Phylogeographic methods can help reveal the movement of genes between populations of organisms. This has been widely done to quantify pathogen movement between different host populations, the migration history of humans, and the geographic spread of languages or gene flow between species using the location or state of samples alongside sequence data. Phylogenies therefore offer insights into migration processes not available from classic epidemiological or occurrence data alone. Phylogeographic methods have however several known shortcomings. In particular, one of the most widely used methods treats migration the same as mutation, and therefore does not incorporate information about population demography. This may lead to severe biases in estimated migration rates for data sets where sampling is biased across populations. The structured coalescent on the other hand allows us to coherently model the migration and coalescent process, but current implementations struggle with complex data sets due to the need to infer ancestral migration histories. Thus, approximations to the structured coalescent, which integrate over all ancestral migration histories, have been developed. However, the validity and robustness of these approximations remain unclear. We present an exact numerical solution to the structured coalescent that does not require the inference of migration histories. Although this solution is computationally unfeasible for large data sets, it clarifies the assumptions of previously developed approximate methods and allows us to provide an improved approximation to the structured coalescent. We have implemented these methods in BEAST2, and we show how these methods compare under different scenarios.
Population dynamics can be inferred from genetic sequence data by using phylodynamic methods. These methods typically quantify the dynamics in unstructured populations or assume migration rates and effective population sizes to be constant through time in structured populations. When considering rates to vary through time in structured populations, the number of parameters to infer increases rapidly and the available data might not be sufficient to inform these. Additionally, it is often of interest to know what predicts these parameters rather than knowing the parameters themselves. Here, we introduce a method to infer the predictors for time-varying migration rates and effective population sizes by using a generalized linear model (GLM) approach under the marginal approximation of the structured coalescent. Using simulations, we show that our approach is able to reliably infer the model parameters and its predictors from phylogenetic trees. Furthermore, when simulating trees under the structured coalescent, we show that our new approach outperforms the discrete trait GLM model. We then apply our framework to a previously described Ebola virus dataset, where we infer the parameters and its predictors from genome sequences while accounting for phylogenetic uncertainty. We infer weekly cases to be the strongest predictor for effective population size and geographic distance the strongest predictor for migration. This approach is implemented as part of the BEAST2 package MASCOT, which allows us to jointly infer population dynamics, i.e. the parameters and predictors, within structured populations, the phylogenetic tree, and evolutionary parameters.
The spatiotemporal patterns of spread of influenza A(H1N1)pdm09 viruses on a countrywide scale are unclear in many tropical/subtropical regions mainly because spatiotemporally representative sequence data are lacking. We isolated, sequenced, and analyzed 383 A(H1N1)pdm09 viral genomes from hospitalized patients between 2009 and 2018 from seven locations across Kenya. Using these genomes and contemporaneously sampled global sequences, we characterized the spread of the virus in Kenya over several seasons using phylodynamic methods. The transmission dynamics of A(H1N1)pdm09 virus in Kenya were characterized by (i) multiple virus introductions into Kenya over the study period, although only a few of those introductions instigated local seasonal epidemics that then established local transmission clusters, (ii) persistence of transmission clusters over several epidemic seasons across the country, (iii) seasonal fluctuations in effective reproduction number (
The spread of infectious diseases is shaped by spatial and temporal aspects, such as host population structure or changes in the transmission rate or number of infected individuals over time. These spatiotemporal dynamics are imprinted in the genome of pathogens and can be recovered from those genomes using phylodynamics methods. However, phylodynamic methods typically quantify either the temporal or spatial transmission dynamics, which leads to unclear biases, as one can potentially not be inferred without the other. Here, we address this challenge by introducing a structured coalescent skyline approach, MASCOT-Skyline that allows us to jointly infer spatial and temporal transmission dynamics of infectious diseases using Markov chain Monte Carlo inference. To do so, we model the effective population size dynamics in different locations using a non-parametric function, allowing us to approximate a range of population size dynamics. We show, using a range of different viral outbreak datasets, potential issues with phylogeographic methods. We then use these viral datasets to motivate simulations of outbreaks that illuminate the nature of biases present in the different phylogeographic methods. We show that spatial and temporal dynamics should be modeled jointly even if one seeks to recover just one of the two. Further, we showcase conditions under which we can expect phylogeographic analyses to be biased, particularly different subsampling approaches, as well as provide recommendations of when we can expect them to perform well. We implemented MASCOT-Skyline as part of the open-source software package MASCOT for the Bayesian phylodynamics platform BEAST2.
The structured coalescent allows inferring migration patterns between viral subpopulations from genetic sequence data. However, these analyses typically assume that no genetic recombination process impacted the sequence evolution of pathogens. For segmented viruses, such as influenza, that can undergo reassortment this assumption is broken. Reassortment reshuffles the segments of different parent lineages upon a coinfection event, which means that the shared history of viruses has to be represented by a network instead of a tree. Therefore, full genome analyses of such viruses are complex or even impossible. Although this problem has been addressed for unstructured populations, it is still impossible to account for population structure, such as induced by different host populations, whereas also accounting for reassortment. We address this by extending the structured coalescent to account for reassortment and present a framework for investigating possible ties between reassortment and migration (host jump) events. This method can accurately estimate subpopulation dependent effective populations sizes, reassortment, and migration rates from simulated data. Additionally, we apply the new model to avian influenza A/H5N1 sequences, sampled from two avian host types, Anseriformes and Galliformes. We contrast our results with a structured coalescent without reassortment inference, which assumes independently evolving segments. This reveals that taking into account segment reassortment and using sequencing data from several viral segments for joint phylodynamic inference leads to different estimates for effective population sizes, migration, and clock rates. This new model is implemented as the Structured Coalescent with Reassortment package for BEAST 2.5 and is available at https://github.com/jugne/SCORE.
Abstract With ever more complex models used to study evolutionary patterns, approaches that facilitate efficient inference under such models are needed. Parallel tempering has long been used to speed up phylogenetic analyses and to make use of multi-core CPUs. Parallel tempering essentially runs multiple MCMC chains in parallel. All chains are heated except for one cold chain that explores the posterior probability space like a regular MCMC chain. This heating allows chains to make bigger jumps in phylogenetic state space. The heated chains can then be used to propose new states for other chains, including the cold chain. One of the practical challenges using this approach, is to find optimal temperatures of the heated chains to efficiently explore state spaces. We here provide an adaptive parallel tempering scheme to Bayesian phylogenetics, where the temperature difference between heated chains is automatically tuned to achieve a target acceptance probability of states being exchanged between individual chains. We first show the validity of this approach by comparing inferences of adaptive parallel tempering to MCMC on several datasets. We then explore where parallel tempering provides benefits over MCMC. We implemented this adaptive parallel tempering approach as an open source package licensed under GPL 3.0 to the Bayesian phylogenetics software BEAST2, available from https://github.com/nicfel/CoupledMCMC .
Abstract As shown during the SARS-CoV-2 pandemic, phylogenetic and phylodynamic methods are essential tools to study the spread and evolution of pathogens. One of the central assumptions of these methods is that the shared history of pathogens isolated from different hosts can be described by a branching phylogenetic tree. Recombination breaks this assumption. This makes it problematic to apply phylogenetic methods to study recombining pathogens, including, for example, coronaviruses. Here, we introduce a Markov chain Monte Carlo approach that allows inference of recombination networks from genetic sequence data under a template switching model of recombination. Using this method, we first show that recombination is extremely common in the evolutionary history of SARS-like coronaviruses. We then show how recombination rates across the genome of the human seasonal coronaviruses 229E, OC43 and NL63 vary with rates of adaptation. This suggests that recombination could be beneficial to fitness of human seasonal coronaviruses. Additionally, this work sets the stage for Bayesian phylogenetic tracking of the spread and evolution of SARS-CoV-2 in the future, even as recombinant viruses become prevalent.
Spatial properties of tumour growth have profound implications for cancer progression, therapeutic resistance and metastasis. Yet, how spatial position governs tumour cell division remains difficult to evaluate in clinical tumours. Here, we demonstrate that faster division on the tumour periphery leaves characteristic genetic patterns, which become evident when a phylogenetic tree is reconstructed from spatially sampled cells. Namely, rapidly dividing peripheral lineages branch more extensively and acquire more mutations than slower-dividing centre lineages. We develop a Bayesian state-dependent evolutionary phylodynamic model (SDevo) that quantifies these patterns to infer the differential division rates between peripheral and central cells. We demonstrate that this approach accurately infers spatially varying birth rates of simulated tumours across a range of growth conditions and sampling strategies. We then show that SDevo outperforms state-of-the-art, non-cancer multi-state phylodynamic methods that ignore differential sequence evolution. Finally, we apply SDevo to single-time-point, multi-region sequencing data from clinical hepatocellular carcinomas and find evidence of a three- to six-times-higher division rate on the tumour edge. With the increasing availability of high-resolution, multi-region sequencing, we anticipate that SDevo will be useful in interrogating spatial growth restrictions and could be extended to model non-spatial factors that influence tumour progression.
The World Health Organization declared mpox a public health emergency of international concern in July 2022. To investigate global mpox transmission and population-level changes associated with controlling spread, we built phylogeographic and phylodynamic models to analyze MPXV genomes from five global regions together with air traffic and epidemiological data. Our models reveal community transmission prior to detection, changes in case reporting throughout the epidemic, and a large degree of transmission heterogeneity. We find that viral introductions played a limited role in prolonging spread after initial dissemination, suggesting that travel bans would have had only a minor impact. We find that mpox transmission in North America began declining before more than 10% of high-risk individuals in the USA had vaccine-induced immunity. Our findings highlight the importance of broader routine specimen screening surveillance for emerging infectious diseases and of joint integration of genomic and epidemiological information for early outbreak control.
In 2016/2017, Washington State experienced a mumps outbreak despite high childhood vaccination rates, with cases more frequently detected among school-aged children and members of the Marshallese community. We sequenced 166 mumps virus genomes collected in Washington and other US states, and traced mumps introductions and transmission within Washington. We uncover that mumps was introduced into Washington approximately 13 times, primarily from Arkansas, sparking multiple co-circulating transmission chains. Although age and vaccination status may have impacted transmission, our data set could not quantify their precise effects. Instead, the outbreak in Washington was overwhelmingly sustained by transmission within the Marshallese community. Our findings underscore the utility of genomic data to clarify epidemiologic factors driving transmission and pinpoint contact networks as critical for mumps transmission. These results imply that contact structures and historic disparities may leave populations at increased risk for respiratory virus disease even when a vaccine is effective and widely used.
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