Radiation and hybridization underpin the spread of the fire ant social supergene.

Supergenes are clusters of tightly linked genes that jointly produce complex phenotypes. Although widespread in nature, how such genomic elements are formed and how they spread are in most cases unclear. In the fire ant Solenopsis invicta and closely related species, a "social supergene controls whether a colony maintains one or multiple queens. Here, we show that the three inversions constituting the Social b (Sb) supergene emerged sequentially during the separation of the ancestral lineages of S. invicta and Solenopsis richteri. The two first inversions arose in the ancestral population of both species, while the third one arose in the S. richteri lineage. Once completely assembled in the S. richteri lineage, the supergene first introgressed into S. invicta, and from there into the other species of the socially polymorphic group of South American fire ant species. Surprisingly, the introgression of this large and important genomic element occurred despite recent hybridization being uncommon between several of the species. These results highlight how supergenes can readily move across species boundaries, possibly because of fitness benefits they provide and/or expression of selfish properties favoring their transmission.

Rapid Genetic Isolation Among Four Lineages Of Silene nutans.

Speciation is the process leading to the emergence of new species. While being usually progressive, it can sometimes be fast with rapid emergence of reproductive barriers leading to high level of reproductive isolation. Some reproductive barriers might leave signatures in the genome, through elevated level of genetic differentiation at specific loci. Similar signatures might also be the results of linked selection acting in low recombination regions. Nottingham catchfly (Silene nutans) is a Caryophyllaceae species composed of four genetically differentiated lineages for which strong and asymmetric levels of reproductive isolation have been identified. Using population transcriptomic data from several individuals of the four lineages, we inferred the best evo-demographic scenario leading to the current reproductive isolation of these four lineages. We also tested whether loci exhibiting high level of genetic differentiation represented barrier loci or were located in low recombination regions, evolving under strong influence of linked selection. Overall, the four lineages of S. nutans have diverged in strict isolation, likely during the different glacial period, through migration in distinct glacial refugia. Speciation between these four lineages appeared to be particularly fast, likely due to fast evolving plastid genome accelerating plastid-nuclear co-evolution and the probability of plastid-nuclear incompatibilities in inter-lineage hybrids.

Searching for genetic evidence of demographic decline in an arctic seabird: beware of overlapping generations.

Genetic data are useful for detecting sudden population declines in species that are difficult to study in the field. Yet this indirect approach has its own drawbacks, including population structure, mutation patterns, and generation overlap. The ivory gull (Pagophila eburnea), a long-lived Arctic seabird, is currently suffering from rapid alteration of its primary habitat (i.e., sea ice), and dramatic climatic events affecting reproduction and recruitment. However, ivory gulls live in remote areas, and it is difficult to assess the population trend of the species across its distribution. Here we present complementary microsatellite- and SNP-based genetic analyses to test a recent bottleneck genetic signal in ivory gulls over a large portion of their distribution. With attention to the potential effects of population structure, mutation patterns, and sample size, we found no significant signatures of population decline worldwide. At a finer scale, we found a significant bottleneck signal at one location in Canada. These results were compared with predictions from simulations showing how generation time and generation overlap can delay and reduce the bottleneck microsatellite heterozygosity excess signal. The consistency of the results obtained with independent methods strongly indicates that the species shows no genetic evidence of an overall decline in population size. However, drawing conclusions related to the species' population trends will require a better understanding of the effect of age structure in long-lived species. In addition, estimates of the effective global population size of ivory gulls were surprisingly low (~1000 ind.), suggesting that the evolutionary potential of the species is not assured.

Population collapse in viviparid gastropods of the Lake Victoria ecoregion started before the Last Glacial Maximum.

Ecosystems of Lake Victoria and riparian communities have been strongly disrupted by the introduction of the invasive Nile perch and its fishing industry. Beyond this invasion and other recent anthropogenic stressors, the Lake Victoria ecoregion also underwent phases of pronounced aridity over the Late Pleistocene, lastly during the Last Glacial Maximum (LGM). The consequences of recent and historic environmental change have been canvassed for the adaptive radiation of haplochromine cichlids occupying the ecoregion, but their effect on freshwater invertebrate diversity remains largely unknown. Here, we use 15 microsatellite loci and approximate Bayesian computation to test whether viviparid gastropods experienced a population bottleneck during the LGM, as did cichlids. Clustering analyses support three viviparid gene pools in the Lake Victoria ecoregion, gathering specimens from 1) Lake Albert and the White Nile, 2) the Victoria Nile and Lake Kyoga and 3) Lake Victoria and tributaries. The last group contains the highest genetic diversity, but all groups have a considerable number of private alleles and are inferred to predate the LGM. Examinations of demographic history reveal a 190- to 500-fold population decline that started ~ 125-150 ka ago, thus substantially before the LGM bottleneck documented in haplochromine cichlids. Population collapses in viviparids are an order of magnitude more severe than declines in cichlids and have not been halted by the re-establishment of freshwater ecosystems since the LGM. Recent anthropogenic ecosystem deterioration is causing homogenization of previously diversified microhabitats, which may contribute to (local) extinction and enhanced gene flow among species within gene pools.

ACPA-positive versus ACPA-negative rheumatoid arthritis: two distinct erosive disease entities on radiography and ultrasonography.

The objective of this study is to assess the prevalence, localization, and severity of bone erosions on radiography (RX) and ultrasonography (US) according to ACPA status in patients with rheumatoid arthritis (RA). 78 patients with ACPA-positive (ACPA+) RA and 30 patients with ACPA-negative (ACPA-) RA fulfilling the ACR 1987 and/or ACR/EULAR 2010 criteria were consecutively included. On RX, a modified Sharp erosion score (SHSe) was evaluated by two blinded readers and one adjudicator for discordant cases (number of eroded joints ≤ three). On US, erosions were scored on six bilateral joints (MCP2, 3, 5; MTP2, 3, 5) with a four-point scale to calculate the total US score for erosions (USSe). The mean total SHSe and USSe were 3.7 and 4.4 times higher in the ACPA+ group than in the ACPA- group, respectively (P < 0.001). On both RX and US, the most discriminating joint between the two groups was MTP5, especially in cases with bilateral erosion. Based on multivariate analyses, ACPA + status was associated with erosive RA on RX according to the EULAR 2013 definition criteria [OR 4.4 (95% CI 1.2-16.4)], and on US according to the following two definitions: the presence of at least two eroded joint facets [OR 3.7 (95% CI 1.4-9.9)] or at least one grade 2 joint facet erosion [OR 9.0 (95% CI 2.8-28.4)]. Compared to ACPA- RA, ACPA + RA is associated independently with more severe erosive disease on RX and US. Both US and RX bilateral erosions in MTP5 joints are highly discriminant for ACPA + RA patients (97.8% in US and 100% in RX).

Codon Usage Bias in Animals: Disentangling the Effects of Natural Selection, Effective Population Size, and GC-Biased Gene Conversion.

Selection on codon usage bias is well documented in a number of microorganisms. Whether codon usage is also generally shaped by natural selection in large organisms, despite their relatively small effective population size (Ne), is unclear. In animals, the population genetics of codon usage bias has only been studied in a handful of model organisms so far, and can be affected by confounding, nonadaptive processes such as GC-biased gene conversion and experimental artefacts. Using population transcriptomics data, we analyzed the relationship between codon usage, gene expression, allele frequency distribution, and recombination rate in 30 nonmodel species of animals, each from a different family, covering a wide range of effective population sizes. We disentangled the effects of translational selection and GC-biased gene conversion on codon usage by separately analyzing GC-conservative and GC-changing mutations. We report evidence for effective translational selection on codon usage in large-Ne species of animals, but not in small-Ne ones, in agreement with the nearly neutral theory of molecular evolution. C- and T-ending codons tend to be preferred over synonymous G- and A-ending ones, for reasons that remain to be determined. In contrast, we uncovered a conspicuous effect of GC-biased gene conversion, which is widespread in animals and the main force determining the fate of AT↔GC mutations. Intriguingly, the strength of its effect was uncorrelated with Ne.

Assessment of the effect of continuous theta burst stimulation of the motor cortex on manual dexterity in non-human primates in a direct comparison with invasive intracortical pharmacological inactivation.

Non-invasive reversible perturbation techniques of brain output such as continuous theta burst stimulation (cTBS), commonly used to modulate cortical excitability in humans, allow investigation of possible roles in functional recovery played by distinct intact cortical areas following stroke. To evaluate the potential of cTBS, the behavioural effects of this non-invasive transient perturbation of the hand representation of the primary motor cortex (M1) in non-human primates (two adult macaques) were compared with an invasive focal transient inactivation based on intracortical microinfusion of GABA-A agonist muscimol. The effects on the contralateral arm produced by cTBS or muscimol were directly compared based on a manual dexterity task performed by the monkeys, the "reach and grasp" drawer task, allowing quantitative assessment of the grip force produced between the thumb and index finger and exerted on the drawer's knob. cTBS only induced modest to moderate behavioural effects, with substantial variability on manual dexterity whereas the intracortical muscimol microinfusion completely impaired manual dexterity, producing a strong and clear cortical inhibition of the M1 hand area. In contrast, cTBS induced mixed inhibitory and facilitatory/excitatory perturbations of M1, though with predominant inhibition. Although cTBS impacted on manual dexterity, its effects appear too limited and variable in order to use it as a reliable proof of cortical vicariation mechanism (cortical area replacing another one) underlying functional recovery following a cortical lesion in the motor control domain, in contrast to potent pharmacological block generated by muscimol infusion, whose application is though limited to an animal model such as non-human primate.

The opposing effects of genetic drift and Haldane's sieve on floral-morph frequencies in tristylous metapopulations.

Tristyly is a genetic floral polymorphism in which three floral morphs are maintained at equal frequencies by negative frequency-dependent selection on alleles at two interacting loci. Because dominant alleles at these loci are maintained at a lower frequency than their recessive counterparts, they are more likely to be lost by founder events and genetic drift. Here we examine the hypothesis that dominant alleles under negative frequency-dependent selection should also be more likely to re-invade populations than recessive alleles, due to Haldane's Sieve, because recessive alleles not expressed in a heterozygote state cannot benefit from positive selection when rare. We used computer simulations of tristylous metapopulations to verify that Haldane's Sieve acting on migrants into occupied demes can indeed reverse the bias in allele frequencies expected for small single tristylous populations, particularly in situations of rapid population growth following colonisation. This effect is manifest both locally and at the metapopulation level. Our study illustrates the potential effect of Haldane's Sieve in the novel context of an iconic plant sexual-system polymorphism under the influence of metapopulation dynamics.

Shedding Light on the Grey Zone of Speciation along a Continuum of Genomic Divergence.

Speciation results from the progressive accumulation of mutations that decrease the probability of mating between parental populations or reduce the fitness of hybrids-the so-called species barriers. The speciation genomic literature, however, is mainly a collection of case studies, each with its own approach and specificities, such that a global view of the gradual process of evolution from one to two species is currently lacking. Of primary importance is the prevalence of gene flow between diverging entities, which is central in most species concepts and has been widely discussed in recent years. Here, we explore the continuum of speciation thanks to a comparative analysis of genomic data from 61 pairs of populations/species of animals with variable levels of divergence. Gene flow between diverging gene pools is assessed under an approximate Bayesian computation (ABC) framework. We show that the intermediate "grey zone" of speciation, in which taxonomy is often controversial, spans from 0.5% to 2% of net synonymous divergence, irrespective of species life history traits or ecology. Thanks to appropriate modeling of among-locus variation in genetic drift and introgression rate, we clarify the status of the majority of ambiguous cases and uncover a number of cryptic species. Our analysis also reveals the high incidence in animals of semi-isolated species (when some but not all loci are affected by barriers to gene flow) and highlights the intrinsic difficulty, both statistical and conceptual, of delineating species in the grey zone of speciation.

Clathrin Heavy Chain Subunits Coordinate Endo- and Exocytic Traffic and Affect Stomatal Movement.

The current model for vesicular traffic to and from the plasma membrane is accepted, but the molecular requirements for this coordination are not well defined. We have identified the hot ABA-deficiency suppressor1 mutant, which has a stomatal function defect, as a clathrin heavy chain1 (CHC1) mutant allele and show that it has a decreased rate of endocytosis and growth defects that are shared with other chc1 mutant alleles. We used chc1 alleles and the related chc2 mutant as tools to investigate the effects that clathrin defects have on secretion pathways and plant growth. We show that secretion and endocytosis at the plasma membrane are sensitive to CHC1 and CHC2 function in seedling roots and that chc mutants have physiological defects in stomatal function and plant growth that have not been described previously. These findings suggest that clathrin supports specific functions in multiple cell types. Stomata movement and gas exchange are altered in chc mutants, indicating that clathrin is important for stomatal regulation. The aberrant function of chc mutant stomata is consistent with the growth phenotypes observed under different water and light conditions, which also are similar to those of the secretory SNARE mutant, syp121 The syp121 and chc mutants have impaired endocytosis and exocytosis compared with the wild type, indicating a link between SYP121-dependent secretion and clathrin-dependent endocytosis at the plasma membrane. Our findings provide evidence that clathrin and SYP121 functions are important for the coordination of endocytosis and exocytosis and have an impact on stomatal function, gas exchange, and vegetative growth in Arabidopsis (Arabidopsis thaliana).

Extensive recent secondary contacts between four European white oak species.

Historical trajectories of tree species during the late Quaternary have been well reconstructed through genetic and palaeobotanical studies. However, many congeneric tree species are interfertile, and the timing and contribution of introgression to species divergence during their evolutionary history remains largely unknown. We quantified past and current gene flow events between four morphologically divergent oak species (Quercus petraea, Q. robur, Q. pyrenaica, Q. pubescens), by two independent inference methods: diffusion approximation to the joint frequency spectrum (∂a∂i) and approximate Bayesian computation (ABC). For each pair of species, alternative scenarios of speciation allowing gene flow over different timescales were evaluated. Analyses of 3524 single nucleotide polymorphisms (SNPs) randomly distributed in the genome, showed that these species evolved in complete isolation for most of their history, but recently came into secondary contact, probably facilitated by the most recent period of postglacial warming. We demonstrated that: there was sufficient genetic differentiation before secondary contact for the accumulation of barriers to gene flow; and current European white oak genomes are a mosaic of genes that have crossed species boundaries and genes impermeable to gene flow.

Inferring the mode of origin of polyploid species from next-generation sequence data.

Many eukaryote organisms are polyploid. However, despite their importance, evolutionary inference of polyploid origins and modes of inheritance has been limited by a need for analyses of allele segregation at multiple loci using crosses. The increasing availability of sequence data for nonmodel species now allows the application of established approaches for the analysis of genomic data in polyploids. Here, we ask whether approximate Bayesian computation (ABC), applied to realistic traditional and next-generation sequence data, allows correct inference of the evolutionary and demographic history of polyploids. Using simulations, we evaluate the robustness of evolutionary inference by ABC for tetraploid species as a function of the number of individuals and loci sampled, and the presence or absence of an outgroup. We find that ABC adequately retrieves the recent evolutionary history of polyploid species on the basis of both old and new sequencing technologies. The application of ABC to sequence data from diploid and polyploid species of the plant genus Capsella confirms its utility. Our analysis strongly supports an allopolyploid origin of C. bursa-pastoris about 80 000 years ago. This conclusion runs contrary to previous findings based on the same data set but using an alternative approach and is in agreement with recent findings based on whole-genome sequencing. Our results indicate that ABC is a promising and powerful method for revealing the evolution of polyploid species, without the need to attribute alleles to a homeologous chromosome pair. The approach can readily be extended to more complex scenarios involving higher ploidy levels.

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.

Threshold levels of visual field and acuity loss related to significant decreases in the quality of life and emotional states of patients with retinitis pigmentosa.

INTRODUCTION: Retinitis pigmentosa (RP) is an inherited retinal disorder, characterized by photoreceptor degeneration inducing progressive vision loss. This study evaluates its impact on quality of life (QOL) and emotional states of patients affected by RP. METHODS: A cross-sectional study was conducted on 60 RP patients diagnosed with rod-cone dystrophy and on 20 control subjects. The RP population has been divided into 3 groups according to visual field (VF) and visual acuity (VA) impairments. Concurrently, scores of self-reported QOL (25-item National Eye Institute Visual Functioning Questionnaire) and of the Hospital Anxiety and Depression Scale for anxiety/depression assessments were collected. RESULTS: For the QOL composite score, we noticed consistent differences between all VF and VA affected groups and their control group. We also found significant differences between both the most affected VF group (VF1: ØVF <20°) and VA group (VA1: VA <0.3) compared to other VF and VA groups. For anxiety/depression scores, consistent differences have been found between the control group and VF1 and VA1, respectively. CONCLUSIONS: This work determines that, for RP patients, a significant QOL and emotional state deterioration correlates with a residual VF diameter below 20° and a VA lower than 0.3. It introduces, for the first time, thresholds to be used in visual restoration or visual preservation therapies to improve QOL of RP patients.

Crossing the species barrier: genomic hotspots of introgression between two highly divergent Ciona intestinalis species.

Inferring a realistic demographic model from genetic data is an important challenge to gain insights into the historical events during the speciation process and to detect molecular signatures of selection along genomes. Recent advances in divergence population genetics have reported that speciation in face of gene flow occurred more frequently than theoretically expected, but the approaches used did not account for genome-wide heterogeneity (GWH) in introgression rates. Here, we investigate the impact of GWH on the inference of divergence with gene flow between two cryptic species of the marine model Ciona intestinalis by analyzing polymorphism and divergence patterns in 852 protein-coding sequence loci. These morphologically similar entities are highly diverged molecular-wise, but evidence of hybridization has been reported in both laboratory and field studies. We compare various speciation models and test for GWH under the approximate Bayesian computation framework. Our results demonstrate the presence of significant extents of gene flow resulting from a recent secondary contact after >3 My of divergence in isolation. The inferred rates of introgression are relatively low, highly variable across loci and mostly unidirectional, which is consistent with the idea that numerous genetic incompatibilities have accumulated over time throughout the genomes of these highly diverged species. A genomic map of the level of gene flow identified two hotspots of introgression, that is, large genome regions of unidirectional introgression. This study clarifies the history and degree of isolation of two cryptic and partially sympatric model species and provides a methodological framework to investigate GWH at various stages of speciation process.

Recent and ancient signature of balancing selection around the S-locus in Arabidopsis halleri and A. lyrata.

Balancing selection can maintain different alleles over long evolutionary times. Beyond this direct effect on the molecular targets of selection, balancing selection is also expected to increase neutral polymorphism in linked genome regions, in inverse proportion to their genetic map distances from the selected sites. The genes controlling plant self-incompatibility are subject to one of the strongest forms of balancing selection, and they show clear signatures of balancing selection. The genome region containing those genes (the S-locus) is generally described as nonrecombining, and the physical size of the region with low recombination has recently been established in a few species. However, the size of the region showing the indirect footprints of selection due to linkage to the S-locus is only roughly known. Here, we improved estimates of this region by surveying synonymous polymorphism and estimating recombination rates at 12 flanking region loci at known physical distances from the S-locus region boundary, in two closely related self-incompatible plants Arabidopsis halleri and A. lyrata. In addition to studying more loci than previous studies and using known physical distances, we simulated an explicit demographic scenario for the divergence between the two species, to evaluate the extent of the genomic region whose diversity departs significantly from neutral expectations. At the closest flanking loci, we detected signatures of both recent and ancient indirect effects of selection on the S-locus flanking genes, finding ancestral polymorphisms shared by both species, as well as an excess of derived mutations private to either species. However, these effects are detected only in a physically small region, suggesting that recombination in the flanking regions is sufficient to quickly break up linkage disequilibrium with the S-locus. Our approach may be useful for distinguishing cases of ancient versus recently evolved balancing selection in other systems.

Compound heterozygous mutations in the kinase domain of IKKα lead to immunodeficiency and immune dysregulation.

IKKα, encoded by CHUK , is crucial in the non-canonical NF-κB pathway and part of the IKK complex activating the canonical pathway alongside IKKß. Absence of IKKα cause fetal encasement syndrome in human, fatal in utero, while an impaired IKKα-NIK interaction was reported in a single patient and cause combined immunodeficiency. Here, we describe compound heterozygous variants in the kinase domain of IKKα in a female patient with hypogammaglobulinemia, recurrent lung infections, and Hay-Wells syndrome-like features. We showed that both variants were loss-of-function. Non-canonical NF-κB activation was profoundly diminished in stromal and immune cells while the canonical pathway was partially impaired. Reintroducing wild-type CHUK restored non-canonical NF-κB activation. The patient had neutralizing autoantibodies against type I IFN, akin to non-canonical NF-κB pathway deficiencies. Thus, this is the first case of bi-allelic CHUK mutations disrupting IKKα kinase function, broadening non-canonical NF-κB defect understanding and suggesting IKKα's role in canonical NF-κB target gene expression in human.

Inferring the Demographic History and Inheritance Mode of Tetraploid Species Using ABC.

Genomic patterns of diversity and divergence are impacted by certain life history traits, reproductive systems, and demographic history. The latter is characterized by fluctuations in population sizes over time, as well as by temporal patterns of introgression. For a given organism, identifying a demographic history that deviates from the standard neutral model allows a better understanding of its evolution but also helps to reduce the risk of false positives when screening for molecular targets of natural selection. Tetraploid organisms and beyond have demographic histories that are complicated by the mode of polyploidization, the mode of inheritance, and different scenarios of gene flow between sub-genomes and diploid parental species. Here we provide guidelines for experimenters wishing to address these issues through a flexible statistical framework: approximate Bayesian computation (ABC). The emphasis is on the general philosophy of the approach to encourage future users to exploit the enormous flexibility of ABC beyond the limitations imposed by generalist data analysis pipelines.

Skin Testing and Drug Provocation Tests in Epidermal Necrolysis: A French Experience.

BACKGROUND: There are limited data on the use of skin testing, other than patch testing, and challenges in the evaluation of epidermal necrolysis (EN), including Stevens-Johnson syndrome and toxic epidermal necrolysis. OBJECTIVE: To report a French multicenter experience in skin testing and challenges in EN, and investigate the factors associated with tests' positivity. METHODS: All patients who were evaluated by patch tests (PTs), skin prick tests, intradermal tests (IDTs), or drug provocation tests (DPTs) for EN between 2010 and 2020 were retrospectively included through 2 French drug reaction networks. RESULTS: In total, 113 patients were included from 8 centers. Median (interquartile range) time from EN to hypersensitivity workup was 7.9 months (5.1-15 months). All patients had PTs, 17 (15%) had skin prick tests or IDTs with delayed readings and 32 (28.3%) had DPTs. One mild reaction occurred after a DPT. Overall, 22 patients (19.5%) had positive PTs, and the only factors associated with positivity were Algorithm of Drug Causality for Epidermal Necrolysis (ALDEN) score and drug class. Only 1 IDT was positive but considered irrelevant. The DPTs were never performed to prove responsibility of a highly suspected drug but were used to confirm current tolerance of needed medications. CONCLUSIONS: Allergological workup in EN, performed by specialists involved in EN, seems safe. Skin tests, although of limited sensitivity, can be helpful for considering the reintroduction of essential drugs according to a benefit-to-risk decision. We propose an algorithm for approaching hypersensitivity testing in patients with EN, to be adapted to each patient.