Revisiting the notion of deleterious sweeps

It has previously been shown that, conditional on its fixation, the time to fixation of a semi-dominant deleterious autosomal mutation in a randomly mating population is the same as that of an advantageous mutation. This result implies that deleterious mutations could generate selective sweep-like effects. Although their fixation probabilities greatly differ, the much larger input of deleterious relative to beneficial mutations suggests that this phenomenon could be important. We here examine how the fixation of mildly deleterious mutations affects levels and patterns of polymorphism at linked sites—both in the presence and absence of interference amongst deleterious mutations—and how this class of sites may contribute to divergence between-populations and species. We find that, while deleterious fixations are unlikely to represent a significant proportion of outliers in polymorphism-based genomic scans within populations, minor shifts in the frequencies of deleterious mutations can influence the proportions of private variants and the value of F_ST after a recent population split. As sites subject to deleterious mutations are necessarily found in functional genomic regions, interpretations in terms of recurrent positive selection may require reconsideration.     

The classical hitchhiking model with continuous mutational pressure and purifying selection

Detecting selective sweeps driven by strong positive selection and localizing the targets of selection in the genome play a major role in modern population genetics and genomics. Most of these analyses are based on the classical model of genetic hitchhiking proposed by Maynard Smith and Haigh (1974, Genetical Research, 23, 23). Here, we consider extensions of the classical two‐locus model. Introducing mutation at the strongly selected site, we analyze the conditions under which soft sweeps may arise. We identify a new parameter (the ratio of the beneficial mutation rate to the selection coefficient) that characterizes the occurrence of multiple‐origin soft sweeps. Furthermore, we quantify the hitchhiking effect when the polymorphism at the linked locus is not neutral but maintained in a mutation‐selection balance. In this case, we find a smaller relative reduction of heterozygosity at the linked site than for a neutral polymorphism. In our analysis, we use a semi‐deterministic approach; i.e., we analyze the frequency process of the beneficial allele in an infinitely large population when its frequency is above a certain threshold; however, for very small frequencies in the initial phase after the onset of selection we rely on diffusion theory.     

Adaptive hitchhiking effects on genome variability

The continuing deluge of nucleotide polymorphism data is providing insights into the role of adaptation in shaping genome-wide patterns of variability and molecular evolution. Population genetic models in which linkage and selection interact (i.e. hitchhiking) predict that selection can leave 'footprints' in closely linked genomic regions. New analytical approaches show promise for distinguishing the signature of adaptation from that of several non-adaptive alternatives. Accounting for the effects of population structure and history poses a challenge for future investigations.     

The role of deleterious mutations in allopatric speciation

Allopatric speciation is often assumed to occur as a consequence of adaptive divergence between two isolated populations. However, there are some scenarios in which reproductive isolation can be favored due to accumulated unconditionally deleterious mutations. If deleterious mutations have synergistic epistatic effects, it is shown here that the average fitness of recombinants between two parental lines with a given number of fixed mutations is lower than that of the parents in both the F1 and F2 generations. If individual mutations are only slightly deleterious, then they will tend to fixation at a high enough rate to cause lower hybrid fitness. If the fitness effects of mutation give rise to antagonistic epistasis, the hybrids tend to have a higher average fitness than the parental lines, suggesting a possible scenario for the origin of hybrid vigor. The other model of deleterious mutations investigated is the accumulation of knockout mutants in a duplicated gene family. While neutral in the parental lines, upon contact the F1 and later generations have a significant probability of carrying double knockouts. Under this scenario, selection may also favor reproductive isolation between the two lines. Even when the selection coefficients generated are too low to drive speciation, epistatic interactions between deleterious mutations offer a possible explanation for both outbreeding depression and hybrid vigor.     

Contrasting response to Pleistocene climate change by ground-living and arboreal Mandarina snails from the oceanic Hahajima archipelago

While the genetic impact of Pleistocene climate change on temperate species has been well characterized, especially in Europe and North America, an effect on the diversification of species on oceanic islands has been less well studied. This is perhaps a surprising observation given the traditional and continuing contribution of island species (e.g. Darwin's finches, Partula snails, Lord Howe Island palms) to understand speciation. Here, we combine mitochondrial and microsatellite data from the ground-living and arboreal Mandarina snails of the oceanic, subtropical Hahajima archipelago (Ogasawara, colloquially 'Galápagos of the Orient') to enable a comparative approach to understand the impact of the Pleistocene glaciations on their phylogeography. Prior work suggested that several narrowly divergent, ground-living species pairs of Mandarina populations on the outlying islands, as well as the low-lying southern and central parts of Hahajima, probably underwent bottlenecks and subsequent expansions during the recent Pleistocene. Here, the most striking finding is that largely arboreal species have deeply divergent, geographically restricted mitochondrial lineages, in contrast to a census size that is at least an order of magnitude lower than ground-living snails. As populations of both types are highly polymorphic at microsatellite loci, the systematic difference at the mitochondrial locus probably indicates a contrasting effect of the Pleistocene climate cycles on the two groups. We speculate that this may have partly come about owing to a reduced efficacy of natural selection on the more greatly structured populations of arboreal snails. If so, then a prediction is that the genome of other snails, or other species with limited mobility, will show a similar response to the Pleistocene climate cycles.     

Mating density and the strength of sexual selection against deleterious alleles in Drosophila melanogaster

Deleterious alleles constantly enter populations via mutation. Their presence reduces mean fitness and may threaten population persistence. It has been suggested that sexual selection may be an efficient way by which deleterious alleles are removed from populations but there is little direct experimental evidence. Because of its potential role in mutational meltdowns, there is particular interest in whether the strength of sexual selection changes with density. For each of eight visible markers in Drosophila melanogaster we have compared the strength of sexual selection at two densities. We find evidence of strong sexual selection against most but not all of these alleles. There is no evidence that sexual selection tends to be stronger (or weaker) at high density relative to low density. In addition, we also measure the effects of these mutations on two key parameters relevant to population productivity--juvenile viability and female fecundity. In most cases, sexual selection is as strong or stronger than these other forms of selection.     

Common bacterial toxins and physiological vulnerability to sudden infant death: the role of deleterious genetic mutations

The common bacterial toxin hypothesis of sudden infant death syndrome (SIDS) is consistent with the epidemiological features of the condition including the age distribution, seasonal incidence, association with prone sleeping and with exposure to tobacco smoke. The hypothesis is supported by experimental evidence but there are two barriers to its acceptance: the speed of onset does not fit with conventional concepts of an infective process; furthermore, the hypothesis appears to offer a single explanation for what is regarded as a multifactorial disease. Concepts from information theory are used to explore these objections. Complex physiological systems process information and need a high level of redundancy to minimise error. Models show that deleterious mutations in such a system will interact synergistically. Environmental perturbations are most likely to cause failure (sudden death) in systems with several mutations. Models also indicate that mutation rates will pose a limit to the size of the functioning genome and, therefore, increased complexity in evolution depends on using old genes in new combinations rather than the chance appearance of new genes. The idea that we share our genes with the rest of creation (same genes but different combinations) leads to the following conjecture: for every receptor controlling the flow of information across a cell membrane there will be a bacterially coded molecule that can switch it off or on. Based on this premise, bacterial toxaemia could cause sudden death, merely the time it takes for a molecule to associate with or dissociate from its receptor. Regardless of the number of physiological systems involved in SIDS, the age distribution will have a unimodal peak corresponding to the age range during which infant serum IgG reaches its nadir. In this way, the two barriers to the common bacterial toxin hypothesis can be overcome: one explanation but multiple bacteria and toxins acting with variable speed on multiple target systems.     

On the accumulation of deleterious mutations during range expansions

We investigate the effect of spatial range expansions on the evolution of fitness when beneficial and deleterious mutations cosegregate. We perform individual‐based simulations of 1D and 2D range expansions and complement them with analytical approximations for the evolution of mean fitness at the edge of the expansion. We find that deleterious mutations accumulate steadily on the wave front during range expansions, thus creating an expansion load. Reduced fitness due to the expansion load is not restricted to the wave front, but occurs over a large proportion of newly colonized habitats. The expansion load can persist and represent a major fraction of the total mutation load for thousands of generations after the expansion. The phenomenon of expansion load may explain growing evidence that populations that have recently expanded, including humans, show an excess of deleterious mutations. To test the predictions of our model, we analyse functional genetic diversity in humans and find patterns that are consistent with our model.     

A Coalescent Model for a Sweep of a Unique Standing Variant

The use of genetic polymorphism data to understand the dynamics of adaptation and identify the loci that are involved has become a major pursuit of modern evolutionary genetics. In addition to the classical “hard sweep” hitchhiking model, recent research has drawn attention to the fact that the dynamics of adaptation can play out in a variety of different ways and that the specific signatures left behind in population genetic data may depend somewhat strongly on these dynamics. One particular model for which a large number of empirical examples are already known is that in which a single derived mutation arises and drifts to some low frequency before an environmental change causes the allele to become beneficial and sweeps to fixation. Here, we pursue an analytical investigation of this model, bolstered and extended via simulation study. We use coalescent theory to develop an analytical approximation for the effect of a sweep from standing variation on the genealogy at the locus of the selected allele and sites tightly linked to it. We show that the distribution of haplotypes that the selected allele is present on at the time of the environmental change can be approximated by considering recombinant haplotypes as alleles in the infinite-alleles model. We show that this approximation can be leveraged to make accurate predictions regarding patterns of genetic polymorphism following such a sweep. We then use simulations to highlight which sources of haplotypic information are likely to be most useful in distinguishing this model from neutrality, as well as from other sweep models, such as the classic hard sweep and multiple-mutation soft sweeps. We find that in general, adaptation from a unique standing variant will likely be difficult to detect on the basis of genetic polymorphism data from a single population time point alone, and when it can be detected, it will be difficult to distinguish from other varieties of selective sweeps. Samples from multiple populations and/or time points have the potential to ease this difficulty.     

Genetic and phenotypic consequences of early domestication in black soldier flies (Hermetia illucens)

The black soldier fly, Hermetia illucens, is an emerging biotechnological agent with its larvae being effective converters of organic waste into usable bio-products including protein and lipids. To date, most operations use unimproved commercial populations produced by mass rearing, without cognisance of specific breeding strategies. The genetic and phenotypic consequences of these commercial practices remain unknown and could have a significant impact on long-term population viability and productivity. The aim of this study was thus to assess the genetic and phenotypic changes during the early phases of colony establishment and domestication in the black soldier fly. An experimental colony was established from wild founder flies and a new microsatellite marker panel was developed to assess population genetic parameters along with the phenotypic characteristics of each generational cohort under captive breeding. The experimental colony was characterised by a small effective population size, subsequent loss of genetic diversity and rapid genetic and phenotypic differentiation between the generational cohorts. Ultimately, the population collapsed by the fifth generation, most likely owing to the adverse effect of inbreeding depression following the fixation of deleterious alleles. Species with r-selected life history characteristics (e.g. short life-span, high fecundity and low larval survival) are known to pose particular challenges for genetic management. The current study suggests that sufficient genetic and phenotypic variations exist in the wild population and that domestication and strain development could be achieved with careful population augmentation and selection during the early stages of colony establishment.     

Seeking signatures of reinforcement at the genetic level: a hitchhiking mapping and candidate gene approach in the house mouse

Reinforcement is the process by which prezygotic isolation is strengthened as a response to selection against hybridization. Most empirical support for reinforcement comes from the observation of its possible phenotypic signature: an accentuated degree of prezygotic isolation in the hybrid zone as compared to allopatry. Here, we implemented a novel approach to this question by seeking for the signature of reinforcement at the genetic level. In the house mouse, selection against hybrids and enhanced olfactory‐based assortative mate preferences are observed in a hybrid zone between the two European subspecies Mus musculus musculus and M. m. domesticus, suggesting a possible recent reinforcement event. To test for the genetic signature of reinforcing selection and identify genes involved in sexual isolation, we adopted a hitchhiking mapping approach targeting genomic regions containing candidate genes for assortative mating in mice. We densely scanned these genomic regions in hybrid zone and allopatric samples using a large number of fast evolving microsatellite loci that allow the detection of recent selection events. We found a handful of loci showing the expected pattern of significant reduction in variability in populations close to the hybrid zone, showing assortative odour preference in mate choice experiments as compared to populations further away and displaying no such preference. These loci lie close to genes that we pinpoint as testable candidates for further investigation.     

A Deep-Learning Approach for Inference of Selective Sweeps from the Ancestral Recombination Graph

Detecting signals of selection from genomic data is a central problem in population genetics. Coupling the rich information in the ancestral recombination graph (ARG) with a powerful and scalable deep-learning framework, we developed a novel method to detect and quantify positive selection: Selection Inference using the Ancestral recombination graph (SIA). Built on a Long Short-Term Memory (LSTM) architecture, a particular type of a Recurrent Neural Network (RNN), SIA can be trained to explicitly infer a full range of selection coefficients, as well as the allele frequency trajectory and time of selection onset. We benchmarked SIA extensively on simulations under a European human demographic model, and found that it performs as well or better as some of the best available methods, including state-of-the-art machine-learning and ARG-based methods. In addition, we used SIA to estimate selection coefficients at several loci associated with human phenotypes of interest. SIA detected novel signals of selection particular to the European (CEU) population at the MC1R and ABCC11 loci. In addition, it recapitulated signals of selection at the LCT locus and several pigmentation-related genes. Finally, we reanalyzed polymorphism data of a collection of recently radiated southern capuchino seedeater taxa in the genus Sporophila to quantify the strength of selection and improved the power of our previous methods to detect partial soft sweeps. Overall, SIA uses deep learning to leverage the ARG and thereby provides new insight into how selective sweeps shape genomic diversity.     

Fixation of new alleles and the extinction of small populations: drift load, beneficial alleles, and sexual selection

With a small effective population size, random genetic drift is more important than selection in determining the fate of new alleles. Small populations therefore accumulate deleterious mutations. Left unchecked, the effect of these fixed alleles is to reduce the reproductive capacity of a species, eventually to the point of extinction. New beneficial mutations, if fixed by selection, can restore some of this lost fitness. This paper derives the overall change in fitness due to fixation of new deleterious and beneficial alleles, as a function of the distribution of effects of new mutations and the effective population size. There is a critical effective size below which a population will on average decline in fitness, but above which beneficial mutations allow the population to persist. With reasonable estimates of the relevant parameters, this critical effective size is likely to be a few hundred. Furthermore, sexual selection can act to reduce the fixation probability of deleterious new mutations and increase the probability of fixing new beneficial mutations. Sexual selection can therefore reduce the risk of extinction of small populations.     

The mean and variance of the number of segregating sites since the last hitchhiking event

 Tight linkage may cause a reduction of nucleotide diversity in a chromosomal region if an advantageous mutation appears in that region which is driven to fixation by directional selection. This process is usually called genetic hitchhiking. If selection is strong, the entire process takes place during a time period of length 2s ln (2N) that is very short relative to 2N generations [s is the selection coefficient of the advantageous mutation and N the effective diploid population size]. On the time scale of 2N generations, which is characteristic for neutral evolution, we may therefore call this process a hitchhiking event. Using coalescent methods, we analyzed a model in which a hitchhiking event occurred in a chromosomal region of zero-recombination in the past at time x. Such a hitchhiking “catastrophe” wipes out completely genetic variation that existed in a population before that time. Standing variation observed at present must therefore be due to mutations that have arisen since time point x. Assuming that all newly arising mutations are neutral, we derived expressions for the expectation, variance and also for the higher moments of the number of nucleotide sites segregating in a sample of n genes as a function of x. The result for the first moment is then used to estimate the time back to the last hitchhiking event based on DNA polymorphism data from Drosophila. Assuming that directional selection is the sole determinant of the level of genetic variation in the gene regions surveyed, we obtained estimates of x that were typically in the order of 0.1N generations. Received 14 May 1996; received in revised form 26 August 1996     

A 2000 km genetic wake yields evidence for northern glacial refugia and hybrid zone movement in a pair of songbirds

Hybrid zones are natural experiments that expose the forces maintaining species differences. But for cases where a trait of one of the hybridizing pair appears shifted into the range of the other, the underlying mechanism can be difficult to infer. For example, hybridization between hermit warbler (Dendroica occidentalis) and Townsend's warbler (Dendroica townsendi) is restricted to narrow hybrid zones in Washington and Oregon, yet hermit mtDNA can be found in phenotypically pure Townsend's populations up to 2000 km north along the Pacific coast. This could reflect introgression of selectively favoured hermit mitochondria north across the hybrid zones, or a neutral genetic wake left behind following southern zone movement. Hermit mitochondrial haplotypes in populations of coastal Townsend's exhibit relatively high genetic diversity and significant divergence from those found in populations of hermit warblers. This contradicts the predictions of selective introgression, but is consistent with a northern population of hermits diverging in a glacial refugium before being replaced by Townsend's via aggressive hybridization. Previous field studies showing Townsend's males to be competitively superior to hermit males support this scenario, and suggest that the extreme hybrid zone movement evidenced by the hermit mitochondrial wake represents an extinction in progress.     

Environmental complexity and the purging of deleterious alleles

Sexual interactions among adults can generate selection on both males and females with genome‐wide consequences. Sexual selection through males is one component of this selection that has been argued to play an important role in purging deleterious alleles. A common technique to assess the influence of sexual selection is by a comparison of experimental evolution under enforced monogamy versus polygamy. Mixed results from past studies may be due to the use of highly simplified laboratory conditions that alter the nature of sexual interactions. Here, we examine the rate of purging of 22 gene disruption mutations in experimental polygamous populations of Drosophila melanogaster in each of two mating environments: a simple, high‐density environment (i.e., typical fly vials), and a lower density, more spatially complex environment. Based on past work, we expect sexual interactions in the latter environment to result in stronger selection in both sexes. Consistent with this, we find that mutations tend to be purged more quickly in populations evolving in complex environments. We discuss possible mechanisms by which environmental complexity might modulate the rate at which deleterious alleles are purged and putatively ascribe a role for sexual interactions in explaining the treatment differences in our experiment.     

Accumulation of deleterious mutations: additional Drosophila melanogaster estimates and a simulation of the effects of selection

We report an assay of egg-to-adult viability in full-sibling mutation accumulation (MA) lines derived from a completely homozygous population of Drosophila melanogaster and maintained for 210 generations. A simultaneous evaluation was also made of a large population derived from the same origin and maintained as a control for the same period. We also present computer simulations to explore the possible decline in viability of the control population due to mutation accumulation and the possible effect of selection within and between MA lines. For this purpose, we used two mutational models independent from the data analyzed and based on radically different assumptions. The first model implies a large number of mutations of small effect, whereas the second implies a much smaller number of mutations with much larger effects. The observed rate of decline in mean viability was very small but significant (0.077%). The rate of increase in among line variance (0.189 x 10(-3)) was similar to those obtained previously in the same lines. The simulation results indicated that a model of many mutations of small effect is incompatible with the evolution of the mean viability of the control and MA lines over generations, the distribution of line means after 210 generations of mutation accumulation, and the pattern of line extinction over generations. Basically, this model predicted a large drop in viability, both in the control and particularly the MA lines, that is not observed empirically. It also predicted a rate of line extinction too low in the early generations and too high in the later ones. In contrast, the model based on few mutations of large effect was generally consistent with all the observations.     

The effect of pathogens on selection against deleterious mutations in Drosophila melanogaster

In natural populations, fitness is reduced by both deleterious mutations and parasites. Few studies have examined interactions between these two factors, particularly at the level of individual genes. We examined how the presence of a bacterial pathogen, Pseudomonas aeruginosa, affected the selection against each of eight deleterious mutations in Drosophila melanogaster. We found that mutations tended to become more deleterious in the presence of disease. This increase in the average selection was primarily due to three genes with the remainder showing little evidence of change.     

Detecting signatures of selection in nine distinct lines of broiler chickens

Modern commercial chickens have been bred for one of two specific purposes: meat production (broilers) or egg production (layers). This has led to large phenotypic changes, so that the genomic signatures of selection may be detectable using statistical techniques. Genetic differentiation between nine distinct broiler lines was calculated using Weir and Cockerham's pairwise F_ST estimator for 11 003 genome‐wide markers to identify regions showing evidence of differential selection across lines. Differentiation measures were averaged into overlapping sliding windows for each line, and a permutation approach was used to determine the significance of each window. A total of 51 regions were found to show significant differentiation between the lines. Several lines were consistently found to share significant regions, suggesting that the pattern of line divergence is related to selection for broiler traits. The majority of the 51 regions contain QTL relating to broiler traits, but only five of them were found to be significantly enriched for broiler QTL, including a region on chromosome 27 containing 39 broiler QTL and 114 genes. Additionally, a number of these regions have been identified by other selection mapping studies. This study has identified a large number of potential selection signatures, and further tests with higher‐density marker data may narrow these regions down to individual genes.