional fluid threshold of 200 mL/24 hours was applied. RESULTS: No differences were evident regarding the occurrence of pleural effusion and dyspnea at discharge and 30 days postoperatively. In the logistic regression analysis, the surgical modality was a risk factor for other complications, and age was the only variable influencing postoperative dyspnea. Time to chest drain removal was identical in both groups, and time to discharge was shorter after open surgery in the test group. CONCLUSIONS: No increased postoperative complications occurred with this weight-based formula, and a trend toward earlier discharge after open surgery was observed in the test group.

Gene surfing of underdominant alleles promotes formation of hybrid zones.

The distribution of genetic diversity over geographical space has long been investigated in population genetics and serves as a useful tool to understand evolution and history of populations. Within some species or across regions of contact between two species, there are instances where there is no apparent ecological determinant of sharp changes in allele frequencies or divergence. To further understand these patterns of spatial genetic structure and potential species divergence, we model the establishment of clines that occur due to the surfing of underdominant alleles during range expansions. We provide analytical approximations for the fixation probability of underdominant alleles at expansion fronts and demonstrate that gene surfing can lead to clines in one-dimensional range expansions. We extend these results to multiple loci via a mixture of analytical theory and individual-based simulations. We study the interaction between the strength of selection against heterozygotes, migration rates, and local recombination rates on the formation of stable hybrid zones. Clines created by surfing at different loci can attract each other and align after expansion, if they are sufficiently close in space and in terms of recombination distance. Our findings suggest that range expansions can set the stage for parapatric speciation due to the alignment of multiple selective clines, even in the absence of ecologically divergent selection. This article is part of the theme issue 'Species' ranges in the face of changing environments (part I)'.

Strong neutral sweeps occurring during a population contraction.

A strong reduction in diversity around a specific locus is often interpreted as a recent rapid fixation of a positively selected allele, a phenomenon called a selective sweep. Rapid fixation of neutral variants can however lead to a similar reduction in local diversity, especially when the population experiences changes in population size, e.g. bottlenecks or range expansions. The fact that demographic processes can lead to signals of nucleotide diversity very similar to signals of selective sweeps is at the core of an ongoing discussion about the roles of demography and natural selection in shaping patterns of neutral variation. Here, we quantitatively investigate the shape of such neutral valleys of diversity under a simple model of a single population size change, and we compare it to signals of a selective sweep. We analytically describe the expected shape of such "neutral sweeps" and show that selective sweep valleys of diversity are, for the same fixation time, wider than neutral valleys. On the other hand, it is always possible to parametrize our model to find a neutral valley that has the same width as a given selected valley. Our findings provide further insight into how simple demographic models can create valleys of genetic diversity similar to those attributed to positive selection.

Dominance and the maintenance of polymorphism in multiallelic migration-selection models with two demes.

The maintenance of genetic variation in a spatially heterogeneous environment has been one of the main research themes in theoretical population genetics. Despite considerable progress in understanding the consequences of spatially structured environments on genetic variation, many problems remain unsolved. One of them concerns the relationship between the number of demes, the degree of dominance, and the maximum number of alleles that can be maintained by selection in a subdivided population. In this work, we study the potential of maintaining genetic variation in a two-deme model with deme-independent degree of intermediate dominance, which includes absence of G x E interaction as a special case. We present a thorough numerical analysis of a two-deme three-allele model, which allows us to identify dominance and selection patterns that harbor the potential for stable triallelic equilibria. The information gained by this approach is then used to construct an example in which existence and asymptotic stability of a fully polymorphic equilibrium can be proved analytically. Noteworthy, in this example the parameter range in which three alleles can coexist is maximized for intermediate migration rates. Our results can be interpreted in a specialist-generalist context and (among others) show when two specialists can coexist with a generalist in two demes if the degree of dominance is deme independent and intermediate. The dominance relation between the generalist allele and the specialist alleles play a decisive role. We also discuss linear selection on a quantitative trait and show that G x E interaction is not necessary for the maintenance of more than two alleles in two demes.

When does gene flow facilitate evolutionary rescue?

Experimental and theoretical studies have highlighted the impact of gene flow on the probability of evolutionary rescue in structured habitats. Mathematical modeling and simulations of evolutionary rescue in spatially or otherwise structured populations showed that intermediate migration rates can often maximize the probability of rescue in gradually or abruptly deteriorating habitats. These theoretical results corroborate the positive effect of gene flow on evolutionary rescue that has been identified in experimental yeast populations. The observations that gene flow can facilitate adaptation are in seeming conflict with traditional population genetics results that show that gene flow usually hampers (local) adaptation. Identifying conditions for when gene flow facilitates survival chances of populations rather than reducing them remains a key unresolved theoretical question. We here present a simple analytically tractable model for evolutionary rescue in a two-deme model with gene flow. Our main result is a simple condition for when migration facilitates evolutionary rescue, as opposed as no migration. We further investigate the roles of asymmetries in gene flow and/or carrying capacities, and the effects of density regulation and local growth rates on evolutionary rescue.