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EscaPRRS-ORF5: a structure-aware evolutionary framework for prioritizing immune escape-prone variants in porcine reproductive and respiratory syndrome virus.

MOTIVATION: Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) is a rapidly evolving RNA virus causing significant economic losses, posing a formidable challenge to vaccine efficacy due to its high mutational variability and immune escape. As the viral mutants evolve, their ability to sustain in population is driven by a range of host biology factors such as receptor binding, fusion, and uncoating. Existing tools that predict viral fitness and escape propensities rely heavily on extensive, up-to-date sequence data and lack integration of biochemical host interactions, limiting mechanistic understanding of the mutational landscape. We introduce Esca, a sequence-only toolchain framework that identifies immune escape-prone residues by exhaustively scanning each residue position for all amino acid substitutions using a Bayesian Variational Autoencoder (VAE) trained on protein language model embeddings. We demonstrate Esca on the GP5(ORF5) glycoprotein of PRRSV (EscaPRRS-ORF5) by training on ESM-2 embeddings of 32 146 GP5 sequences (2015-2022) spanning 140 sub-lineages. RESULTS: Despite being trained only on GP5 sequence data, EscaPRRS-ORF5 recovered 85.7% of the surface-exposed receptor binding interfaces as escape-prone regions. We use a mutation-sensitive fitness scoring scheme that goes beyond Hamming distances, to predict antibody escape tendencies, supporting surveillance of (re) emerging PRRSV variants. We do not claim that ORF5 alone captures PRRSV evolution or serves as a surveillance endpoint; rather, Esca offers a scalable path toward whole-genome, structure-aware surveillance. AVAILABILITY AND IMPLEMENTATION: EscaPRRS-ORF5 is freely available at https://doi.org/10.6084/m9.figshare.32661033 with an interactive Colab notebook at https://colab.research.google.com/drive/1TEgzAhPwvNAZ01VXeJbIFibfri2jnDA5? usp=sharing.

Porcine respiratory and reproductive syndrome viru↗

Molecular phylogenetics of the exoneurine allodapine bees reveal an ancient and puzzling dispersal from Africa to Australia.

Previous phylogenetic studies of the bee tribe Allodapini suggested a puzzling biogeographic problem: one of the key basal divergences involved separation of the southern African and southern Australian clades at a very early stage in allodapine evolution, but no taxa occur in the Palaearctic or Asian regions that might suggest a Laurasian dispersal route. However, these studies lacked sufficient sequence data and appropriate maximum likelihood partition models to provide reliable phylogenetic estimates and enable alternative biogeographic hypotheses to be distinguished. Using Bayesian and penalized likelihood approaches and an expanded sequence and taxon set we examine phylogenetic relationships between the Australian, African, and Malagasy groups and estimate divergence times for key nodes. We show that divergence of the three basal Australian clades (known as the exoneurines) occurred at least 25 Mya following a single colonization event, and that this group diverged from the African + Madagascan clade at least 30 Mya, but actual divergence dates are likely to be much older than these very conservative limits. The bifurcation order of the exoneurine clades was not resolved and analyses could not rule out the existence of a hard polytomy, suggesting rapid radiation after colonization of Australia. Their divergence involved major transitions in life history traits and these placed constraints on the kinds of social organization that subsequently evolved in each lineage. Early divergence between the African, Malagasy, and Australian clades presents a major puzzle for historical biogeography: node ages are too recent for Gondwanan vicariance hypotheses, but too early for Laurasian dispersal scenarios. We suggest a scenario involving island hopping across the Indian Ocean via a series of now largely submerged elements of the Kergulen Plateau and Broken Ridge provinces, both of which are known to have had subaerial formations during the Cenozoic. [Bayesian; biogeography; dispersal; Gondwana; Kerguelen Plateau; penalized likelihood.].

Africa↗

Pharmacokinetic-pharmacodynamic relationships describing the efficacy of oritavancin in patients with Staphylococcus aureus bacteremia.

Bloodstream infections due to antimicrobial-resistant Staphylococcus aureus occur with increasing frequency and represent an important cause of morbidity and mortality. To date, the evaluation of pharmacokinetic-pharmacodynamic relationships for efficacy among patients with bacteremia has been limited. The objectives of these analyses were to evaluate relationships between microbiological and clinical responses for patients with S. aureus bacteremia and exposures for oritavancin, a novel bactericidal glycopeptide in development. Bayesian oritavancin exposure predictions, following treatment with 5, 6.5, 8, or 10 mg/kg of body weight/day, were derived using a validated population pharmacokinetic model for 55 patients with S. aureus bacteremia. Using classification and regression tree analysis, a breakpoint of the percentage of the dosing interval duration for which free-drug concentrations were above the MIC (free-drug % time > MIC) of 22% was identified for microbiological response; the probabilities of success greater than or equal to and less than this value were 93% and 76%, respectively. Using logistic regression, a relationship was found between microbiological response and free-drug % time > MIC (odds ratio = 4.42, P = 0.09, and odds ratio = 8.84, P = 0.05, when one patient, a medical outlier, was excluded). A similar relationship was found for clinical response. These results will be valuable in supporting dose selection of oritavancin for patients with S. aureus bacteremia.

Anti-Bacterial Agents↗

Inference of viral evolutionary rates from molecular sequences.

The processes of mutation and nucleotide substitution contribute to the observed variability in virulence, transmission and persistence of viral pathogens. Since most viruses evolve many times faster than their human hosts, we are in the unusual position of being able to measure these processes directly by comparing viral genes that have been isolated and sequenced at different points in time. The analysis of such data requires the use of specific statistical methods that take into account the shared ancestry of the sequences and the randomness inherent in the process of nucleotide substitution. In this paper we describe the various statistical methods for estimating evolutionary rates, which can be classified into three general approaches: linear regression, maximum likelihood, and Bayesian inference. We discuss the advantages and shortcomings of each approach and illustrate their use through the analysis of two example viruses; human immunodeficiency virus type 1 and dengue virus serotype 4. Reliable estimates of viral substitution rates have many important applications in population genetics and phylogenetics, including dating evolutionary events and divergence times, estimating demographic parameters such as population size and generation time, and investigating the effect of natural selection on molecular evolution.

Base Sequence↗

Introgression in natural populations of bioindicators: a case study of Carabus splendens and Carabus punctatoauratus.

The evolutionary importance of hybridization in wild plants and animals has become increasingly widely recognized in the last decade. In practical terms, hybridization provides an exceptionally tough set of problems for conservation biologists. We illustrate this in a case study of two Carabidae species widely used to evaluate the impact of human activities on biodiversity. These two species live in a complex mosaic of sympatry/allopatry and are known to hybridize in controlled conditions. Hybridization has not been quantified in natural populations to date due to the lack of a simple set of phenotypic traits for identifying hybrids. We thus screened for hybrids in natural populations, by multilocus genotyping at nine microsatellite loci. A high level of genetic differentiation between these two taxa was observed, as shown by allelic frequency distributions. Two Bayesian assignment procedures without obligatory pure taxon references were used to infer different classes of hybrids (F(1), F(2) and backcrosses) and mixture proportions between the two species. A low level of hybridization (F(1) genotypes) was observed in natural populations, contrasting with results obtained in controlled conditions. A high level of introgression was, however, detected at three of 12 sites, as revealed by the detection of backcrossed genotypes. This interspecific gene flow was detected in a limited zone of the common geographical range of the two species and was not related to the pattern of sympatry/allopatry. We then considered the origin and repercussions of this introgression, based on intraspecific genetic diversity and geographical structure.

Animals↗

Nonparametric prediction of event times in randomized clinical trials.

In clinical trials with planned interim analysis, it can be valuable for logistical reasons to predict the times of landmark events such as the 50th and 100th event. Bagiella and Heitjan (Stat Med 2001; 20: 2055-63) proposed a parametric prediction model for failure-time outcomes assuming exponential survival and Poisson enrollment. When little is known about the distributions of interest, there is concern that parametric prediction methods may be biased and inefficient if their underlying distributional assumptions are invalid. We propose nonparametric approaches to make point and interval predictions for landmark dates during the course of the trial. We obtain point predictions using the Kaplan-Meier estimator to extrapolate the survival probability into the future, selecting the time when the expected number of events is equal to the landmark number. To construct prediction intervals, we use a simulation strategy based on the Bayesian bootstrap. Monte Carlo results demonstrate the superiority of the nonparametric method when the assumptions underlying the parametric model are incorrect. We demonstrate the methods using data from a trial of immunotherapy of chronic granulomatous disease.

Granulomatous Disease, Chronic↗

A molecular time-scale for eukaryote evolution recalibrated with the continuous microfossil record.

Recent attempts to establish a molecular time-scale of eukaryote evolution failed to provide a congruent view on the timing of the origin and early diversification of eukaryotes. The major discrepancies in molecular time estimates are related to questions concerning the calibration of the tree. To limit these uncertainties, we used here as a source of calibration points the rich and continuous microfossil record of dinoflagellates, diatoms and coccolithophorids. We calibrated a small-subunit ribosomal RNA tree of eukaryotes with four maximum and 22 minimum time constraints. Using these multiple calibration points in a Bayesian relaxed molecular clock framework, we inferred that the early radiation of eukaryotes occurred near the Mesoproterozoic-Neoproterozoic boundary, about 1100 million years ago. Our results indicate that most Proterozoic fossils of possible eukaryotic origin cannot be confidently assigned to extant lineages and should therefore not be used as calibration points in molecular dating.

Amoeba↗

Probabilistic reasoning in obsessive-compulsive and delusional disorders.

BACKGROUND: Delusional disorder (DD) and obsessive-compulsive disorder (OCD) have been investigated in previous studies using probabilistic reasoning paradigms and abnormalities in each group have been reported. No study to date has compared results between these groups. This study compares patients with these disorders with those who have both phenomena. METHODS: Thirty subjects with DD, 29 with OCD and 16 with obsessive and delusional features were compared with 30 normal controls in a study of probabilistic reasoning using two different computer-based tasks involving a Bayesian paradigm. RESULTS: Deluded subjects showed a 'jump to conclusions' reasoning style, but on a test that added a consequence to their choices did not differ from normals. OCD subjects deviated from Bayesian and control norms to a greater degree than did DD subjects. In subjects with mixed psychopathology, the presence of both phenomena appeared to 'normalize' these probability estimates. CONCLUSIONS: Our findings extend those of others but require cautious interpretation as to the role of probabilistic reasoning in the genesis of delusions or obsessions. Obsessionals in both the OCD and Mixed groups, showed substantial deviation from Bayesian norms, suggesting that obsessionality leads to a reasoning style that is less 'normal' than that of delusionals. Further work is required to investigate clinical correlates of these findings which provide modest support for the proposal that the combination of obsessions and delusions confers greater functional advantages than simply having delusions or obsessions.

Adult↗

Probabilistic small area risk assessment using GIS-based data: a case study on Finnish childhood diabetes. Geographic information systems.

A Bayesian hierarchical spatial model is constructed to describe the regional incidence of insulin dependent diabetes mellitus (IDDM) among the under 15-year-olds in Finland. The model exploits aggregated pixel-wise locations for both the cases and the population at risk. Typically such data arise from combining geographic information systems (GIS) with large databases. The dates of diagnosis and locations of the cases are observed from 1987 to 1996. The population at risk counts are available for every second year during the same period. A hierarchical model is suggested for the pixel wise case counts, including a population model to account for the uncertainty of the population at risk over the years. The model is applied in the construction of disease maps (aggregated 100 km(2) pixels), and spatial posterior predictive distributions are computed to study whether there can be found a statistically exceptional number of cases in a small area of interest.

Bayes Theorem↗

Phylogenetic relationships, divergence time estimation, and global biogeographic patterns of calopterygoid damselflies (odonata, zygoptera) inferred from ribosomal DNA sequences.

The calopterygoid superfamily (Calopterygidae + Hetaerinidae) is composed of more than twenty genera in two families: the Calopterygidae (at least 17) and the Hetaerinidae (at least 4). Here, 62 calopterygoid (ingroup) taxa representing 18 genera and 15 outgroup taxa are subjected to phylogenetic analysis using the ribosomal 18S and 5.8S genes and internal transcribed spacers (ITS1, ITS2). The five other families of calopterid affinity (Polythoridae, Dicteriadidae, Amphipterygidae, Euphaeidae, and Chlorocyphidae) are included in the outgroup. For phylogenetic inference, we applied maximum parsimony, maximum likelihood, and the Bayesian inference methods. A molecular phylogeny combined with a geographic analysis produced a well-supported phylogenetic hypothesis that partly confirms the traditional taxonomy and describes distributional patterns. A monophyletic origin of the calopterygoids emerges, revealing the Hetaerinid clade as sister group to the Calopterygidae sensu strictu. Within Calopterygidae, seven clades of subfamily rank are recognized. Phylogenetic dating was performed with semiparametric rate smoothing by penalized likelihood, using seven reference fossils for calibration. Divergence time based on the ribosomal genes and spacers and fossil constraints indicate that Calopteryginae (10 genera, approximately 50% of all Calopterygid taxa studied here), Vestalinae (1 genus), and Hetaerinidae (1 genus out of 4 studied here) started radiating around 65 Mya (K/T boundary). The South American Iridictyon (without distinctive morphology except for wing venation) and Southeast Asian Noguchiphaea (with distinctive morphology) are older (about 86 My) and may be survivors of old clades with a Gondwanian range that went extinct at the K/T boundary. The same reasoning (and an even older age, ca. 150 My) applies to the amphipterygids Rimanella and Pentaphlebia (South America-Africa). The extant Calopterygidae show particular species and genus richness between west China and Japan, with genera originating between the early Oligocene and Pleistocene. Much of that richness probably extended much wider in preglacial times. The Holarctic Calopteryx, of Miocene age, was deeply affected by the climatic cooling of the Pliocene and by the Pleistocene glaciations. Its North American and Japanese representatives are of Miocene and Pliocene age, respectively, but its impoverished Euro-Siberian taxa are late Pliocene-Pleistocene, showing reinvasion, speciation, and introgression events. The five other calopterid families combine with the Calopterygidae and Hetaerinidae to form the monophyletic cohort Caloptera, with Polythoridae, Dicteriadidae, and Amphipterygidae sister group to Calopterygoidea. The crown node age of the latter three families has an age of about 157 My, but the Dicteriadidae and Polythoridae themselves are of Eocene age, and the same is true for the Euphaeidae and Chlorocyphidae. The cohort Caloptera itself, with about 197 My of age, goes back to the early Jurassic.

Animals↗

Phylogenomics and the number of characters required for obtaining an accurate phylogeny of eukaryote model species.

MOTIVATION: Through the most extensive phylogenomic analysis carried out to date, complete genomes of 11 eukaryotic species have been examined in order to find the homologous of more than 25,000 amino acid sequences. These sequences correspond to the exons of more than 3000 genes and were used as presence/absence characters to test one of the most controversial hypotheses concerning animal evolution, namely the Ecdysozoa hypothesis. Distance, maximum parsimony and Bayesian methods of phylogenetic reconstruction were used to test the hypothesis. RESULTS: The reliability of the ecdysozoa, grouping arthropods and nematodes in a single clade was unequivocally rejected in all the consensus trees. The Coelomata clade, grouping arthropods and chordates, was supported by the highest statistical confidence in all the reconstructions. The study of the dependence of the genomes' tree accuracy on the number of exons used, demonstrated that an unexpectedly larger number of characters are necessary to obtain robust phylogenies. Previous studies supporting ecdysozoa, could not guarantee an accurate phylogeny because the number of characters used was clearly below the minimum required.

Animals↗

A new method for computing the multipoint posterior probability of linkage.

The posterior probability of linkage (PPL) is a Bayesian statistic which directly measures the probability of linkage between a trait locus and a marker (in the 2-point case) or a genomic region (in the multipoint case). It has several benefits, including ease of interpretation, the ability to incorporate prior genomic information, and a mathematically rigorous and robust procedure for accumulating linkage information across multiple heterogeneous datasets. To date, the majority of work on the PPL has focused on the development of the 2-point statistic, with only preliminary attempts at the development of an equivalent multipoint version. In this paper we present a new way of computing of the multipoint PPL. This new version imputes to each genomic point an estimate of the 2-point PPL we would have obtained from a fully informative marker giving similar evidence for linkage. This version, which we call the imputed PPL, is shown to be superior to previously developed versions.

Bayes Theorem↗

Further use of nearly complete 28S and 18S rRNA genes to classify Ecdysozoa: 37 more arthropods and a kinorhynch.

This work expands on a study from 2004 by Mallatt, Garey, and Shultz [Mallatt, J.M., Garey, J.R., Shultz, J.W., 2004. Ecdysozoan phylogeny and Bayesian inference: first use of nearly complete 28S and 18S rRNA gene sequences to classify the arthropods and their kin. Mol. Phylogenet. Evol. 31, 178-191] that evaluated the phylogenetic relationships in Ecdysozoa (molting animals), especially arthropods. Here, the number of rRNA gene-sequences was effectively doubled for each major group of arthropods, and sequences from the phylum Kinorhyncha (mud dragons) were also included, bringing the number of ecdysozoan taxa to over 80. The methods emphasized maximum likelihood, Bayesian inference and statistical testing with parametric bootstrapping, but also included parsimony and minimum evolution. Prominent findings from our combined analysis of both genes are as follows. The fundamental subdivisions of Hexapoda (insects and relatives) are Insecta and Entognatha, with the latter consisting of collembolans (springtails) and a clade of proturans plus diplurans. Our rRNA-gene data provide the strongest evidence to date that the sister group of Hexapoda is Branchiopoda (fairy shrimps, tadpole shrimps, etc.), not Malacostraca. The large, Pancrustacea clade (hexapods within a paraphyletic Crustacea) divided into a few basic subclades: hexapods plus branchiopods; cirripedes (barnacles) plus malacostracans (lobsters, crabs, true shrimps, isopods, etc.); and the basally located clades of (a) ostracods (seed shrimps) and (b) branchiurans (fish lice) plus the bizarre pentastomids (tongue worms). These findings about Pancrustacea agree with a recent study by Regier, Shultz, and Kambic that used entirely different genes [Regier, J.C., Shultz, J.W., Kambic, R.E., 2005a. Pancrustacean phylogeny: hexapods are terrestrial crustaceans and maxillopods are not monophyletic. Proc. R. Soc. B 272, 395-401]. In Malacostraca, the stomatopod (mantis shrimp) was not at the base of the eumalacostracans, as is widely claimed, but grouped instead with an euphausiacean (krill). Within centipedes, Craterostigmus was the sister to all other pleurostigmophorans, contrary to the consensus view. Our trees also united myriapods (millipedes and centipedes) with chelicerates (horseshoe crabs, spiders, scorpions, and relatives) and united pycnogonids (sea spiders) with chelicerates, but with much less support than in the previous rRNA-gene study. Finally, kinorhynchs joined priapulans (penis worms) at the base of Ecdysozoa.

Animals↗

Molecular phylogeny of musk deer: a genomic view with mitochondrial 16S rRNA and cytochrome b gene.

The phylogenetic status of the infra order Pecora is controversial, even though it is supported by paleontological, morphological, and molecular evidence. We analyzed two mitochondrial genes (i.e., 16S rRNA and cytochrome b) to resolve the phylogenetic position of pecoran species, i.e., the Bovidae, Cervidae, and Moschidae endemic to the Indian subcontinent. We used phylogenetic analysis based on different algorithms, including neighbor joining, maximum parsimony, Bayesian inference, maximum likelihood, minimum evolution, median joining network, along with multidimensional scaling, and DNA word analysis. Our results established the basal position of Tragulidae and the monophyly of the infra order Pecora within the Suborder Ruminantia. Our results also demonstrated that Bovidae, Cervidae, and Moschidae are allied with the placement of musk deer as more closely related to bovids than to cervids. Molecular dating based on sequence analysis shows that the radiation of Pecora occurred during the early Oligocene and that the majority of the pecoran families radiated and dispersed rapidly during the Oligocene/Miocene transition.

Animals↗

Statistical distributions of uncertainty and variability in activated sludge model parameters.

All models used in activated sludge design and analysis use parameters to characterize process performance. The values of these parameters are often assumed based on default values recommended in the literature, but to date, no quantitative estimates of the parameter uncertainties have been published. Similarly, little attention has been given to quantifying site-specific parameter variability, even though its occurrence has been observed several times in the literature. In this paper, universal uncertainty distributions of the model parameters from Activated Sludge Model No. 1 are developed from a database of parameter values reported in the literature using Bayesian statistics. Site-specific distributions of parameter variability were developed using the same techniques. All parameter distributions developed demonstrated that significant uncertainty and variability exist, which could lead to overdesign or plant failure if not considered during the design process.

Bayes Theorem↗

The phylogenetic history and biogeography of the frankincense and myrrh family (Burseraceae) based on nuclear and chloroplast sequence data.

Generalized hypotheses for the vicariant, Gondwanan origin of pantropically distributed eudicotyledon families must be refined to accommodate recently revised dates that indicate major continental rifting events predate the evolution of many tricolpate angiosperm clades. Here, we use molecular phylogenies of an eudicotyledon family previously hypothesized to have a Gondwanan origin, the Burseraceae, to test this and other alternative biogeographical hypotheses in light of recalibrated geological events. Phylogenies based on nuclear and chloroplast data were reconstructed for 13 of the 18 genera (50 spp. total) of Burseraceae using parsimony, maximum likelihood, and Bayesian methods. Ages of all lineages were estimated using penalized likelihood and semiparametric rate smoothing [Bioinformatics 2003 (19) 301], which allows the user to calibrate phylogenies based on non-clock-like DNA sequence data with fossil information. Biogeographical hypotheses were tested by comparing ages of species and more inclusive lineages with their extant and most parsimonious ancestral distributions. Our data support a North American Paleocene origin for the Burseraceae followed by dispersal of ancestral lineages to eastern Laurasia and Southern Hemisphere continents.

Base Sequence↗

Source population of dispersing rock-wallabies (Petrogale lateralis) identified by assignment tests on multilocus genotypic data.

The ability to confidently identify or exclude a population as the source of an individual has numerous powerful applications in molecular ecology. Several alternative assignment methods have recently been developed and are yet to be fully evaluated with empirical data. In this study we tested the efficacy of different assignment methods by using a translocated rock-wallaby (Petrogale lateralis) population, of known provenance. Specimens from the translocated population (n = 43), its known source population (n = 30) and four other nearby populations (n = 19-32) were genotyped for 11 polymorphic microsatellite loci. The results identified Bayesian clustering, frequency and Bayesian methods as the most consistent and accurate, correctly assigning 93-100% of individuals up to a significance threshold of P = 0.01. Performance was variable among the distance-based methods, with the Cavalli-Sforza and Edwards chord distance performing best, whereas Goldstein et al.'s (deltamu)2 consistently performed poorly. Using Bayesian clustering, frequency and Bayesian methods we then attempted to determine the source of rock-wallabies which have recently recolonized an outcrop (Gardners) 8 km from the nearest rock-wallaby population. Results indicate that the population at Gardners originated via a recent dispersal event from the eastern end of Mt. Caroline. This is only the second published record of dispersal by rock-wallabies between habitat patches and is the longest movement recorded to date. Molecular techniques and methods of analysis are now available to allow detailed studies of dispersal in rock-wallabies and should also be possible for many other taxa.

Animals↗

Genetic entities and mating system in hermaphroditic Fucus spiralis and its close dioecious relative F. vesiculosus (Fucaceae, Phaeophyceae).

To date, molecular markers have not settled the question of the specific status of the closely related, but phylogenetically unresolved, brown seaweeds, hermaphroditic Fucus spiralis and dioecious Fucus vesiculosus, nor their propensity for natural hybridization. To test the degree of species integrity and to assess effect of the mating system on the population genetic structure, 288 individuals coming from parapatric (discontinuous) and sympatric (contiguous) spatial configurations at two sites were genotyped with five microsatellite loci. Using a Bayesian admixture analysis, our results show that F. spiralis and F. vesiculosus comprise clearly distinct genetic entities (clusters) generally characterized by cosexual and unisexual individuals, respectively. Genetic diversity within each entity suggests that F. spiralis reproduces primarily through selfing while F. vesiculosus is characterized by an endogamous breeding regime. Nevertheless, aberrant sexual phenotypes were observed in each cluster, no diagnostic alleles were revealed and 10% of study individuals were intermediate between the two genetic entities. This pattern can be explained by recent divergence of two taxa with retention of ancestral polymorphism or asymmetrical, introgressive hybridization. However, given (i) coincident monomorphism at three loci in spiralis clusters and (ii) that significantly more intermediates were observed in sympatric stations than in parapatric stations, we argue that interspecific gene flow has occurred after divergence of the two taxa. Finally, we show that whether recently separated or recently introgressive, the divergent breeding systems probably contribute to species integrity in these two taxa.

Bayes Theorem↗