Purging due to self-fertilization does not prevent accumulation of expansion load.

As species expand their geographic ranges, colonizing populations face novel ecological conditions, such as new environments and limited mates, and suffer from evolutionary consequences of demographic change through bottlenecks and mutation load accumulation. Self-fertilization is often observed at species range edges and, in addition to countering the lack of mates, is hypothesized as an evolutionary advantage against load accumulation through increased homozygosity and purging. We study how selfing impacts the accumulation of genetic load during range expansion via purging and/or speed of colonization. Using simulations, we disentangle inbreeding effects due to demography versus due to selfing and find that selfers expand faster, but still accumulate load, regardless of mating system. The severity of variants contributing to this load, however, differs across mating system: higher selfing rates purge large-effect recessive variants leaving a burden of smaller-effect alleles. We compare these predictions to the mixed-mating plant Arabis alpina, using whole-genome sequences from refugial outcrossing populations versus expanded selfing populations. Empirical results indicate accumulation of expansion load along with evidence of purging in selfing populations, concordant with our simulations, suggesting that while purging is a benefit of selfing evolving during range expansions, it is not sufficient to prevent load accumulation due to range expansion.

How chromosomal inversions reorient the evolutionary process.

Inversions are structural mutations that reverse the sequence of a chromosome segment and reduce the effective rate of recombination in the heterozygous state. They play a major role in adaptation, as well as in other evolutionary processes such as speciation. Although inversions have been studied since the 1920s, they remain difficult to investigate because the reduced recombination conferred by them strengthens the effects of drift and hitchhiking, which in turn can obscure signatures of selection. Nonetheless, numerous inversions have been found to be under selection. Given recent advances in population genetic theory and empirical study, here we review how different mechanisms of selection affect the evolution of inversions. A key difference between inversions and other mutations, such as single nucleotide variants, is that the fitness of an inversion may be affected by a larger number of frequently interacting processes. This considerably complicates the analysis of the causes underlying the evolution of inversions. We discuss the extent to which these mechanisms can be disentangled, and by which approach.

OMA orthology in 2021: website overhaul, conserved isoforms, ancestral gene order and more.

OMA is an established resource to elucidate evolutionary relationships among genes from currently 2326 genomes covering all domains of life. OMA provides pairwise and groupwise orthologs, functional annotations, local and global gene order conservation (synteny) information, among many other functions. This update paper describes the reorganisation of the database into gene-, group- and genome-centric pages. Other new and improved features are detailed, such as reporting of the evolutionarily best conserved isoforms of alternatively spliced genes, the inferred local order of ancestral genes, phylogenetic profiling, better cross-references, fast genome mapping, semantic data sharing via RDF, as well as a special coronavirus OMA with 119 viruses from the Nidovirales order, including SARS-CoV-2, the agent of the COVID-19 pandemic. We conclude with improvements to the documentation of the resource through primers, tutorials and short videos. OMA is accessible at https://omabrowser.org.

Chromosomal inversions can limit adaptation to new environments.

Chromosomal inversions are often thought to facilitate local adaptation and population divergence because they can link multiple adaptive alleles into non-recombining genomic blocks. Selection should thus be more efficient in driving inversion-linked adaptive alleles to high frequency in a population, particularly in the face of maladaptive gene flow. But what if ecological conditions and hence selection on inversion-linked alleles change? Reduced recombination within inversions could then constrain the formation of optimal combinations of pre-existing alleles under these new ecological conditions. Here, we outline this idea of inversions limiting adaptation and divergence when ecological conditions change across time or space. We reason and use simulations to illustrate that the benefit of inversions for local adaptation and divergence under one set of ecological conditions can come with a concomitant constraint for adaptation to novel sets of ecological conditions. This limitation of inversions to adaptation may contribute to the maintenance of polymorphism within species.

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.

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.

Effect of the anther-smut fungus Microbotryum on the juvenile growth of its host Silene latifolia.

PREMISE OF THE STUDY: Plant pathogens that form persistent systemic infections within plants have the potential to affect multiple plant life history traits, yet we tend to focus only on visible symptoms. Anther smut of Silene latifolia caused by the fungus Microbotryum lychnidis-dioicae induces the anthers of its host to support fungal spore production instead of pollen, and the pathogen is primarily transmitted among flowering plants by pollinators. Nevertheless, most of its life cycle is spent in the asymptomatic vegetative phase, and spores falling on seedlings or nonflowering plants can also infect the host. The purpose of this study was to ask whether the fungus also had an effect on its host plant in the juvenile vegetative phase before flowering as this is important for the disease dynamics in species where infection of seedlings is commonplace. METHODS: Leaf length and leaf number of inoculated and uninoculated juvenile plants were compared in greenhouse experiments, and in one experiment, disease status of the plants at flowering was determined. KEY RESULTS: Inoculated plants had shorter but more leaves, and reduced root mass at the early juvenile (preflowering) stage. Some of these effects were detectable in plants that were inoculated but showed no disease symptoms at flowering. CONCLUSIONS: These results show that pathogenic fungi can have endophyte-like effects even in the total absence of their typical and more charismatic symptoms, and conversely that the assessment of endophyte effects on the fitness of their hosts should include all stages of the host life cycle.

Local Adaptation Interacts with Expansion Load during Range Expansion: Maladaptation Reduces Expansion Load.

The biotic and abiotic factors that facilitate or hinder species range expansions are many and complex. We examine the impact of two genetic processes and their interaction on fitness at expanding range edges: local maladaptation resulting from the presence of an environmental gradient and expansion load resulting from increased genetic drift at the range edge. Results from spatially explicit simulations indicate that the presence of an environmental gradient during range expansion reduces expansion load; conversely, increasing expansion load allows only locally adapted populations to persist at the range edge. Increased maladaptation reduces the speed of range expansion, resulting in less genetic drift at the expanding front and more immigration from the range center, therefore reducing expansion load at the range edge. These results may have ramifications for species being forced to shift their ranges because of climate change or other anthropogenic changes. If rapidly changing climate leads to faster expansion as populations track their shifting climatic optima, populations may suffer increased expansion load beyond previous expectations.

Analysis of the clinical safety of intralesional injection of collagenase Clostridium histolyticum (CCH) for adults with Peyronie's disease (PD).

OBJECTIVE: To examine the safety of intralesional injection of collagenase Clostridium histolyticum (CCH) for the treatment of Peyronie's disease (PD), using a pooled safety analysis of patients who received at least one dose of CCH in any of six clinical studies. PATIENTS AND METHODS: Patients from six clinical studies, including three randomised, double-blind, placebo-controlled studies and three open-label safety and efficacy studies, were included if they had received at least one dose of 0.58 mg CCH. Adverse events (AEs), including treatment-emergent AEs, treatment-related AEs, and serious AEs (SAEs), were characterised. Potential immunogenicity-related AEs were evaluated through examination of increased anti-AUX-I and anti-AUX-II antibody levels, AEs, and reported terms possibly associated with immunological or hypersensitivity events. RESULTS: Overall, 85.8% of 1 044 pooled patients reported at least one treatment-related AE. The most frequently reported (≥25.0% of patients) treatment-related AEs included penile haematoma (82.7% had the verbatim 'penile bruising'), penile pain, and penile swelling. Most patients (75.2%) had mild- or moderate-severity treatment-related AEs, and 14.2% had no treatment-related AEs. Nine patients (0.9%) had treatment-related SAEs: five with penile haematoma and four with corporal rupture. There was no association between AEs and anti-AUX-I or anti-AUX-II antibody levels across treatment cycles, and no systemic hypersensitivity reactions occurred. CONCLUSIONS: This pooled safety analysis shows that although non-serious and serious treatment-related AEs can occur after CCH treatment for PD, most were non-serious and the SAEs were manageable. Providers should be prepared to manage possible SAEs.

Landscape structure and the genetic effects of a population collapse.

Both landscape structure and population size fluctuations influence population genetics. While independent effects of these factors on genetic patterns and processes are well studied, a key challenge is to understand their interaction, as populations are simultaneously exposed to habitat fragmentation and climatic changes that increase variability in population size. In a population network of an alpine butterfly, abundance declined 60-100% in 2003 because of low over-winter survival. Across the network, mean microsatellite genetic diversity did not change. However, patch connectivity and local severity of the collapse interacted to determine allelic richness change within populations, indicating that patch connectivity can mediate genetic response to a demographic collapse. The collapse strongly affected spatial genetic structure, leading to a breakdown of isolation-by-distance and loss of landscape genetic pattern. Our study reveals important interactions between landscape structure and temporal demographic variability on the genetic diversity and genetic differentiation of populations. Projected future changes to both landscape and climate may lead to loss of genetic variability from the studied populations, and selection acting on adaptive variation will likely occur within the context of an increasing influence of genetic drift.

Mandated data archiving greatly improves access to research data.

The data underlying scientific papers should be accessible to researchers both now and in the future, but how best can we ensure that these data are available? Here we examine the effectiveness of four approaches to data archiving: no stated archiving policy, recommending (but not requiring) archiving, and two versions of mandating data deposition at acceptance. We control for differences between data types by trying to obtain data from papers that use a single, widespread population genetic analysis, structure. At one extreme, we found that mandated data archiving policies that require the inclusion of a data availability statement in the manuscript improve the odds of finding the data online almost 1000-fold compared to having no policy. However, archiving rates at journals with less stringent policies were only very slightly higher than those with no policy at all. We also assessed the effectiveness of asking for data directly from authors and obtained over half of the requested datasets, albeit with ∼8 d delay and some disagreement with authors. Given the long-term benefits of data accessibility to the academic community, we believe that journal-based mandatory data archiving policies and mandatory data availability statements should be more widely adopted.

Arg287Gln variant of EPHX2 and epoxyeicosatrienoic acids are associated with insulin sensitivity in humans.

Epoxyeicosatrienoic acids (EETs) protect against the development of insulin resistance in rodents. EETs are hydrolyzed to less biologically active diols by soluble epoxide hydrolase (encoded for by EPHX2). Functional variants of EPHX2 encode for enzymes with increased (Lys55Arg) or decreased (Arg287Gln) hydrolase activity. This study tested the hypothesis that variants of EPHX2 are associated with insulin sensitivity or secretion in humans. Subjects participating in metabolic phenotyping studies were genotyped. Eighty-five subjects underwent hyperglycemic clamps. There was no relationship between the Lys55Arg genotype and insulin sensitivity or secretion. In contrast, the EPHX2 287Gln variant was associated with higher insulin sensitivity index (p=0.019 controlling for body mass index and metabolic syndrome). Also, there was an interactive effect of EPHX2 Arg287Gln genotype and body mass index on insulin sensitivity index (p=0.029). There was no relationship between EPHX2 Arg287Gln genotype and acute or late-phase glucose-stimulated insulin secretion, but disposition index was higher in 287Gln carriers compared with Arg/Arg (p=0.022). Plasma EETs correlated with insulin sensitivity index (r=0.64, p=0.015 for total EETs) and were decreased in the metabolic syndrome. A genetic variant that results in decreased soluble epoxide hydrolase activity is associated with increased insulin sensitivity, as are higher EETs.

Using Runs of Homozygosity and Machine Learning to Disentangle Sources of Inbreeding and Infer Self-Fertilization Rates.

Runs of homozygosity (ROHs) are indicative of elevated homozygosity and inbreeding due to mating of closely related individuals. Self-fertilization can be a major source of inbreeding which elevates genome-wide homozygosity and thus should also create long ROHs. While ROHs are frequently used to understand inbreeding in the context of conservation and selective breeding, as well as for consanguinity of populations and their demographic history, it remains unclear how ROH characteristics are altered by selfing and if this confounds expected signatures of inbreeding due to demographic change. Using simulations, we study the impact of the mode of reproduction and demographic history on ROHs. We apply random forests to identify unique characteristics of ROHs, indicative of different sources of inbreeding. We pinpoint distinct features of ROHs that can be used to better characterize the type of inbreeding the population was subjected to and to predict outcrossing rates and complex demographic histories. Using additional simulations and four empirical datasets, two from highly selfing species and two from mixed-maters, we predict the selfing rate and validate our estimations. We find that self-fertilization rates are successfully identified even with complex demography. Population genetic summary statistics improve algorithm accuracy particularly in the presence of additional inbreeding, e.g. from population bottlenecks. Our findings highlight the importance of ROHs in disentangling confounding factors related to various sources of inbreeding and demonstrate situations where such sources cannot be differentiated. Additionally, our random forest models provide a novel tool to the community for inferring selfing rates using genomic data.

Bayesian inference of a complex invasion history revealed by nuclear and chloroplast genetic diversity in the colonizing plant, Silene latifolia.

Species invading new ranges are subject to a series of demographic events that can strongly shape genetic diversity. Describing this demographic history is important for understanding where invasive species come from and how they spread, and is critical to testing hypotheses of postinvasion adaptation. Here, we analyse nuclear and chloroplast genetic diversity to study the invasion history of the widespread colonizing weed, Silene latifolia (Caryophyllaceae). Bayesian clustering and PCA revealed strong population structure in the native range of Europe, and although genotypes from multiple native sources were present in the introduced range of North America, the spatial distribution of genetic variance was dramatically reorganized. Using approximate Bayesian computation (ABC), we compared support for different invasion scenarios, including the number and size of independent introduction events and the amount of admixture occurring between sources of introduced genotypes. Our results supported independent introductions into eastern and western North America, with the latter forming a bridgehead for a secondary invasion into the Great Lakes region of central North America. Despite small estimated founder population sizes, the duration of the demographic bottleneck after the initial introduction appeared extremely short-lived. This pattern of repeated colonization and rapid expansion has effectively eroded the strong population structure and cytonuclear associations present in Europe, but has retained overall high genetic diversity since invasion. Our results highlight the flexibility of the ABC approach for constructing a narrative of the demographic history of species invasions and provide baseline for future studies of evolutionary changes in introduced S. latifolia populations.

Recommendations for utilizing and reporting population genetic analyses: the reproducibility of genetic clustering using the program STRUCTURE.

Reproducibility is the benchmark for results and conclusions drawn from scientific studies, but systematic studies on the reproducibility of scientific results are surprisingly rare. Moreover, many modern statistical methods make use of 'random walk' model fitting procedures, and these are inherently stochastic in their output. Does the combination of these statistical procedures and current standards of data archiving and method reporting permit the reproduction of the authors' results? To test this, we reanalysed data sets gathered from papers using the software package STRUCTURE to identify genetically similar clusters of individuals. We find that reproducing structure results can be difficult despite the straightforward requirements of the program. Our results indicate that 30% of analyses were unable to reproduce the same number of population clusters. To improve this, we make recommendations for future use of the software and for reporting STRUCTURE analyses and results in published works.

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)'.

The distribution of mutational effects on fitness in Caenorhabditis elegans inferred from standing genetic variation.

The distribution of fitness effects (DFE) for new mutations is one of the most theoretically important but difficult to estimate properties in population genetics. A crucial challenge to inferring the DFE from natural genetic variation is the sensitivity of the site frequency spectrum to factors like population size change, population substructure, genome structure, and nonrandom mating. Although inference methods aim to control for population size changes, the influence of nonrandom mating remains incompletely understood, despite being a common feature of many species. We report the DFE estimated from 326 genomes of Caenorhabditis elegans, a nematode roundworm with a high rate of self-fertilization. We evaluate the robustness of DFE inferences using simulated data that mimics the genomic structure and reproductive life history of C. elegans. Our observations demonstrate how the combined influence of self-fertilization, genome structure, and natural selection on linked sites can conspire to compromise estimates of the DFE from extant polymorphisms with existing methods. These factors together tend to bias inferences toward weakly deleterious mutations, making it challenging to have full confidence in the inferred DFE of new mutations as deduced from standing genetic variation in species like C. elegans. Improved methods for inferring the DFE are needed to appropriately handle strong linked selection and selfing. These results highlight the importance of understanding the combined effects of processes that can bias our interpretations of evolution in natural populations.

Transition from Background Selection to Associative Overdominance Promotes Diversity in Regions of Low Recombination.

Linked selection is a major driver of genetic diversity. Selection against deleterious mutations removes linked neutral diversity (background selection [BGS]) [1], creating a positive correlation between recombination rates and genetic diversity. Purifying selection against recessive variants, however, can also lead to associative overdominance (AOD) [2, 3], due to an apparent heterozygote advantage at linked neutral loci that opposes the loss of neutral diversity by BGS. Zhao and Charlesworth [3] identified the conditions under which AOD should dominate over BGS in a single-locus model and suggested that the effect of AOD could become stronger if multiple linked deleterious variants co-segregate. We present a model describing how and under which conditions multi-locus dynamics can amplify the effects of AOD. We derive the conditions for a transition from BGS to AOD due to pseudo-overdominance [4], i.e., a form of balancing selection that maintains complementary deleterious haplotypes that mask the effect of recessive deleterious mutations. Simulations confirm these findings and show that multi-locus AOD can increase diversity in low-recombination regions much more strongly than previously appreciated. While BGS is known to drive genome-wide diversity in humans [5], the observation of a resurgence of genetic diversity in regions of very low recombination is indicative of AOD. We identify 22 such regions in the human genome consistent with multi-locus AOD. Our results demonstrate that AOD may play an important role in the evolution of low-recombination regions of many species.

Dental considerations in the management of the cardiac transplant patient.

Every year, more than 25,000 transplantation procedures are performed in the United States to replace solid organs, including the heart, intestine, kidney, liver, lung, and pancreas. Cardiac transplant patients need specialized dental care. The compromised health and immune systems of these patients place them at increased risk for systemic and oral infections, which must be considered when planning dental treatment before and after cardiac transplantation. This article reviews the current status of dental care practices that have been recommended and presents a rationale that can be applied as the basis of guidelines and recommendations for treating cardiac transplant patients.