Rates of evolution span orders of magnitude among RNA viruses with important implications for vir... more Rates of evolution span orders of magnitude among RNA viruses with important implications for viral transmission and emergence. Although the tempo of viral evolution is often ascribed to viral features such as mutation rates and transmission mode, these factors alone cannot explain variation among closely related viruses, where host biology might operate more strongly on viral evolution. Here, we analyzed sequence data from hundreds of rabies viruses collected from bats throughout the Americas to describe dramatic variation in the speed of rabies virus evolution when circulating in ecologically distinct reservoir species. Integration of ecological and genetic data through a comparative Bayesian analysis revealed that viral evolutionary rates were labile following historical jumps between bat species and nearly four times faster in tropical and subtropical bats compared to temperate species. The association between geography and viral evolution could not be explained by host metabolism, phylogeny or variable selection pressures, and instead appeared to be a consequence of reduced seasonality in bat activity and virus transmission associated with climate. Our results demonstrate a key role for host ecology in shaping the tempo of evolution in multi-host viruses and highlight the power of comparative phylogenetic methods to identify the host and environmental features that influence transmission dynamics.
Rotaviruses are the most important etiological agent of acute gastroenteritis in young children w... more Rotaviruses are the most important etiological agent of acute gastroenteritis in young children worldwide. Among the first countries to introduce rotavirus vaccines into their national immunization programs were Belgium (November, 2006) and Australia (July, 2007). Surveillance programs in Belgium (since 1999) and Australia (since 1989) offer the opportunity to perform a detailed comparison of rotavirus strains circulating pre- and post-vaccine introduction.G1P[8] rotaviruses are the most prominent genotype in humans, and a total of 157 G1P[8] rotaviruses isolated between 1999 and 2011 were selected from Belgium and Australia and their complete genomes were sequenced. Phylogenetic analysis showed evidence of frequent reassortment among Belgian and Australian G1P[8] rotaviruses. Although many different phylogenetic subclusters were present before and after vaccine introduction, some unique clusters were only identified after vaccine introduction, which could be due to natural fluctuat...
Understanding which phenotypic traits are consistently correlated throughout evolution is a highl... more Understanding which phenotypic traits are consistently correlated throughout evolution is a highly pertinent problem in modern evolutionary biology. Here, we propose a multivariate phylogenetic latent liability model for assessing the correlation between multiple types of data, while simultaneously controlling for their unknown shared evolutionary history informed through molecular sequences. The latent formulation enables us to consider in a single model combinations of continuous traits, discrete binary traits, and discrete traits with multiple ordered and unordered states. Previous approaches have entertained a single data type generally along a fixed history, precluding estimation of correlation between traits and ignoring uncertainty in the history. We implement our model in a Bayesian phylogenetic framework, and discuss inference techniques for hypothesis testing. Finally, we showcase the method through applications to columbine flower morphology, antibiotic resistance in Salmonella, and epitope evolution in influenza.
Understanding the spatiotemporal patterns of emergence and circulation of new human seasonal infl... more Understanding the spatiotemporal patterns of emergence and circulation of new human seasonal influenza virus variants is a key scientific and public health challenge. The global circulation patterns of influenza A/H3N2 viruses are well characterized, but the patterns of A/H1N1 and B viruses have remained largely unexplored. Here we show that the global circulation patterns of A/H1N1 (up to 2009), B/Victoria, and B/Yamagata viruses differ substantially from those of A/H3N2 viruses, on the basis of analyses of 9,604 haemagglutinin sequences of human seasonal influenza viruses from 2000 to 2012. Whereas genetic variants of A/H3N2 viruses did not persist locally between epidemics and were reseeded from East and Southeast Asia, genetic variants of A/H1N1 and B viruses persisted across several seasons and exhibited complex global dynamics with East and Southeast Asia playing a limited role in disseminating new variants. The less frequent global movement of influenza A/H1N1 and B viruses c...
AMIA Joint Summits on Translational Science proceedings AMIA Summit on Translational Science, 2014
Bioinformatics and phylogeography models use viral sequence data to analyze spread of epidemics a... more Bioinformatics and phylogeography models use viral sequence data to analyze spread of epidemics and pandemics. However, few of these models have included analytical methods for testing whether certain predictors such as population density, rates of disease migration, and climate are drivers of spatial spread. Understanding the specific factors that drive spatial diffusion of viruses is critical for targeting public health interventions and curbing spread. In this paper we describe the application and evaluation of a model that integrates demographic and environmental predictors with molecular sequence data. The approach parameterizes evolutionary spread of RNA viruses as a generalized linear model (GLM) within a Bayesian inference framework using Markov chain Monte Carlo (MCMC). We evaluate this approach by reconstructing the spread of H5N1 in Egypt while assessing the impact of individual predictors on evolutionary diffusion of the virus.
The complex and unresolved evolutionary origins of the 2009 H1N1 influenza pandemic exposed major... more The complex and unresolved evolutionary origins of the 2009 H1N1 influenza pandemic exposed major gaps in our knowledge of the global spatial ecology and evolution of influenza A viruses in swine (swIAVs). Here we undertake an expansive phylogenetic analysis of swIAV sequence data and demonstrate that the global live swine trade strongly predicts the spatial dissemination of swIAVs, with Europe and North America acting as sources of viruses in Asian countries. In contrast, China has the world's largest swine population but is not a major exporter of live swine, and is not an important source of swIAVs in neighbouring Asian countries or globally. A meta-population simulation model incorporating trade data predicts that the global ecology of swIAVs is more complex than previously thought, and the United States and China's large swine populations are unlikely to be representative of swIAV diversity in their respective geographic regions, requiring independent surveillance effor...
Iran is a large country that covers the northern coast of the Persian Gulf. Iranian residents of ... more Iran is a large country that covers the northern coast of the Persian Gulf. Iranian residents of this coastal region interact closely with people from neighboring countries because of historical and cultural relationships, as well as economic activities. In addition, the inhabitants of this border region have experienced several wars, which have affected public health infrastructures. This study characterized for the first time, the evolution of the full-length genome of HBV strains in asymptomatic carrier patients living in this particular region. In addition, this study was compared and complemented by a comprehensive evolutionary analysis of the worldwide geographical distribution of HBV subgenotype D1. Evolutionary analysis demonstrates that patients living in the northern coast of the Persian Gulf are mainly infected with HBV subgenotype D1, subtype ayw2. Specific mutations related to advanced liver disease were found more frequently in these strains compared to other strains i...
Here, we present an analysis of the H1N1pdm genetic data sampled over the initial stages in the e... more Here, we present an analysis of the H1N1pdm genetic data sampled over the initial stages in the epidemic. To infer phylodynamic spread in time and space we employ a recently developed Bayesian statistical inference framework (Lemey et al., in press). We model spatial diffusion as a continuous-time Markov chain process along time-measured genealogies. In this analysis, we consider 40 locations for which sequence data were available on 06-Aug-2009. The sampling time interval of the 242 sequences spans from 30-Mar-2009 to 12-Jul-2009. The Bayesian inference typically results in a posterior distribution of phylogenetic trees, each having an estimate of the epidemic locations at the ancestral nodes in the tree. We summarize these trees using the most representative clustering pattern and annotate these clusters with the most probable location states. We can visualize this information as tree that grows over time, seeding locations each time an ancestral node is inferred to exist at a dif...
Phylogeographic approaches help uncover the imprint that spatial epidemiological processes leave ... more Phylogeographic approaches help uncover the imprint that spatial epidemiological processes leave in the genomes of fast evolving viruses. Recent Bayesian inference methods that consider phylogenetic diffusion of discretely and continuously distributed traits offer a unique opportunity to explore genotypic and phenotypic evolution in greater detail. To provide a taste of the recent advances in viral diffusion approaches, we highlight key findings arising at the intrahost, local and global epidemiological scales. We also outline future areas of research and discuss how these may contribute to a quantitative understanding of the phylodynamics of RNA viruses.
Molecular phylogenetic and phylogeographic reconstructions generally assume time-homogeneous subs... more Molecular phylogenetic and phylogeographic reconstructions generally assume time-homogeneous substitution processes. Motivated by computational convenience, this assumption sacrifices biological realism and offers little opportunity to uncover the temporal dynamics in evolutionary histories. Here, we propose an evolutionary approach that explicitly relaxes the time-homogeneity assumption by allowing the specification of different infinitesimal substitution rate matrices across different time intervals, called epochs, along the evolutionary history. We focus on an epoch model implementation in a Bayesian inference framework that offers great modeling flexibility in drawing inference about any discrete data type characterized as a continuous-time Markov chain, including phylogeographic traits. To alleviate the computational burden that the additional temporal heterogeneity imposes, we adopt a massively parallel approach that achieves both fine- and coarse-grain parallelization of the ...
The HIV evolutionary processes continuously unfold, leaving a measurable footprint in viral gene ... more The HIV evolutionary processes continuously unfold, leaving a measurable footprint in viral gene sequences. A variety of statistical models and inference techniques have been developed to reconstruct the HIV evolutionary history and to investigate the population genetic processes that shape viral diversity. Remarkably different population genetic forces are at work within and among hosts. Population-level HIV phylogenies are mainly shaped by selectively neutral epidemiologic processes, implying that genealogy-based population genetic inference can be useful to study the HIV epidemic history. Such evolutionary analyses have shed light on the origins of HIV, and on the epidemic spread of viral variants in different geographic locations and in different populations. The HIV genealogies reconstructed from within-host sequences indicate the action of selection pressure. In addition, recombination has a significant impact on HIV genetic diversity. Accurately quantifying both the adaptatio...
Rates of evolution span orders of magnitude among RNA viruses with important implications for vir... more Rates of evolution span orders of magnitude among RNA viruses with important implications for viral transmission and emergence. Although the tempo of viral evolution is often ascribed to viral features such as mutation rates and transmission mode, these factors alone cannot explain variation among closely related viruses, where host biology might operate more strongly on viral evolution. Here, we analyzed sequence data from hundreds of rabies viruses collected from bats throughout the Americas to describe dramatic variation in the speed of rabies virus evolution when circulating in ecologically distinct reservoir species. Integration of ecological and genetic data through a comparative Bayesian analysis revealed that viral evolutionary rates were labile following historical jumps between bat species and nearly four times faster in tropical and subtropical bats compared to temperate species. The association between geography and viral evolution could not be explained by host metabolism, phylogeny or variable selection pressures, and instead appeared to be a consequence of reduced seasonality in bat activity and virus transmission associated with climate. Our results demonstrate a key role for host ecology in shaping the tempo of evolution in multi-host viruses and highlight the power of comparative phylogenetic methods to identify the host and environmental features that influence transmission dynamics.
Rotaviruses are the most important etiological agent of acute gastroenteritis in young children w... more Rotaviruses are the most important etiological agent of acute gastroenteritis in young children worldwide. Among the first countries to introduce rotavirus vaccines into their national immunization programs were Belgium (November, 2006) and Australia (July, 2007). Surveillance programs in Belgium (since 1999) and Australia (since 1989) offer the opportunity to perform a detailed comparison of rotavirus strains circulating pre- and post-vaccine introduction.G1P[8] rotaviruses are the most prominent genotype in humans, and a total of 157 G1P[8] rotaviruses isolated between 1999 and 2011 were selected from Belgium and Australia and their complete genomes were sequenced. Phylogenetic analysis showed evidence of frequent reassortment among Belgian and Australian G1P[8] rotaviruses. Although many different phylogenetic subclusters were present before and after vaccine introduction, some unique clusters were only identified after vaccine introduction, which could be due to natural fluctuat...
Understanding which phenotypic traits are consistently correlated throughout evolution is a highl... more Understanding which phenotypic traits are consistently correlated throughout evolution is a highly pertinent problem in modern evolutionary biology. Here, we propose a multivariate phylogenetic latent liability model for assessing the correlation between multiple types of data, while simultaneously controlling for their unknown shared evolutionary history informed through molecular sequences. The latent formulation enables us to consider in a single model combinations of continuous traits, discrete binary traits, and discrete traits with multiple ordered and unordered states. Previous approaches have entertained a single data type generally along a fixed history, precluding estimation of correlation between traits and ignoring uncertainty in the history. We implement our model in a Bayesian phylogenetic framework, and discuss inference techniques for hypothesis testing. Finally, we showcase the method through applications to columbine flower morphology, antibiotic resistance in Salmonella, and epitope evolution in influenza.
Understanding the spatiotemporal patterns of emergence and circulation of new human seasonal infl... more Understanding the spatiotemporal patterns of emergence and circulation of new human seasonal influenza virus variants is a key scientific and public health challenge. The global circulation patterns of influenza A/H3N2 viruses are well characterized, but the patterns of A/H1N1 and B viruses have remained largely unexplored. Here we show that the global circulation patterns of A/H1N1 (up to 2009), B/Victoria, and B/Yamagata viruses differ substantially from those of A/H3N2 viruses, on the basis of analyses of 9,604 haemagglutinin sequences of human seasonal influenza viruses from 2000 to 2012. Whereas genetic variants of A/H3N2 viruses did not persist locally between epidemics and were reseeded from East and Southeast Asia, genetic variants of A/H1N1 and B viruses persisted across several seasons and exhibited complex global dynamics with East and Southeast Asia playing a limited role in disseminating new variants. The less frequent global movement of influenza A/H1N1 and B viruses c...
AMIA Joint Summits on Translational Science proceedings AMIA Summit on Translational Science, 2014
Bioinformatics and phylogeography models use viral sequence data to analyze spread of epidemics a... more Bioinformatics and phylogeography models use viral sequence data to analyze spread of epidemics and pandemics. However, few of these models have included analytical methods for testing whether certain predictors such as population density, rates of disease migration, and climate are drivers of spatial spread. Understanding the specific factors that drive spatial diffusion of viruses is critical for targeting public health interventions and curbing spread. In this paper we describe the application and evaluation of a model that integrates demographic and environmental predictors with molecular sequence data. The approach parameterizes evolutionary spread of RNA viruses as a generalized linear model (GLM) within a Bayesian inference framework using Markov chain Monte Carlo (MCMC). We evaluate this approach by reconstructing the spread of H5N1 in Egypt while assessing the impact of individual predictors on evolutionary diffusion of the virus.
The complex and unresolved evolutionary origins of the 2009 H1N1 influenza pandemic exposed major... more The complex and unresolved evolutionary origins of the 2009 H1N1 influenza pandemic exposed major gaps in our knowledge of the global spatial ecology and evolution of influenza A viruses in swine (swIAVs). Here we undertake an expansive phylogenetic analysis of swIAV sequence data and demonstrate that the global live swine trade strongly predicts the spatial dissemination of swIAVs, with Europe and North America acting as sources of viruses in Asian countries. In contrast, China has the world's largest swine population but is not a major exporter of live swine, and is not an important source of swIAVs in neighbouring Asian countries or globally. A meta-population simulation model incorporating trade data predicts that the global ecology of swIAVs is more complex than previously thought, and the United States and China's large swine populations are unlikely to be representative of swIAV diversity in their respective geographic regions, requiring independent surveillance effor...
Iran is a large country that covers the northern coast of the Persian Gulf. Iranian residents of ... more Iran is a large country that covers the northern coast of the Persian Gulf. Iranian residents of this coastal region interact closely with people from neighboring countries because of historical and cultural relationships, as well as economic activities. In addition, the inhabitants of this border region have experienced several wars, which have affected public health infrastructures. This study characterized for the first time, the evolution of the full-length genome of HBV strains in asymptomatic carrier patients living in this particular region. In addition, this study was compared and complemented by a comprehensive evolutionary analysis of the worldwide geographical distribution of HBV subgenotype D1. Evolutionary analysis demonstrates that patients living in the northern coast of the Persian Gulf are mainly infected with HBV subgenotype D1, subtype ayw2. Specific mutations related to advanced liver disease were found more frequently in these strains compared to other strains i...
Here, we present an analysis of the H1N1pdm genetic data sampled over the initial stages in the e... more Here, we present an analysis of the H1N1pdm genetic data sampled over the initial stages in the epidemic. To infer phylodynamic spread in time and space we employ a recently developed Bayesian statistical inference framework (Lemey et al., in press). We model spatial diffusion as a continuous-time Markov chain process along time-measured genealogies. In this analysis, we consider 40 locations for which sequence data were available on 06-Aug-2009. The sampling time interval of the 242 sequences spans from 30-Mar-2009 to 12-Jul-2009. The Bayesian inference typically results in a posterior distribution of phylogenetic trees, each having an estimate of the epidemic locations at the ancestral nodes in the tree. We summarize these trees using the most representative clustering pattern and annotate these clusters with the most probable location states. We can visualize this information as tree that grows over time, seeding locations each time an ancestral node is inferred to exist at a dif...
Phylogeographic approaches help uncover the imprint that spatial epidemiological processes leave ... more Phylogeographic approaches help uncover the imprint that spatial epidemiological processes leave in the genomes of fast evolving viruses. Recent Bayesian inference methods that consider phylogenetic diffusion of discretely and continuously distributed traits offer a unique opportunity to explore genotypic and phenotypic evolution in greater detail. To provide a taste of the recent advances in viral diffusion approaches, we highlight key findings arising at the intrahost, local and global epidemiological scales. We also outline future areas of research and discuss how these may contribute to a quantitative understanding of the phylodynamics of RNA viruses.
Molecular phylogenetic and phylogeographic reconstructions generally assume time-homogeneous subs... more Molecular phylogenetic and phylogeographic reconstructions generally assume time-homogeneous substitution processes. Motivated by computational convenience, this assumption sacrifices biological realism and offers little opportunity to uncover the temporal dynamics in evolutionary histories. Here, we propose an evolutionary approach that explicitly relaxes the time-homogeneity assumption by allowing the specification of different infinitesimal substitution rate matrices across different time intervals, called epochs, along the evolutionary history. We focus on an epoch model implementation in a Bayesian inference framework that offers great modeling flexibility in drawing inference about any discrete data type characterized as a continuous-time Markov chain, including phylogeographic traits. To alleviate the computational burden that the additional temporal heterogeneity imposes, we adopt a massively parallel approach that achieves both fine- and coarse-grain parallelization of the ...
The HIV evolutionary processes continuously unfold, leaving a measurable footprint in viral gene ... more The HIV evolutionary processes continuously unfold, leaving a measurable footprint in viral gene sequences. A variety of statistical models and inference techniques have been developed to reconstruct the HIV evolutionary history and to investigate the population genetic processes that shape viral diversity. Remarkably different population genetic forces are at work within and among hosts. Population-level HIV phylogenies are mainly shaped by selectively neutral epidemiologic processes, implying that genealogy-based population genetic inference can be useful to study the HIV epidemic history. Such evolutionary analyses have shed light on the origins of HIV, and on the epidemic spread of viral variants in different geographic locations and in different populations. The HIV genealogies reconstructed from within-host sequences indicate the action of selection pressure. In addition, recombination has a significant impact on HIV genetic diversity. Accurately quantifying both the adaptatio...
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