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Plant breeding, like other fields in applied quantitative genetics, has embraced large-scale phenotype data as a way to rapidly and accurately create the next generations of crops. High-throughput phenotyping technologies and large-scale multi-environment breeding trials generate an unprecedented scale of data for breeders to use to make selections and crosses in breeding programs. However, the statistical foundation of multi-trait breeding is based on the multivariate linear mixed effect model, a tool notorious for its fragility when applied to more than a handful of traits. We present MegaLMM, a statistical framework and associated software package that facilitates flexible mixed model analyses on a virtually unlimited number of traits. Using three examples with real plant data, we show that MegaLMM can efficiently model the genetic architecture of thousands of traits at once while significantly improving genetic value prediction accuracy.

The interaction of evolutionary processes to determine quantitative genetic variation has implications for contemporary and future phenotypic evolution, as well as for our ability to detect causal genetic variants. While theoretical studies have provided robust predictions to discriminate among competing models, empirical assessment of these has been limited. In particular, theory highlights the importance of pleiotropy in resolving observations of selection and mutation, but empirical investigations have typically been limited to few traits. Here, we applied high-dimensional Bayesian Sparse Factor Genetic modeling to gene expression datasets in 2 species, Drosophila melanogaster and Drosophila serrata, to explore the distributions of genetic variance across high-dimensional phenotypic space. Surprisingly, most of the heritable trait covariation was due to few lines (genotypes) with extreme [>3 interquartile ranges (IQR) from the median] values. Intriguingly, while genotypes extreme for a multivariate factor also tended to have a higher proportion of individual traits that were extreme, we also observed genotypes that were extreme for multivariate factors but not for any individual trait. We observed other consistent differences between heritable multivariate factors with outlier lines vs those factors without extreme values, including differences in gene functions. We use these observations to identify further data required to advance our understanding of the evolutionary dynamics and nature of standing genetic variation for quantitative traits.

The multispecies coalescent (MSC) model accommodates both species divergences and within-species coalescent and provides a natural framework for phylogenetic analysis of genomic data when the gene trees vary across the genome. The MSC model implemented in the program bpp assumes a molecular clock and the Jukes–Cantor model, and is suitable for analyzing genomic data from closely related species. Here we extend our implementation to more general substitution models and relaxed clocks to allow the rate to vary among species. The MSC-with-relaxed-clock model allows the estimation of species divergence times and ancestral population sizes using genomic sequences sampled from contemporary species when the strict clock assumption is violated, and provides a simulation framework for evaluating species tree estimation methods. We conducted simulations and analyzed two real datasets to evaluate the utility of the new models. We confirm that the clock-JC model is adequate for inference of shallow trees with closely related species, but it is important to account for clock violation for distant species. Our simulation suggests that there is valuable phylogenetic information in the gene-tree branch lengths even if the molecular clock assumption is seriously violated, and the relaxed-clock models implemented in bpp are able to extract such information. Our Markov chain Monte Carlo algorithms suffer from mixing problems when used for species tree estimation under the relaxed clock and we discuss possible improvements. We conclude that the new models are currently most effective for estimating population parameters such as species divergence times when the species tree is fixed.

Simulation can be an efficient approach to design, evaluate, and optimize breeding programs. In the era of modern agriculture, breeding programs can benefit from a simulator that integrates various sources of big data and accommodates state-of-the-art statistical models. The initial release of XSim, in which stochastic descendants can be efficiently simulated with a drop-down strategy, has mainly been used to validate genomic selection results. In this article, we present XSim Version 2 that is an open-source tool and has been extensively redesigned with additional features to meet the needs in modern breeding programs. It seamlessly incorporates multiple statistical models for genetic evaluations, such as GBLUP, Bayesian alphabets, and neural networks, and it can effortlessly simulate successive generations of descendants based on complex mating schemes by the aid of its modular design. Case studies are presented to demonstrate the flexibility of XSim Version 2 in simulating crossbreeding in animal and plant populations. Modern biotechnology, including double haploids and embryo transfer, can all be simultaneously integrated into the mating plans that drive the simulation. From a computing perspective, XSim Version 2 is implemented in Julia, which is a computer language that retains the readability of scripting languages (e.g. R and Python) without sacrificing much computational speed compared to compiled languages (e.g. C). This makes XSim Version 2 a simulation tool that is relatively easy for both champions and community members to maintain, modify, or extend in order to improve their breeding programs. Functions and operators are overloaded for a better user interface so they may concatenate, subset, summarize, and organize simulated populations at each breeding step. With the strong and foreseeable demands in the community, XSim Version 2 will serve as a modern simulator bridging the gaps between theories and experiments with its flexibility, extensibility, and friendly interface.

To investigate the time origin, genetic diversity, and transmission dynamics of the recent 2019‐nCoV outbreak in China and beyond, a total of 32 genomes of virus strains sampled from China, Thailand, and the USA with sampling dates between 24 December 2019 and 23 January 2020 were analyzed. Phylogenetic, transmission network, and likelihood‐mapping analyses of the genome sequences were performed. On the basis of the likelihood‐mapping analysis, the increasing tree‐like signals (from 0% to 8.2%, 18.2%, and 25.4%) over time may be indicative of increasing genetic diversity of 2019‐nCoV in human hosts. We identified three phylogenetic clusters using the Bayesian inference framework and three transmission clusters using transmission network analysis, with only one cluster identified by both methods using the above genome sequences of 2019‐nCoV strains. The estimated mean evolutionary rate for 2019‐nCoV ranged from 1.7926 × 10−3 to 1.8266 × 10−3 substitutions per site per year. On the basis of our study, undertaking epidemiological investigations and genomic data surveillance could positively impact public health in terms of guiding prevention efforts to reduce 2019‐nCOV transmission in real‐time., Highlights On the basis of our results in the present study, the increasing tree‐like signals (from 0 to 8.2%, 18.2%, and 25.4%) over time may be indicative of increasing genetic diversity of 2019‐nCoV in human hosts. We only find one cluster identified by two methods (phylogenetic clusters using the Bayesian inference framework and transmission clusters using transmission network analysis). We estimated mean evolutionary rate for 2019‐nCoV ranged from 1.7926 × 10‐3 to 1.8266 × 10‐3 substitutions per site per year. Our study also highlights that undertaking epidemiological investigations and genomic data surveillance could positively impact public health in terms of guiding prevention efforts to reduce 2019‐nCOV transmission in real time.

The ability to connect genetic information between traits over time allow Bayesian networks to offer a powerful probabilistic framework to construct genomic prediction models. In this study, we phenotyped a diversity panel of 869 biomass sorghum (Sorghum bicolor (L.) Moench) lines, which had been genotyped with 100,435 SNP markers, for plant height (PH) with biweekly measurements from 30 to 120 days after planting (DAP) and for end-of-season dry biomass yield (DBY) in four environments. We evaluated five genomic prediction models: Bayesian network (BN), Pleiotropic Bayesian network (PBN), Dynamic Bayesian network (DBN), multi-trait GBLUP (MTr-GBLUP), and multi-time GBLUP (MTi-GBLUP) models. In fivefold cross-validation, prediction accuracies ranged from 0.46 (PBN) to 0.49 (MTr-GBLUP) for DBY and from 0.47 (DBN, DAP120) to 0.75 (MTi-GBLUP, DAP60) for PH. Forward-chaining cross-validation further improved prediction accuracies of the DBN, MTi-GBLUP and MTr-GBLUP models for PH (training slice: 30-45 DAP) by 36.4–52.4% relative to the BN and PBN models. Coincidence indices (target: biomass, secondary: PH) and a coincidence index based on lines (PH time series) showed that the ranking of lines by PH changed minimally after 45 DAP. These results suggest a two-level indirect selection method for PH at harvest (first-level target trait) and DBY (second-level target trait) could be conducted earlier in the season based on ranking of lines by PH at 45 DAP (secondary trait). With the advance of high-throughput phenotyping technologies, our proposed two-level indirect selection framework could be valuable for enhancing genetic gain per unit of time when selecting on developmental traits.

With the growing amount and diversity of intermediate omics data complementary to genomics (e.g. DNA methylation, gene expression, and protein abundance), there is a need to develop methods to incorporate intermediate omics data into conventional genomic evaluation. The omics data help decode the multiple layers of regulation from genotypes to phenotypes, thus forms a connected multilayer network naturally. We developed a new method named NN-MM to model the multiple layers of regulation from genotypes to intermediate omics features, then to phenotypes, by extending conventional linear mixed models (“MM”) to multilayer artificial neural networks (“NN”). NN-MM incorporates intermediate omics features by adding middle layers between genotypes and phenotypes. Linear mixed models (e.g. pedigree-based BLUP, GBLUP, Bayesian Alphabet, single-step GBLUP, or single-step Bayesian Alphabet) can be used to sample marker effects or genetic values on intermediate omics features, and activation functions in neural networks are used to capture the nonlinear relationships between intermediate omics features and phenotypes. NN-MM had significantly better prediction performance than the recently proposed single-step approach for genomic prediction with intermediate omics data. Compared to the single-step approach, NN-MM can handle various patterns of missing omics measures and allows nonlinear relationships between intermediate omics features and phenotypes. NN-MM has been implemented in an open-source package called “JWAS”.

In conventional linear models for whole-genome prediction and genome-wide association studies (GWAS), it is usually assumed that the relationship between genotypes and phenotypes is linear. Bayesian neural networks have been used to account for non-linearity such as complex genetic architectures. Here, we introduce a method named NN-Bayes, where “NN” stands for neural networks, and “Bayes” stands for Bayesian Alphabet models, including a collection of Bayesian regression models such as BayesA, BayesB, BayesC, and Bayesian LASSO. NN-Bayes incorporates Bayesian Alphabet models into non-linear neural networks via hidden layers between single-nucleotide polymorphisms (SNPs) and observed traits. Thus, NN-Bayes attempts to improve the performance of genome-wide prediction and GWAS by accommodating non-linear relationships between the hidden nodes and the observed trait, while maintaining genomic interpretability through the Bayesian regression models that connect the SNPs to the hidden nodes. For genomic interpretability, the posterior distribution of marker effects in NN-Bayes is inferred by Markov chain Monte Carlo approaches and used for inference of association through posterior inclusion probabilities and window posterior probability of association. In simulation studies with dominance and epistatic effects, performance of NN-Bayes was significantly better than conventional linear models for both GWAS and whole-genome prediction, and the differences on prediction accuracy were substantial in magnitude. In real-data analyses, for the soy dataset, NN-Bayes achieved significantly higher prediction accuracies than conventional linear models, and results from other four different species showed that NN-Bayes had similar prediction performance to linear models, which is potentially due to the small sample size. Our NN-Bayes is optimized for high-dimensional genomic data and implemented in an open-source package called “JWAS.” NN-Bayes can lead to greater use of Bayesian neural networks to account for non-linear relationships due to its interpretability and computational performance.

The rooting of the SARS-CoV-2 phylogeny is important for understanding the origin and early spread of the virus. Previously published phylogenies have used different rootings that do not always provide consistent results. We investigate several different strategies for rooting the SARS-CoV-2 tree and provide measures of statistical uncertainty for all methods. We show that methods based on the molecular clock tend to place the root in the B clade, whereas methods based on outgroup rooting tend to place the root in the A clade. The results from the two approaches are statistically incompatible, possibly as a consequence of deviations from a molecular clock or excess back-mutations. We also show that none of the methods provide strong statistical support for the placement of the root in any particular edge of the tree. These results suggest that phylogenetic evidence alone is unlikely to identify the origin of the SARS-CoV-2 virus and we caution against strong inferences regarding the early spread of the virus based solely on such evidence.

Bayesian regression methods that incorporate different mixture priors for marker effects are used in multi-trait genomic prediction. These methods can also be extended to genome-wide association studies (GWAS). In multiple-trait GWAS, incorporating the underlying causal structures among traits is essential for comprehensively understanding the relationship between genotypes and traits of interest. Therefore, we develop a GWAS methodology, SEM-BayesCΠ, which, by applying the structural equation model (SEM), can be used to incorporate causal structures into a multi-trait Bayesian regression method using mixture priors. The performance of SEM-BayesCΠ was demonstrated by comparing its GWAS results with those from multi-trait BayesCΠ. Through the inductive causation (IC) algorithm, three potential causal structures were inferred of 0.9 highest posterior density (HPD) interval. SEM-BayesCΠ provides a more comprehensive understanding of the genotype-phenotype mapping than multi-trait BayesCΠ by performing GWAS based on indirect, direct and overall marker effects. The software tool JWAS offers open-source routines to perform these analyses.

The effectiveness of immune responses depends on the precision of stimulus-responsive gene expression programs. Cells specify which genes to express by activating stimulus-specific combinations of stimulus-induced transcription factors (TFs). Their activities are decoded by a gene regulatory strategy (GRS) associated with each response gene. Here, we examined whether the GRSs of target genes may be inferred from stimulus-response (input-output) datasets, which remains an unresolved model-identifiability challenge. We developed a mechanistic modeling framework and computational workflow to determine the identifiability of all possible combinations of synergistic (AND) or non-synergistic (OR) GRSs involving three transcription factors. Considering different sets of perturbations for stimulus-response studies, we found that two thirds of GRSs are easily distinguishable but that substantially more quantitative data is required to distinguish the remaining third. To enhance the accuracy of the inference with timecourse experimental data, we developed an advanced error model that avoids error overestimates by distinguishing between value and temporal error. Incorporating this error model into a Bayesian framework, we show that GRS models can be identified for individual genes by considering multiple datasets. Our analysis rationalizes the allocation of experimental resources by identifying most informative TF stimulation conditions. Applying this computational workflow to experimental data of immune response genes in macrophages, we found that a much greater fraction of genes are combinatorially controlled than previously reported by considering compensation among transcription factors. Specifically, we revealed that a group of known NFκB target genes may also be regulated by IRF3, which is supported by chromatin immuno-precipitation analysis. Our study provides a computational workflow for designing and interpreting stimulus-response gene expression studies to identify underlying gene regulatory strategies and further a mechanistic understanding., Author summary Cells need to sense environmental cues and respond appropriately. One important notion is that different stimuli activate different combinations of transcription factors and that responsive genes are regulated by distinct subsets of these. However, identifying the regulatory strategies by which genes interpret transcription factor activities remains a largely unsolved challenge. In this work we address the question: to what extent are combinatorial transcription factor regulatory strategies identifiable from stimulus-response (input-output) datasets? We present a computational framework to determine the identifiability of gene regulatory strategies, and examine how reliable and quantitative model inference is a function of the quality and quantity of available data. We present an error model that more precisely quantifies uncertainty for perturbation-timecourse data sets by also considering error in the time domain, and achieves an improved performance in identifying and quantifying gene regulatory strategies. With these tools, we generate guidelines for experimental design that optimize limited resources for generating data for model inference. Finally, we apply the workflow to immune response datasets and uncover evidence that many more genes are subject to combinatorial control than previously thought; we offer physical transcription factor binding data to support this finding for one particular group of genes. This demonstrates that the computational workflow may guide studies of the regulatory strategies that govern stimulus-responsive gene expression programs.

This study aimed to investigate the genetic and putative causal relationships between fertility traits [i.e., days open (DO) and calving rate (CR)] and milk quality, composition, and fatty acid contents (milk composition traits) in Holstein-Friesian, Brown Swiss, and Simmental cattle, using recursive models within a Bayesian framework. Trivariate animal models were run, each including one fertility trait, one milk composition trait, and, in all models, milk yield. The DO and CR data were merged with the test days closest to the insemination date for milk composition traits. After editing, 16,468 to 23,424 records for Holstein-Friesian, 23,424 to 46,660 for Brown Swiss, and 26,105 to 35,574 for Simmental were available for the analyses. Recursive animal models were applied to investigate the possible causal influences of milk composition traits on fertility and the genetic relationships among these traits. The results suggested a potential cause-and-effect relationship between milk composition traits and fertility traits, with the first trait influencing the latter. We also found greater recursive effects of milk composition traits on DO than on CR, the latter with some putative differences among breeds in terms of sensitivity. For instance, the putative causal effects of somatic cell score on CR (on the observed scale, %) varied from -0.96 to -1.39%, depending on the breed. Concerning fatty acids, we found relevant putative effects of C18:0 on CR, with estimates varying from -7.8 to -9.9%. Protein and casein percentages, and short-chain fatty acid showed larger recursive effects on CR, whereas fat, protein, and casein percentages, C16:0, C18:0, and long-chain fatty acid had larger effects on DO. The results obtained suggested that these milk traits could be considered as effective indicators of the effects of animal metabolic and physiological status on fertility.

Markov models of character substitution on phylogenies form the foundation of phylogenetic inference frameworks. Early models made the simplifying assumption that the substitution process is homogeneous over time and across sites in the molecular sequence alignment. While standard practice adopts extensions that accommodate heterogeneity of substitution rates across sites, heterogeneity in the process over time in a site-specific manner remains frequently overlooked. This is problematic, as evolutionary processes that act at the molecular level are highly variable, subjecting different sites to different selective constraints over time, impacting their substitution behavior. We propose incorporating time variability through Markov-modulated models (MMMs), which extend covarion-like models and allow the substitution process (including relative character exchange rates as well as the overall substitution rate) at individual sites to vary across lineages. We implement a general MMM framework in BEAST, a popular Bayesian phylogenetic inference software package, allowing researchers to compose a wide range of MMMs through flexible XML specification. Using examples from bacterial, viral, and plastid genome evolution, we show that MMMs impact phylogenetic tree estimation and can substantially improve model fit compared to standard substitution models. Through simulations, we show that marginal likelihood estimation accurately identifies the generative model and does not systematically prefer the more parameter-rich MMMs. To mitigate the increased computational demands associated with MMMs, our implementation exploits recent developments in BEAGLE, a high-performance computational library for phylogenetic inference. [Bayesian inference; BEAGLE; BEAST; covarion, heterotachy; Markov-modulated models; phylogenetics.]. ispartof: SYSTEMATIC BIOLOGY vol:70 issue:1 pages:181-189 ispartof: location:England status: published

The probability of point mutations is expected to be highly influenced by the flanking nucleotides that surround them, known as the sequence context. This phenomenon may be mainly attributed to the enzyme that modifies or mutates the genetic material, because most enzymes tend to have specific sequence contexts that dictate their activity. Here, we develop a statistical model that allows for the detection and evaluation of the effects of different sequence contexts on mutation rates from deep population sequencing data. This task is computationally challenging, as the complexity of the model increases exponentially as the context size increases. We established our novel Bayesian method based on sparse model selection methods, with the leading assumption that the number of actual sequence contexts that directly influence mutation rates is minuscule compared with the number of possible sequence contexts. We show that our method is highly accurate on simulated data using pentanucleotide contexts, even when accounting for noisy data. We next analyze empirical population sequencing data from polioviruses and HIV-1 and detect a significant enrichment in sequence contexts associated with deamination by the cellular deaminases ADAR 1/2 and APOBEC3G, respectively. In the current era, where next-generation sequencing data are highly abundant, our approach can be used on any population sequencing data to reveal context-dependent base alterations and may assist in the discovery of novel mutable sites or editing sites.

Recent analyses suggest that cross-species gene flow or introgression is common in nature, especially during species divergences. Genomic sequence data can be used to infer introgression events and to estimate the timing and intensity of introgression, providing an important means to advance our understanding of the role of gene flow in speciation. Here, we implement the multispecies-coalescent-with-introgression model, an extension of the multispecies-coalescent model to incorporate introgression, in our Bayesian Markov chain Monte Carlo program Bpp. The multispecies-coalescent-with-introgression model accommodates deep coalescence (or incomplete lineage sorting) and introgression and provides a natural framework for inference using genomic sequence data. Computer simulation confirms the good statistical properties of the method, although hundreds or thousands of loci are typically needed to estimate introgression probabilities reliably. Reanalysis of data sets from the purple cone spruce confirms the hypothesis of homoploid hybrid speciation. We estimated the introgression probability using the genomic sequence data from six mosquito species in the Anopheles gambiae species complex, which varies considerably across the genome, likely driven by differential selection against introgressed alleles.

Allelic imbalance (AI) indicates the presence of functional variation in cis regulatory regions. Detecting cis regulatory differences using AI is widespread, yet there is no formal statistical methodology that tests whether AI differs between conditions. Here, we present a novel model and formally test differences in AI across conditions using Bayesian credible intervals. The approach tests AI by environment (G×E) interactions, and can be used to test AI between environments, genotypes, sex, and any other condition. We incorporate bias into the modeling process. Bias is allowed to vary between conditions, making the formulation of the model general. As gene expression affects power for detection of AI, and, as expression may vary between conditions, the model explicitly takes coverage into account. The proposed model has low type I and II error under several scenarios, and is robust to large differences in coverage between conditions. We reanalyze RNA-seq data from a Drosophila melanogaster population panel, with F1 genotypes, to compare levels of AI between mated and virgin female flies, and we show that AI × genotype interactions can also be tested. To demonstrate the use of the model to test genetic differences and interactions, a formal test between two F1s was performed, showing the expected 20% difference in AI. The proposed model allows a formal test of G×E and G×G, and reaffirms a previous finding that cis regulation is robust between environments.

Multi-marker association tests can be more powerful than single-locus analyses because they aggregate the variant information within a gene/region. However, combining the association signals of multiple markers within a gene/region may cause noise due to the inclusion of neutral variants, which usually compromises the power of a test. To reduce noise, the “adaptive combination of P-values” (ADA) method removes variants with larger P-values. However, when both rare and common variants are considered, it is not optimal to truncate variants according to their P-values. An alternative summary measure, the Bayes factor (BF), is defined as the ratio of the probability of the data under the alternative hypothesis to that under the null hypothesis. The BF quantifies the “relative” evidence supporting the alternative hypothesis. Here, we propose an “adaptive combination of Bayes factors” (ADABF) method that can be directly applied to variants with a wide spectrum of minor allele frequencies. The simulations show that ADABF is more powerful than single-nucleotide polymorphism (SNP)-set kernel association tests and burden tests. We also analyzed 1,109 case-parent trios from the Schizophrenia Trio Genomic Research in Taiwan. Three genes on chromosome 19p13.2 were found to be associated with schizophrenia at the suggestive significance level of 5 × 10−5.

Linear mixed effect models are powerful tools used to account for population structure in genome-wide association studies (GWASs) and estimate the genetic architecture of complex traits. However, fully-specified models are computationally demanding and common simplifications often lead to reduced power or biased inference. We describe Grid-LMM (https://github.com/deruncie/GridLMM), an extendable algorithm for repeatedly fitting complex linear models that account for multiple sources of heterogeneity, such as additive and non-additive genetic variance, spatial heterogeneity, and genotype-environment interactions. Grid-LMM can compute approximate (yet highly accurate) frequentist test statistics or Bayesian posterior summaries at a genome-wide scale in a fraction of the time compared to existing general-purpose methods. We apply Grid-LMM to two types of quantitative genetic analyses. The first is focused on accounting for spatial variability and non-additive genetic variance while scanning for QTL; and the second aims to identify gene expression traits affected by non-additive genetic variation. In both cases, modeling multiple sources of heterogeneity leads to new discoveries., Author summary The goal of quantitative genetics is to characterize the relationship between genetic variation and variation in quantitative traits such as height, productivity, or disease susceptibility. A statistical method known as the linear mixed effect model has been critical to the development of quantitative genetics. First applied to animal breeding, this model now forms the basis of a wide-range of modern genomic analyses including genome-wide associations, polygenic modeling, and genomic prediction. The same model is also widely used in ecology, evolutionary genetics, social sciences, and many other fields. Mixed models are frequently multi-faceted, which is necessary for accurately modeling data that is generated from complex experimental designs. However, most genomic applications use only the simplest form of linear mixed methods because the computational demands for model fitting can be too great. We develop a flexible approach for fitting linear mixed models to genome scale data that greatly reduces their computational burden and provides flexibility for users to choose the best statistical paradigm for their data analysis. We demonstrate improved accuracy for genetic association tests, increased power to discover causal genetic variants, and the ability to provide accurate summaries of model uncertainty using both simulated and real data examples.

Chlamydiaceae are obligate intracellular bacteria that cause a diversity of severe infections among humans and livestock on a global scale. Identification of new species since 1989 and emergence of zoonotic infections, including abortion in women, underscore the need for genome sequencing of multiple strains of each species to advance our knowledge of evolutionary dynamics across Chlamydiaceae. Here, we genome sequenced isolates from avian, lower mammalian and human hosts. Based on core gene phylogeny, five isolates previously classified as Chlamydia abortus were identified as members of Chlamydia psittaci and Chlamydia pecorum. Chlamydia abortus is the most recently emerged species and is a highly monomorphic group that lacks the conserved virulence-associated plasmid. Low-level recombination and evidence for adaptation to the placenta echo evolutionary processes seen in recently emerged, highly virulent niche-restricted pathogens, such as Bacillus anthracis. In contrast, gene flow occurred within C. psittaci and other Chlamydiaceae species. The C. psittaci strain RTH, isolated from a red-tailed hawk (Buteo jamaicensis), is an outlying strain with admixture of C. abortus, C. psittaci, and its own population markers. An average nucleotide identity of less than 94% compared with other Chlamydiaceae species suggests that RTH belongs to a new species intermediary between C. psittaci and C. abortus. Hawks, as scavengers and predators, have extensive opportunities to acquire multiple species in their intestinal tract. This could facilitate transformation and homologous recombination with the potential for new species emergence. Our findings indicate that incubator hosts such as birds-of-prey likely promote Chlamydiaceae evolution resulting in novel pathogenic lineages.

Influenza is responsible for up to 500,000 deaths every year, and antigenic variability represents much of its epidemiological burden. To visualize antigenic differences across many viral strains, antigenic cartography methods use multidimensional scaling on binding assay data to map influenza antigenicity onto a low-dimensional space. Analysis of such assay data ideally leads to natural clustering of influenza strains of similar antigenicity that correlate with sequence evolution. To understand the dynamics of these antigenic groups, we present a framework that jointly models genetic and antigenic evolution by combining multidimensional scaling of binding assay data, Bayesian phylogenetic machinery and nonparametric clustering methods. We propose a phylogenetic Chinese restaurant process that extends the current process to incorporate the phylogenetic dependency structure between strains in the modeling of antigenic clusters. With this method, we are able to use the genetic information to better understand the evolution of antigenicity throughout epidemics, as shown in applications of this model to H1N1 influenza. Copyright © 2017 John Wiley & Sons, Ltd.

Bayesian multiple-regression methods incorporating different mixture priors for marker effects are used widely in genomic prediction. Improvement in prediction accuracies from using those methods, such as BayesB, BayesC, and BayesCπ, have been shown in single-trait analyses with both simulated and real data. These methods have been extended to multi-trait analyses, but only under the restrictive assumption that a locus simultaneously affects all the traits or none of them. This assumption is not biologically meaningful, especially in multi-trait analyses involving many traits. In this paper, we develop and implement a more general multi-trait BayesCΠ and BayesB methods allowing a broader range of mixture priors. Our methods allow a locus to affect any combination of traits, e.g., in a 5-trait analysis, the “restrictive” model only allows two situations, whereas ours allow all 32 situations. Further, we compare our methods to single-trait methods and the “restrictive” multi-trait formulation using real and simulated data. In the real data analysis, higher prediction accuracies were observed from both our new broad-based multi-trait methods and the “restrictive” formulation. The broad-based and restrictive multi-trait methods showed similar prediction accuracies. In the simulated data analysis, higher prediction accuracies to the “restrictive” method were observed from our general multi-trait methods for intermediate training population size. The software tool JWAS offers open-source routines to perform these analyses.

International audience; Deciphering invasion routes from molecular data is crucial to understanding biological invasions, including identifying bottlenecks in population size and admixture among distinct populations. Here, we unravel the invasion routes of the invasive pest Drosophila suzukii using a multi-locus microsatellite dataset (25 loci on 23 worldwide sampling locations). To do this, we use approximate Bayesian computation (ABC), which has improved the reconstruction of invasion routes, but can be computationally expensive. We use our study to illustrate the use of a new, more efficient, ABC method, ABC random forest (ABC-RF) and compare it to a standard ABC method (ABC-LDA). We find that Japan emerges as the most probable source of the earliest recorded invasion into Hawaii. Southeast China and Hawaii together are the most probable sources of populations in western North America, which then in turn served as sources for those in eastern North America. European populations are genetically more homogeneous than North American populations, and their most probable source is northeast China, with evidence of limited gene flow from the eastern US as well. All introduced populations passed through bottlenecks, and analyses reveal five distinct admixture events. These findings can inform hypotheses concerning how this species evolved between different and independent source and invasive populations. Methodological comparisons indicate that ABC-RF and ABC-LDA show concordant results if ABC-LDA is based on a large number of simulated datasets but that ABC-RF out-performs ABC-LDA when using a comparable and more manageable number of simulated datasets, especially when analyzing complex introduction scenarios.

The work described in the present article is part of the TiMet project on linking the circadian clock to metabolism in plants. TiMet is a collaborative project (Grant Agreement 245143) funded by the European Commission FP7, in response to call FP7-KBBE-2009-3. Parts of the work were done while M.G. was supported by the German Research Foundation (DFG), research grant GR3853/1-1. A.A. is supported by the BBSRC and the TiMet project. We assess the accuracy of various state-of-the-art statistics and machine learning methods for reconstructing gene and protein regulatory networks in the context of circadian regulation. Our study draws on the increasing availability of gene expression and protein concentration time series for key circadian clock components in Arabidopsis thaliana. In addition, gene expression and protein concentration time series are simulated from a recently published regulatory network of the circadian clock in A. thaliana, in which protein and gene interactions are described by a Markov jump process based on Michaelis-Menten kinetics. We closely follow recent experimental protocols, including the entrainment of seedlings to different light-dark cycles and the knock-out of various key regulatory genes. Our study provides relative network reconstruction accuracy scores for a critical comparative performance evaluation, and sheds light on a series of highly relevant questions: it quantifies the influence of systematically missing values related to unknown protein concentrations and mRNA transcription rates, it investigates the dependence of the performance on the network topology and the degree of recurrency, it provides deeper insight into when and why non-linear methods fail to outperform linear ones, it offers improved guidelines on parameter settings in different inference procedures, and it suggests new hypotheses about the structure of the central circadian gene regulatory network in A. thaliana. Publisher PDF

International audience; AbstractBackgroundTwo types of models have been used for single-step genomic prediction and genome-wide association studies that include phenotypes from both genotyped animals and their non-genotyped relatives. The two types are breeding value models (BVM) that fit breeding values explicitly and marker effects models (MEM) that express the breeding values in terms of the effects of observed or imputed genotypes. MEM can accommodate a wider class of analyses, including variable selection or mixture model analyses. The order of the equations that need to be solved and the inverses required in their construction vary widely, and thus the computational effort required depends upon the size of the pedigree, the number of genotyped animals and the number of loci.TheoryWe present computational strategies to avoid storing large, dense blocks of the MME that involve imputed genotypes. Furthermore, we present a hybrid model that fits a MEM for animals with observed genotypes and a BVM for those without genotypes. The hybrid model is computationally attractive for pedigree files containing millions of animals with a large proportion of those being genotyped.ApplicationWe demonstrate the practicality on both the original MEM and the hybrid model using real data with 6,179,960 animals in the pedigree with 4,934,101 phenotypes and 31,453 animals genotyped at 40,214 informative loci. To complete a single-trait analysis on a desk-top computer with four graphics cards required about 3 h using the hybrid model to obtain both preconditioned conjugate gradient solutions and 42,000 Markov chain Monte-Carlo (MCMC) samples of breeding values, which allowed making inferences from posterior means, variances and covariances. The MCMC sampling required one quarter of the effort when the hybrid model was used compared to the published MEM.ConclusionsWe present a hybrid model that fits a MEM for animals with genotypes and a BVM for those without genotypes. Its practicality and considerable reduction in computing effort was demonstrated. This model can readily be extended to accommodate multiple traits, multiple breeds, maternal effects, and additional random effects such as polygenic residual effects.

Invasive species have great ecological and economic impacts and are difficult to control once established, making the ability to understand and predict invasive behavior highly desirable. Preemptive measures to prevent potential invasive species from reaching new habitats are the most economically and environmentally efficient form of management. Darwin's naturalization hypothesis predicts that invaders less related to native flora are more likely to be successful than those that are closely related to natives. Here we test this hypothesis, using the weed-rich thistle tribe, Cardueae, in the California Floristic Province, a biodiversity hotspot, as our study system. An exhaustive molecular phylogenetic approach was used, generating and examining more than 100,000 likely phylogenies of the tribe based on nuclear and chloroplast DNA markers, representing the most in-depth reconstruction of the clade to date. Branch lengths separating invasive and noninvasive introduced taxa from native California taxa were used to represent phylogenetic distances between these groups and were compared at multiple biogeographical scales to ascertain whether invasive thistles are more or less closely related to natives than noninvasive introduced thistles are. Patterns within this highly supported clade show that not only are introduced thistles more closely related to natives more likely to be invasive, but these invasive species are also evolutionarily closer to native flora than by chance. This suggests that preadaptive traits are important in determining an invader's success. Such rigorous molecular phylogenetic analyses may prove a fruitful means for furthering our understanding of biological invasions and developing predictive frameworks for screening potential invasive taxa.

Close relatives can share large segments of their genome identical by descent (IBD) that can be identified in genome-wide polymorphism data sets. There are a range of methods to use these IBD segments to identify relatives and estimate their relationship. These methods have focused on sharing on the autosomes, as they provide a rich source of information about genealogical relationships. We hope to learn additional information about recent ancestry through shared IBD segments on the X chromosome, but currently lack the theoretical framework to use this information fully. Here, we fill this gap by developing probability distributions for the number and length of X chromosome segments shared IBD between an individual and an ancestor k generations back, as well as between half- and full-cousin relationships. Due to the inheritance pattern of the X and the fact that X homologous recombination occurs only in females (outside of the pseudoautosomal regions), the number of females along a genealogical lineage is a key quantity for understanding the number and length of the IBD segments shared among relatives. When inferring relationships among individuals, the number of female ancestors along a genealogical lineage will often be unknown. Therefore, our IBD segment length and number distributions marginalize over this unknown number of recombinational meioses through a distribution of recombinational meioses we derive. By using Bayes’ theorem to invert these distributions, we can estimate the number of female ancestors between two relatives, giving us details about the genealogical relations between individuals not possible with autosomal data alone.

Phylodynamic reconstructions rely on a measurable molecular footprint of epidemic processes in pathogen genomes. Identifying the factors that govern the tempo and mode by which these processes leave a footprint in pathogen genomes represents an important goal towards understanding infectious disease evolution. Discriminating between synonymous and non-synonymous substitution rates is crucial for testing hypotheses about the sources of evolutionary rate variation. Here, we implement a codon substitution model in a Bayesian statistical framework to estimate absolute rates of synonymous and non-synonymous substitution in unknown evolutionary histories. To demonstrate how this model can provide critical insights into pathogen evolutionary dynamics, we adopt hierarchical phylogenetic modelling with fixed effects and apply it to two viral examples. Using within-host HIV-1 data from patients with different host genetic background and different disease progression rates, we show that viral populations undergo faster absolute synonymous substitution rates in patients with faster disease progression, probably reflecting faster replication rates. We also re-analyse rabies data from different bat species in the Americas to demonstrate that climate predicts absolute synonymous substitution rates, which can be attributed to climate-associated bat activity and viral transmission dynamics. In conclusion, our model to estimate absolute rates of synonymous and non-synonymous substitution can provide a powerful approach to investigate how host ecology can shape the tempo of pathogen evolution. ispartof: MICROBIAL GENOMICS vol:2 issue:6 ispartof: location:England status: published

Marginal likelihood estimates to compare models using Bayes factors frequently accompany Bayesian phylogenetic inference. Approaches to estimate marginal likelihoods have garnered increased attention over the past decade. In particular, the introduction of path sampling (PS) and stepping-stone sampling (SS) into Bayesian phylogenetics has tremendously improved the accuracy of model selection. These sampling techniques are now used to evaluate complex evolutionary and population genetic models on empirical data sets, but considerable computational demands hamper their widespread adoption. Further, when very diffuse, but proper priors are specified for model parameters, numerical issues complicate the exploration of the priors, a necessary step in marginal likelihood estimation using PS or SS. To avoid such instabilities, generalized SS (GSS) has recently been proposed, introducing the concept of "working distributions" to facilitate-or shorten-the integration process that underlies marginal likelihood estimation. However, the need to fix the tree topology currently limits GSS in a coalescent-based framework. Here, we extend GSS by relaxing the fixed underlying tree topology assumption. To this purpose, we introduce a "working" distribution on the space of genealogies, which enables estimating marginal likelihoods while accommodating phylogenetic uncertainty. We propose two different "working" distributions that help GSS to outperform PS and SS in terms of accuracy when comparing demographic and evolutionary models applied to synthetic data and real-world examples. Further, we show that the use of very diffuse priors can lead to a considerable overestimation in marginal likelihood when using PS and SS, while still retrieving the correct marginal likelihood using both GSS approaches. The methods used in this article are available in BEAST, a powerful user-friendly software package to perform Bayesian evolutionary analyses. ispartof: Systematic Biology vol:65 issue:2 pages:250-64 ispartof: location:England status: published

With a combined carrier frequency of 1:200, heteroplasmic mitochondrial DNA (mtDNA) mutations cause human disease in ~1:5000 of the population. Rapid shifts in the level of heteroplasmy seen within a single generation contribute to the wide range in the severity of clinical phenotypes seen in families transmitting mtDNA disease, consistent with a genetic bottleneck during transmission. Although preliminary evidence from human pedigrees points towards a random drift process underlying the shifting heteroplasmy, some reports describe differences in segregation pattern between different mtDNA mutations. However, based on limited observations and with no direct comparisons, it is not clear whether these observations simply reflect pedigree ascertainment and publication bias. To address this issue, we studied 577 mother-child pairs transmitting the m.11778G > A, m.3460G > A, m.8344A > G, m.8993T > G/C and m.3243A > G mtDNA mutations. Our analysis controlled for inter-assay differences, inter-laboratory variation and ascertainment bias. We found no evidence of selection during transmission but show that different mtDNA mutations segregate at different rates in human pedigrees. m.8993T > G/C segregated significantly faster than m.11778G > A, m.8344A > G and m.3243A > G, consistent with a tighter mtDNA genetic bottleneck in m.8993T > G/C pedigrees. Our observations support the existence of different genetic bottlenecks primarily determined by the underlying mtDNA mutation, explaining the different inheritance patterns observed in human pedigrees transmitting pathogenic mtDNA mutations.

Background We currently have the ability to quantify transcript abundance of messenger RNA (mRNA), genome-wide, using microarray technologies. Analyzing genotype, phenotype and expression data from 20 pedigrees, the members of our Genetic Analysis Workshop (GAW) 19 gene expression group published 9 papers, tackling some timely and important problems and questions. To study the complexity and interrelationships of genetics and gene expression, we used established statistical tools, developed newer statistical tools, and developed and applied extensions to these tools. Methods To study gene expression correlations in the pedigree members (without incorporating genotype or trait data into the analysis), 2 papers used principal components analysis, weighted gene coexpression network analysis, meta-analyses, gene enrichment analyses, and linear mixed models. To explore the relationship between genetics and gene expression, 2 papers studied expression quantitative trait locus allelic heterogeneity through conditional association analyses, and epistasis through interaction analyses. A third paper assessed the feasibility of applying allele-specific binding to filter potential regulatory single-nucleotide polymorphisms (SNPs). Analytic approaches included linear mixed models based on measured genotypes in pedigrees, permutation tests, and covariance kernels. To incorporate both genotype and phenotype data with gene expression, 4 groups employed linear mixed models, nonparametric weighted U statistics, structural equation modeling, Bayesian unified frameworks, and multiple regression. Results and discussion Regarding the analysis of pedigree data, we found that gene expression is familial, indicating that at least 1 factor for pedigree membership or multiple factors for the degree of relationship should be included in analyses, and we developed a method to adjust for familiality prior to conducting weighted co-expression gene network analysis. For SNP association and conditional analyses, we found FaST-LMM (Factored Spectrally Transformed Linear Mixed Model) and SOLAR-MGA (Sequential Oligogenic Linkage Analysis Routines –Major Gene Analysis) have similar type 1 and type 2 errors and can be used almost interchangeably. To improve the power and precision of association tests, prior knowledge of DNase-I hypersensitivity sites or other relevant biological annotations can be incorporated into the analyses. On a biological level, eQTL (expression quantitative trait loci) are genetically complex, exhibiting both allelic heterogeneity and epistasis. Including both genotype and phenotype data together with measurements of gene expression was found to be generally advantageous in terms of generating improved levels of significance and in providing more interpretable biological models. Conclusions Pedigrees can be used to conduct analyses of and enhance gene expression studies.

The advent of accessible ancient DNA technology now allows the direct ascertainment of allele frequencies in ancestral populations, thereby enabling the use of allele frequency time series to detect and estimate natural selection. Such direct observations of allele frequency dynamics are expected to be more powerful than inferences made using patterns of linked neutral variation obtained from modern individuals. We develop a Bayesian method to make use of allele frequency time series data and infer the parameters of general diploid selection, along with allele age, in non-equilibrium populations. We introduce a novel path augmentation approach, in which we use Markov chain Monte Carlo to integrate over the space of allele frequency trajectories consistent with the observed data. Using simulations, we show that this approach has good power to estimate selection coefficients and allele age. Moreover, when applying our approach to data on horse coat color, we find that ignoring a relevant demographic history can significantly bias the results of inference. Our approach is made available in a C++ software package., Comment: 27 pages

It is becoming clear that interconnected functional gene networks, rather than individual genes, govern stem cell self-renewal and differentiation. To identify epigenetic factors that impact on human epidermal stem cells we performed siRNA-based genetic screens for 332 chromatin modifiers. We developed a Bayesian mixture model to predict putative functional interactions between epigenetic modifiers that regulate differentiation. We discovered a network of genetic interactions involving EZH2, UHRF1 (both known to regulate epidermal self-renewal), ING5 (a MORF complex component), BPTF and SMARCA5 (NURF complex components). Genome-wide localization and global mRNA expression analysis revealed that these factors impact two distinct but functionally related gene sets, including integrin extracellular matrix receptors that mediate anchorage of epidermal stem cells to their niche. Using a competitive epidermal reconstitution assay we confirmed that ING5, BPTF, SMARCA5, EZH2 and UHRF1 control differentiation under physiological conditions. Thus, regulation of distinct gene expression programs through the interplay between diverse epigenetic strategies protects epidermal stem cells from differentiation.

International audience; AbstractBackground In whole-genome analyses, the number p of marker covariates is often much larger than the number n of observations. Bayesian multiple regression models are widely used in genomic selection to address this problem of p≫n.\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$p\gg n.$$\end{document} The primary difference between these models is the prior assumed for the effects of the covariates. Usually in the BayesB method, a Metropolis–Hastings (MH) algorithm is used to jointly sample the marker effect and the locus-specific variance, which may make BayesB computationally intensive. In this paper, we show how the Gibbs sampler without the MH algorithm can be used for the BayesB method.ResultsWe consider three different versions of the Gibbs sampler to sample the marker effect and locus-specific variance for each locus. Among the Gibbs samplers that were considered, the most efficient sampler is about 2.1 times as efficient as the MH algorithm proposed by Meuwissen et al. and 1.7 times as efficient as that proposed by Habier et al.ConclusionsThe three Gibbs samplers presented here were twice as efficient as Metropolis–Hastings samplers and gave virtually the same results.

Characterizing the distribution of effects from genome-wide genotyping data is crucial for understanding important aspects of the genetic architecture of complex traits, such as number or proportion of non-null loci, average proportion of phenotypic variance explained per non-null effect, power for discovery, and polygenic risk prediction. To this end, previous work has used effect-size models based on various distributions, including the normal and normal mixture distributions, among others. In this paper we propose a scale mixture of two normals model for effect size distributions of genome-wide association study (GWAS) test statistics. Test statistics corresponding to null associations are modeled as random draws from a normal distribution with zero mean; test statistics corresponding to non-null associations are also modeled as normal with zero mean, but with larger variance. The model is fit via minimizing discrepancies between the parametric mixture model and resampling-based nonparametric estimates of replication effect sizes and variances. We describe in detail the implications of this model for estimation of the non-null proportion, the probability of replication in de novo samples, the local false discovery rate, and power for discovery of a specified proportion of phenotypic variance explained from additive effects of loci surpassing a given significance threshold. We also examine the crucial issue of the impact of linkage disequilibrium (LD) on effect sizes and parameter estimates, both analytically and in simulations. We apply this approach to meta-analysis test statistics from two large GWAS, one for Crohn’s disease (CD) and the other for schizophrenia (SZ). A scale mixture of two normals distribution provides an excellent fit to the SZ nonparametric replication effect size estimates. While capturing the general behavior of the data, this mixture model underestimates the tails of the CD effect size distribution. We discuss the implications of pervasive small but replicating effects in CD and SZ on genomic control and power. Finally, we conclude that, despite having very similar estimates of variance explained by genotyped SNPs, CD and SZ have a broadly dissimilar genetic architecture, due to differing mean effect size and proportion of non-null loci., Author Summary We describe in detail the implications of a particular mixture model (a scale mixture of two normals) for effect size distributions from genome-wide genotyping data. Parameters from this model can be used for estimation of the non-null proportion, the probability of replication in de novo samples, the local false discovery rate, power for detecting non-null loci, and proportion of variance explained from additive effects. Here, we fit this model by minimizing discrepancies with nonparametric estimates from a resampling-based algorithm. We examine the effects of linkage disequilibrium (LD) on effect sizes and parameter estimates, both analytically and in simulations. We validate this approach using meta-analysis test statistics (“z-scores”) from two large GWAS, one for Crohn’s disease and the other for schizophrenia. We demonstrate that for these studies a scale mixture of two normal distributions generally fits empirical replication effect sizes well, providing an excellent fit for the schizophrenia effect sizes but underestimating the tails of the distribution for Crohn’s disease.

Estimating the phylogeny of lacertid lizards, and particularly the tribe Lacertini has been challenging, possibly due to the fast radiation of this group resulting in a hard polytomy. However this is still an open question, as concatenated data primarily from mitochondrial markers have been used so far whereas in a recent phylogeny based on a compilation of these data within a squamate supermatrix the basal polytomy seems to be resolved. In this study, we estimate phylogenetic relationships between all Lacertini genera using for the first time DNA sequences from five fast evolving nuclear genes (acm4, mc1r, pdc, βfib and reln) and two mitochondrial genes (nd4 and 12S). We generated a total of 529 sequences from 88 species and used Maximum Likelihood and Bayesian Inference methods based on concatenated multilocus dataset as well as a coalescent-based species tree approach with the aim of (i) shedding light on the basal relationships of Lacertini (ii) assessing the monophyly of genera which were previously questioned, and (iii) discussing differences between estimates from this and previous studies based on different markers, and phylogenetic methods., Results uncovered (i) a new phylogenetic clade formed by the monotypic genera Archaeolacerta, Zootoca, Teira and Scelarcis; and (ii) support for the monophyly of the Algyroides clade, with two sister species pairs represented by western (A. marchi and A. fitzingeri) and eastern (A. nigropunctatus and A. moreoticus) lineages. In both cases the members of these groups show peculiar morphology and very different geographical distributions, suggesting that they are relictual groups that were once diverse and widespread. They probably originated about 11–13 million years ago during early events of speciation in the tribe, and the split between their members is estimated to be only slightly older. This scenario may explain why mitochondrial markers (possibly saturated at higher divergence levels) or slower nuclear markers used in previous studies (likely lacking enough phylogenetic signal) failed to recover these relationships. Finally, the phylogenetic position of most remaining genera was unresolved, corroborating the hypothesis of a hard polytomy in the Lacertini phylogeny due to a fast radiation. This is in agreement with all previous studies but in sharp contrast with a recent squamate megaphylogeny. We show that the supermatrix approach may provide high support for incorrect nodes that are not supported either by original sequence data or by new data from this study. This finding suggests caution when using megaphylogenies to integrate inter-generic relationships in comparative ecological and evolutionary studies., This study was partially funded by the Project “Genomics and Evolutionary Biology” cofinanced by North Portugal Regional Operational Programme 2007/2013 (ON.2–O Novo Norte), under the National Strategic Reference Framework (NSRF), through the European Regional Development Fund (ERDF). JM, DJH, and DS are supported by the Fundação para a Ciência e a Tecnologia (FCT, Portugal): JM, doctoral grant SFRH/BD/81528/2011; DS, post-doctoral grant SFRH/BPD/105274/2014. SC is supported by Grant CGL2012-36970 from the Ministerio de Economía y Competitividad, Spain (co-funded by Fondos FEDER – EU).

Gibbons are believed to have diverged from the larger great apes ∼16.8 MYA and today reside in the rainforests of Southeast Asia. Based on their diploid chromosome number, the family Hylobatidae is divided into four genera, Nomascus, Symphalangus, Hoolock, and Hylobates. Genetic studies attempting to elucidate the phylogenetic relationships among gibbons using karyotypes, mitochondrial DNA (mtDNA), the Y chromosome, and short autosomal sequences have been inconclusive . To examine the relationships among gibbon genera in more depth, we performed second-generation whole genome sequencing (WGS) to a mean of ∼15× coverage in two individuals from each genus. We developed a coalescent-based approximate Bayesian computation (ABC) method incorporating a model of sequencing error generated by high coverage exome validation to infer the branching order, divergence times, and effective population sizes of gibbon taxa. Although Hoolock and Symphalangus are likely sister taxa, we could not confidently resolve a single bifurcating tree despite the large amount of data analyzed. Instead, our results support the hypothesis that all four gibbon genera diverged at approximately the same time. Assuming an autosomal mutation rate of 1 × 10−9/site/year this speciation process occurred ∼5 MYA during a period in the Early Pliocene characterized by climatic shifts and fragmentation of the Sunda shelf forests. Whole genome sequencing of additional individuals will be vital for inferring the extent of gene flow among species after the separation of the gibbon genera., Support for this work was provided by the National Institutes of Health to J.D.W. and M.F.H. (R01_HG005226) and an European Research Council Starting Grant (260372) and Ministerio de Ciencia e Innovación (Spain) BFU2011-28549 to T.M.-B.

The introduction of invasive species to new locations (that is, biological invasions) can have major impact on biodiversity, agriculture and public health. As such, determining the routes and modality of introductions with genetic data has become a fundamental goal in molecular ecology. To assist with this goal, new statistical methods and frameworks have been developed, such as approximate Bayesian computation (ABC) for inferring invasion history. Here, we present a model of invasion accounting for multiple introductions from a single source (MISS), a heretofore largely unexplored model. We simulate microsatellite data to evaluate the power of ABC to distinguish between single and multiple introductions from the same source, under a range of demographic parameters. We also apply ABC to microsatellite data from three invasions of bumblebee in New Zealand. In addition, we assess the performance of several methods of summary statistics selection. Our simulated results suggested good ability to distinguish between one- and two-wave models over much but not all of the parameter space tested, independent of summary statistics used. Globally, parameter estimation was good except for bottleneck timing. For one of the bumblebee species, we clearly rejected the MISS model, while for the other two we found inconclusive results. Since a second wave may provide genetic reinforcement to initial colonists, help relieve inbreeding among founders, or increase the hazard of the invasion, its detection may be crucial for managing invasions; we suggest that the MISS model could be considered as a potential model in future theoretical and empirical studies of invasions.

© 2014 Elsevier Inc. Manta and devil rays are an iconic group of globally distributed pelagic filter feeders, yet their evolutionary history remains enigmatic. We employed next generation sequencing of mitogenomes for nine of the 11 recognized species and two outgroups; as well as additional Sanger sequencing of two mitochondrial and two nuclear genes in an extended taxon sampling set. Analysis of the mitogenome coding regions in a Maximum Likelihood and Bayesian framework provided a well-resolved phylogeny. The deepest divergences distinguished three clades with high support, one containing Manta birostris, Manta alfredi, Mobula tarapacana, Mobula japanica and Mobula mobular; one containing Mobula kuhlii, Mobula eregoodootenkee and Mobula thurstoni; and one containing Mobula munkiana, Mobula hypostoma and Mobula rochebrunei. Mobula remains paraphyletic with the inclusion of Manta, a result that is in agreement with previous studies based on molecular and morphological data. A fossil-calibrated Bayesian random local clock analysis suggests that mobulids diverged from Rhinoptera around 30 Mya. Subsequent divergences are characterized by long internodes followed by short bursts of speciation extending from an initial episode of divergence in the Early and Middle Miocene (19-17 Mya) to a second episode during the Pliocene and Pleistocene (3.6 Mya - recent). Estimates of divergence dates overlap significantly with periods of global warming, during which upwelling intensity - and related high primary productivity in upwelling regions - decreased markedly. These periods are hypothesized to have led to fragmentation and isolation of feeding regions leading to possible regional extinctions, as well as the promotion of allopatric speciation. The closely shared evolutionary history of mobulids in combination with ongoing threats from fisheries and climate change effects on upwelling and food supply, reinforces the case for greater protection of this charismatic family of pelagic filter feeders.

Several studies have reported that the number of crossovers increases with maternal age in humans, but others have found the opposite. Resolving the true effect has implications for understanding the maternal age effect on aneuploidies. Here, we revisit this question in the largest sample to date using single nucleotide polymorphism (SNP)-chip data, comprising over 6,000 meioses from nine cohorts. We develop and fit a hierarchical model to allow for differences between cohorts and between mothers. We estimate that over 10 years, the expected number of maternal crossovers increases by 2.1% (95% credible interval (0.98%, 3.3%)). Our results are not consistent with the larger positive and negative effects previously reported in smaller cohorts. We see heterogeneity between cohorts that is likely due to chance effects in smaller samples, or possibly to confounders, emphasizing that care should be taken when interpreting results from any specific cohort about the effect of maternal age on recombination., The question of whether recombination rate increases with maternal age is controversial, with conflicting prior evidence. Here, Martin et al. analyse nine cohorts in the largest SNP-based analysis of this question and find a small positive increase with maternal age in the number of crossovers.

The Kra-Dai linguistic family includes Thai and Lao as well as a great number of languages spoken by ethnic minorities in Southeast Asia. In Thailand, a dozen of other Kra-Dai languages are spoken in addition to Thai, the national language. The genetic structure of the Kra-Dai-speaking populations in Thailand has been studied extensively using uniparentally inherited markers. To extend this line of genetic investigation, this study used 15 autosomal microsatellites of 500 individuals from 11 populations, belonging to nine Kra-Dai ethnicities, namely, the Kaleung, Phu Thai, Saek, Nyo, Lao Isan, Yuan, Black Tai, Phuan and Lue. These ethnolinguistic groups are dispersed in three different geographic regions of Thailand, that is, Northern, Northeastern and Central. The results show a very low average of pairwised F(st) (0.0099), as well as no population substructure based on STRUCTURE analysis, indicating genetic homogeneity within the Kra-Dai-speaking group, possibly owing to shared linguistic ancestry. The Mantel test, an analysis of molecular variance, and the approximate Bayesian computation procedure employed to evaluate potential factors for driving genetic diversity revealed that language is the predominant factor affecting genetic variations, whereas geography is not. The result of distance-based clustering analyses and spatial analysis of molecular variance revealed genetic distinctions of some populations, reflecting the effects of genetic drift and gene flow on allele frequency within populations, in concordance with the result of R-matrix regression. The genetic and linguistic affiliations of the contemporary Kra-Dai-speaking groups are consistent with each other despite certain deviation due to various evolutionary factors that may have occurred during their migrations and resettlements.

Interferon lambda 4 gene (IFNL4) encodes IFN-λ4, a new member of the IFN-λ family with antiviral activity. In humans IFNL4 open reading frame is truncated by a polymorphic frame-shift insertion that eliminates IFN-λ4 and turns IFNL4 into a polymorphic pseudogene. Functional IFN-λ4 has antiviral activity but the elimination of IFN-λ4 through pseudogenization is strongly associated with improved clearance of hepatitis C virus (HCV) infection. We show that functional IFN-λ4 is conserved and evolutionarily constrained in mammals and thus functionally relevant. However, the pseudogene has reached moderately high frequency in Africa, America, and Europe, and near fixation in East Asia. In fact, the pseudogenizing variant is among the 0.8% most differentiated SNPs between Africa and East Asia genome-wide. Its raise in frequency is associated with additional evidence of positive selection, which is strongest in East Asia, where this variant falls in the 0.5% tail of SNPs with strongest signatures of recent positive selection genome-wide. Using a new Approximate Bayesian Computation (ABC) approach we infer that the pseudogenizing allele appeared just before the out-of-Africa migration and was immediately targeted by moderate positive selection; selection subsequently strengthened in European and Asian populations resulting in the high frequency observed today. This provides evidence for a changing adaptive process that, by favoring IFN-λ4 inactivation, has shaped present-day phenotypic diversity and susceptibility to disease., Author Summary The genetic association with clearance of Hepatitis C virus (HCV) is one of the strongest and most elusive known associations with disease. The genetic variant more strongly associated with improved HCV clearance inactivates the recently discovered IFNL4 gene, which encodes for antiviral IFN-λ4 protein, and turns it into a polymorphic pseudogene. We show that functional IFN-λ4 is conserved and functionally important in mammals. In humans though the inactivating mutation appeared in Africa just before the out-of-Africa migration and quickly became advantageous, with the strength of selection (the degree of advantage) varying across human groups. In particular, selection became stronger out of Africa and was strongest in East Asia, raising the frequency of the pseudogene and resulting in the virtual loss of functional IFN-λ4 protein in several Asian populations. Although the environmental force driving selection is unknown, this process resulted in variable clearance of HCV in modern human populations. The complex selective history of IFNL4-inactivating allele has thus shaped present-day heterogeneity across populations not only in genetic variation, but also in relevant phenotypes and susceptibility to disease.

Recombination generates variation and facilitates evolution. Recombination (or lack thereof) also contributes to human genetic disease. Methods for mapping genes influencing complex genetic diseases via association rely on linkage disequilibrium (LD) in human populations, which is influenced by rates of recombination across the genome. Comparative population genomic analyses of recombination using related primate species can identify factors influencing rates of recombination in humans. Such studies can indicate how variable hotspots for recombination may be both among individuals (or populations) and over evolutionary timescales. Previous studies have suggested that locations of recombination hotspots are not conserved between humans and chimpanzees. We made use of the data sets from recent resequencing projects and applied a Bayesian method for identifying hotspots and estimating recombination rates. We also reanalyzed SNP data sets for regions with known hotspots in humans using samples from the human and chimpanzee. The Bayes factors (BF) of shared recombination hotspots between human and chimpanzee across regions were obtained. Based on the analysis of the aligned regions of human chromosome 21, locations where the two species show evidence of shared recombination hotspots (with high BFs) were identified. Interestingly, previous comparative studies of human and chimpanzee that focused on the known human recombination hotspots within the β-globin and HLA regions did not find overlapping of hotspots. Our results show high BFs of shared hotspots at locations within both regions, and the estimated locations of shared hotspots overlap with the locations of human recombination hotspots obtained from sperm-typing studies.

A general Bayesian model, Diploffect, is described for estimating the effects of founder haplotypes at quantitative trait loci (QTL) detected in multiparental genetic populations; such populations include the Collaborative Cross (CC), Heterogeneous Socks (HS), and many others for which local genetic variation is well described by an underlying, usually probabilistically inferred, haplotype mosaic. Our aim is to provide a framework for coherent estimation of haplotype and diplotype (haplotype pair) effects that takes into account the following: uncertainty in haplotype composition for each individual; uncertainty arising from small sample sizes and infrequently observed haplotype combinations; possible effects of dominance (for noninbred subjects); genetic background; and that provides a means to incorporate data that may be incomplete or has a hierarchical structure. Using the results of a probabilistic haplotype reconstruction as prior information, we obtain posterior distributions at the QTL for both haplotype effects and haplotype composition. Two alternative computational approaches are supplied: a Markov chain Monte Carlo sampler and a procedure based on importance sampling of integrated nested Laplace approximations. Using simulations of QTL in the incipient CC (pre-CC) and Northport HS populations, we compare the accuracy of Diploffect, approximations to it, and more commonly used approaches based on Haley–Knott regression, describing trade-offs between these methods. We also estimate effects for three QTL previously identified in those populations, obtaining posterior intervals that describe how the phenotype might be affected by diplotype substitutions at the modeled locus.

Recent progress in resolving the tree of life continues to expose relationships that resist resolution, which drives the search for novel sources of information to solve these difficult phylogenetic problems. A recent example, the presence and absence of microRNA families, has been vigorously promoted as an ideal source of phylogenetic data and has been applied to several perennial phylogenetic problems. The utility of such data for phylogenetic inference hinges critically both on developing stochastic models that provide a reasonable description of the process that give rise to these data, and also on the careful validation of those models in real inference scenarios. Remarkably, however, the statistical behavior and phylogenetic utility of microRNA data have not yet been rigorously characterized. Here we explore the behavior and performance of microRNA presence/absence data under a variety of evolutionary models and reexamine datasets from several previous studies. We find that highly heterogeneous rates of microRNA gain and loss, pervasive secondary loss, and sampling error collectively render microRNA-based inference of phylogeny difficult. Moreover, our reanalyses fundamentally alter the conclusions for four of the five studies that we reexamined. Our results indicate that the capacity of miRNA data to resolve the tree of life has been overstated, and we urge caution in their application and interpretation.

Several archaeological studies in the Central Andes have pointed at the temporal coincidence of climatic fluctuations (both long- and short-term) and episodes of cultural transition and changes of socioeconomic structures throughout the pre-Columbian period. Although most scholars explain the connection between environmental and cultural changes by the impact of climatic alterations on the capacities of the ecosystems inhabited by pre-Columbian cultures, direct evidence for assumed demographic consequences is missing so far. In this study, we address directly the impact of climatic changes on the spatial population dynamics of the Central Andes. We use a large dataset of pre-Columbian mitochondrial DNA sequences from the northern Rio Grande de Nasca drainage (RGND) in southern Peru, dating from ∼840 BC to 1450 AD. Alternative demographic scenarios are tested using Bayesian serial coalescent simulations in an approximate Bayesian computational framework. Our results indicate migrations from the lower coastal valleys of southern Peru into the Andean highlands coincident with increasing climate variability at the end of the Nasca culture at ∼640 AD. We also find support for a back-migration from the highlands to the coast coincident with droughts in the southeastern Andean highlands and improvement of climatic conditions on the coast after the decline of the Wari and Tiwanaku empires (∼1200 AD), leading to a genetic homogenization in the RGND and probably southern Peru as a whole.

Bottle gourd (Lagenaria siceraria) was one of the first domesticated plants, and the only one with a global distribution during pre-Columbian times. Although native to Africa, bottle gourd was in use by humans in east Asia, possibly as early as 11,000 y ago (BP) and in the Americas by 10,000 BP. Despite its utilitarian importance to diverse human populations, it remains unresolved how the bottle gourd came to be so widely distributed, and in particular how and when it arrived in the New World. A previous study using ancient DNA concluded that Paleoindians transported already domesticated gourds to the Americas from Asia when colonizing the New World [Erickson et al. (2005) Proc Natl Acad Sci USA 102(51):18315-18320]. However, this scenario requires the propagation of tropical-adapted bottle gourds across the Arctic. Here, we isolate 86,000 base pairs of plastid DNA from a geographically broad sample of archaeological and living bottle gourds. In contrast to the earlier results, we find that all pre-Columbian bottle gourds are most closely related to African gourds, not Asian gourds. Ocean-current drift modeling shows that wild African gourds could have simply floated across the Atlantic during the Late Pleistocene. Once they arrived in the New World, naturalized gourd populations likely became established in the Neotropics via dispersal by megafaunal mammals. These wild populations were domesticated in several distinct New World locales, most likely near established centers of food crop domestication.

Cyanobacteria possess the unique capacity to naturally produce hydrocarbons from fatty acids. Hydrocarbon compositions of thirty-two strains of cyanobacteria were characterized to reveal novel structural features and insights into hydrocarbon biosynthesis in cyanobacteria. This investigation revealed new double bond (2- and 3-heptadecene) and methyl group positions (3-, 4- and 5-methylheptadecane) for a variety of strains. Additionally, results from this study and literature reports indicate that hydrocarbon production is a universal phenomenon in cyanobacteria. All cyanobacteria possess the capacity to produce hydrocarbons from fatty acids yet not all accomplish this through the same metabolic pathway. One pathway comprises a two-step conversion of fatty acids first to fatty aldehydes and then alkanes that involves a fatty acyl ACP reductase (FAAR) and aldehyde deformylating oxygenase (ADO). The second involves a polyketide synthase (PKS) pathway that first elongates the acyl chain followed by decarboxylation to produce a terminal alkene (olefin synthase, OLS). Sixty-one strains possessing the FAAR/ADO pathway and twelve strains possessing the OLS pathway were newly identified through bioinformatic analyses. Strains possessing the OLS pathway formed a cohesive phylogenetic clade with the exception of three Moorea strains and Leptolyngbya sp. PCC 6406 which may have acquired the OLS pathway via horizontal gene transfer. Hydrocarbon pathways were identified in one-hundred-forty-two strains of cyanobacteria over a broad phylogenetic range and there were no instances where both the FAAR/ADO and the OLS pathways were found together in the same genome, suggesting an unknown selective pressure maintains one or the other pathway, but not both. © 2014 Coates et al.

The Hawaiian Drosophilidae radiation is an ecologically and morphologically diverse clade of almost 700 described species. A phylogenetic approach is key to understanding the evolutionary forces that have given rise to this diverse lineage. Here we infer the phylogeny for the antopocerus, modified tarsus and ciliated tarsus (AMC) clade, a lineage comprising 16% (91 of 687 species) of the described Hawaiian Drosophilidae. To improve on previous analyses we constructed the largest dataset to date for the AMC, including a matrix of 15 genes for 68 species. Results strongly support most of the morphologically defined species groups as monophyletic. We explore the correlation of increased diversity in biogeography, sexual selection and ecology on the present day diversity seen in this lineage using a combination of dating methods, rearing records, and distributional data. Molecular dating analyses indicate that AMC lineage started diversifying about 4.4 million years ago, culminating in the present day AMC diversity. We do not find evidence that ecological speciation or sexual selection played a part in generating this diversity, but given the limited number of described larval substrates and secondary sexual characters analyzed we can not rule these factors out entirely. An increased rate of diversification in the AMC is found to overlap with the emergence of multiple islands in the current chain of high islands, specifically Oahu and Kauai.

Here we present vB_BanS-Tsamsa, a novel temperate phage isolated from Bacillus anthracis, the agent responsible for anthrax infections in wildlife, livestock and humans. Tsamsa phage is a giant siphovirus (order Caudovirales), featuring a long, flexible and non-contractile tail of 440 nm (not including baseplate structure) and an isometric head of 82 nm in diameter. We induced Tsamsa phage in samples from two different carcass sites in Etosha National Park, Namibia. The Tsamsa phage genome is the largest sequenced Bacillus siphovirus, containing 168,876 bp and 272 ORFs. The genome features an integrase/recombinase enzyme, indicative of a temperate lifestyle. Among bacterial strains tested, the phage infected only certain members of the Bacillus cereus sensu lato group (B. anthracis, B. cereus and B. thuringiensis) and exhibited moderate specificity for B. anthracis. Tsamsa lysed seven out of 25 B. cereus strains, two out of five B. thuringiensis strains and six out of seven B. anthracis strains tested. It did not lyse B. anthracis PAK-1, an atypical strain that is also resistant to both gamma phage and cherry phage. The Tsamsa endolysin features a broader lytic spectrum than the phage host range, indicating possible use of the enzyme in Bacillus biocontrol., PLoS ONE, 9 (1), ISSN:1932-6203