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1.  An Allometric Relationship between the Genome Length and Virion Volume of Viruses 
Journal of Virology  2014;88(11):6403-6410.
Virions vary in size by at least 4 orders of magnitude, yet the evolutionary forces responsible for this enormous diversity are unknown. We document a significant allometric relationship, with an exponent of approximately 1.5, between the genome length and virion volume of viruses and find that this relationship is not due to geometric constraints. Notably, this allometric relationship holds regardless of genomic nucleic acid, genome structure, or type of virion architecture and therefore represents a powerful scaling law. In contrast, no such relationship is observed at the scale of individual genes. Similarly, after adjusting for genome length, no association is observed between virion volume and the number of proteins, ruling out protein number as the explanation for the relationship between genome and virion sizes. Such a fundamental allometric relationship not only sheds light on the constraints to virus evolution, in that increases in virion size but not necessarily structure are associated with concomitant increases in genome size, but also implies that virion sizes in nature can be broadly predicted from genome sequence data alone.
IMPORTANCE Viruses vary dramatically in both genome and virion sizes, but the factors responsible for this diversity are uncertain. Through a comparative and quantitative investigation of these two fundamental biological parameters across diverse viral taxa, we show that genome length and virion volume conform to a simple allometric scaling law. Notably, this allometric relationship holds regardless of the type of virus, including those with both RNA and DNA genomes, and encompasses viruses that exhibit more than 3 logs of genome size variation. Accordingly, this study helps to reveal the basic rules of virus design.
PMCID: PMC4093846  PMID: 24672040
2.  Avian oncogenesis induced by lymphoproliferative disease virus: a neglected or emerging retroviral pathogen? 
Virology  2013;0:2-12.
Lymphoproliferative disease virus (LPDV) is an exogenous oncogenic retrovirus that induces lymphoid tumors in some galliform species of birds. Historically, outbreaks of LPDV have been reported from Europe and Israel. Although the virus has previously never been detected in North America, herein we describe the widespread distribution, genetic diversity, pathogenesis, and evolution of LPDV in the United States. Characterization of the provirus genome of the index LPDV case from North America demonstrated an 88% nucleotide identity to the Israeli prototype strain. Although phylogenetic analysis indicated that the majority of viruses fell into a single North American lineage, a small subset of viruses from South Carolina were most closely related to the Israeli prototype. These results suggest that LPDV was transferred between continents to initiate outbreaks of disease. However, the direction (New World to Old World or vice versa), mechanism, and time frame of the transcontinental spread currently remain unknown.
PMCID: PMC3925403  PMID: 24503062
Lymphoproliferative disease virus (LPDV); alpharetrovirus; avian tumor viruses; exogenous retrovirus; oncogenesis; Order Galliformes
3.  Emergence of a New Lineage of Dengue Virus Type 2 Identified in Travelers Entering Western Australia from Indonesia, 2010-2012 
PLoS Neglected Tropical Diseases  2015;9(1):e0003442.
Dengue virus (DENV) transmission is ubiquitous throughout the tropics. More than 70% of the current global dengue disease burden is borne by people who live in the Asia-Pacific region. We sequenced the E gene of DENV isolated from travellers entering Western Australia between 2010–2012, most of whom visited Indonesia, and identified a diverse array of DENV1-4, including multiple co-circulating viral lineages. Most viruses were closely related to lineages known to have circulated in Indonesia for some time, indicating that this geographic region serves as a major hub for dengue genetic diversity. Most notably, we identified a new lineage of DENV-2 (Cosmopolitan genotype) that emerged in Bali in 2011–2012. The spread of this lineage should clearly be monitored. Surveillance of symptomatic returned travellers provides important and timely information on circulating DENV serotypes and genotypes, and can reveal the herald wave of dengue and other emerging infectious diseases.
Author Summary
Dengue is currently the most rapidly spreading mosquito-borne viral disease of humans, and is endemic in most tropical and sub-tropical countries. An estimated 390 million infections occur annually, and over 70% of the current global dengue disease burden is borne by people who live in Southeast Asia and the Western Pacific region. DENV serotype and genotype data is lacking in many parts of this region, limiting our attempts to understand the observed patterns of hyperendemicity and disease severity. Many countries in the Southeast Asia and Western Pacific region are popular tourist destinations, and dengue has been identified as a cause of travel-related illness in people returning from endemic countries. We sequenced the E gene of DENV isolated from travellers returning to Western Australia from 7 countries throughout Asia between 2010 and 2012. The majority of DENV originated in Indonesia, predominantly Bali, a popular travel destination for Australians. We identified hyperendemic transmission of all four DENV serotypes in Bali in 2010; circulating DENV included dominant local strains which had circulated for several years in Indonesia and Singapore, as well as strains more recently introduced into Bali from other countries in the region. Finally, we show the emergence of a new lineage of DENV2 (Cosmopolitan genotype) in 2011–2012, which should be monitored. Travellers may act as sentinels and provide important information on DENV genotypes and linages circulating in countries where locally generated detailed genetic data may not be available.
PMCID: PMC4311992  PMID: 25635775
4.  Gene duplication and phylogeography of North American members of the Hart Park serogroup of avian rhabdoviruses 
Virology  2013;448:10.1016/j.virol.2013.10.024.
Flanders virus (FLAV) and Hart Park virus (HPV) are rhabdoviruses that circulate in mosquito-bird cycles in the eastern and western United States, respectively, and constitute the only two North American representatives of the Hart Park serogroup. Previously, it was suggested that FLAV is unique among the rhabdoviruses in that it contains two pseudogenes located between the P and M genes, while the cognate sequence for HPV has been lacking. Herein, we demonstrate that FLAV and HPV do not contain pseudogenes in this region, but encode three small functional proteins designated as U1, U2, and U3 that apparently arose by gene duplication. To further investigate the U1-U2-U3 region, we conducted the first large-scale evolutionary analysis of a member of the Hart Park serogroup by analyzing over 100 spatially and temporally distinct FLAV isolates. Our phylogeographic analysis demonstrates that although FLAV appears to be slowly evolving, phylogenetically divergent lineages co-circulate sympatrically.
PMCID: PMC3873333  PMID: 24314659
Flanders virus; Hart Park virus; Hart Park serogroup; rhabdovirus; gene duplication; U1, U2, and U3 proteins; SH protein; coupled translation; bird-associated arbovirus
5.  Pandemics–Keep Calm and Carry On 
PLoS Biology  2014;12(2):e1001780.
Evolutionary biologist Edward Holmes reviews Peter Doherty's book, Pandemics: What Everyone Needs to Know.
PMCID: PMC3913555
6.  Low frequency of paleoviral infiltration across the avian phylogeny 
Genome Biology  2014;15(12):539.
Mammalian genomes commonly harbor endogenous viral elements. Due to a lack of comparable genome-scale sequence data, far less is known about endogenous viral elements in avian species, even though their small genomes may enable important insights into the patterns and processes of endogenous viral element evolution.
Through a systematic screening of the genomes of 48 species sampled across the avian phylogeny we reveal that birds harbor a limited number of endogenous viral elements compared to mammals, with only five viral families observed: Retroviridae, Hepadnaviridae, Bornaviridae, Circoviridae, and Parvoviridae. All nonretroviral endogenous viral elements are present at low copy numbers and in few species, with only endogenous hepadnaviruses widely distributed, although these have been purged in some cases. We also provide the first evidence for endogenous bornaviruses and circoviruses in avian genomes, although at very low copy numbers. A comparative analysis of vertebrate genomes revealed a simple linear relationship between endogenous viral element abundance and host genome size, such that the occurrence of endogenous viral elements in bird genomes is 6- to 13-fold less frequent than in mammals.
These results reveal that avian genomes harbor relatively small numbers of endogenous viruses, particularly those derived from RNA viruses, and hence are either less susceptible to viral invasions or purge them more effectively.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0539-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4272516  PMID: 25496498
7.  Kolente virus, a rhabdovirus species isolated from ticks and bats in the Republic of Guinea 
The Journal of General Virology  2013;94(Pt 12):2609-2615.
Kolente virus (KOLEV) is a rhabdovirus originally isolated from ticks and a bat in Guinea, West Africa, in 1985. Although tests at the time of isolation suggested that KOLEV is a novel rhabdovirus, it has remained largely uncharacterized. We assembled the complete genome sequence of the prototype strain DakAr K7292, which was found to encode the five canonical rhabdovirus structural proteins (N, P, M, G and L) with alternative ORFs (>180 nt) in the P and L genes. Serologically, KOLEV exhibited a weak antigenic relationship with Barur and Fukuoka viruses in the Kern Canyon group. Phylogenetic analysis revealed that KOLEV represents a distinct and divergent lineage that shows no clear relationship to any rhabdovirus except Oita virus, although with limited phylogenetic resolution. In summary, KOLEV represents a novel species in the family Rhabdoviridae.
PMCID: PMC3836499  PMID: 24062532
8.  Seasonal Drivers of the Epidemiology of Arthropod-Borne Viruses in Australia 
Arthropod-borne viruses are a major cause of emerging disease with significant public health and economic impacts. However, the factors that determine their activity and seasonality are not well understood. In Australia, a network of sentinel cattle herds is used to monitor the distribution of several such viruses and to define virus-free regions. Herein, we utilize these serological data to describe the seasonality, and its drivers, of three economically important animal arboviruses: bluetongue virus, Akabane virus and bovine ephemeral fever virus. Through epidemiological time-series analyses of sero-surveillance data of 180 sentinel herds between 2004–2012, we compared seasonal parameters across latitudes, ranging from the tropical north (−10°S) to the more temperate south (−40°S). This analysis revealed marked differences in seasonality between distinct geographic regions and climates: seasonality was most pronounced in southern regions and gradually decreased as latitude decreased toward the Equator. Further, we show that both the timing of epidemics and the average number of seroconversions have a strong geographical component, which likely reflect patterns of vector abundance through co-varying climatic factors, especially temperature and rainfall. Notably, despite their differences in biology, including insect vector species, all three viruses exhibited very similar seasonality. By revealing the factors that shape spatial and temporal distributions, our study provides a more complete understanding of arbovirus seasonality that will enable better risk predictions.
Author Summary
Arthropod-borne viruses (arboviruses) are a group of viruses that can have major impacts on public health, animal health and agricultural trade, and appear to be increasing in both number and prevalence worldwide. Despite their importance as emerging pathogens, the spatial patterns, long-term seasonal characteristics and drivers of seasonality in many arboviruses are poorly understood. The island continent of Australia provides an ideal case study for the spatial analysis of emerging arboviruses, harboring diverse climatic conditions across a wide range of latitudes. Herein we utilize long-term serological data from a nationwide network of sentinel herds in Australia to describe the seasonality of three economically important animal arboviruses: bluetongue virus, Akabane virus and bovine ephemeral fever virus. Using epidemiological time series analysis, we demonstrate that these viruses exhibit a distinct spatial pattern in both the peak timing and intensity of annual epidemic cycles, with the strongest seasonality observed in southerly geographic regions. In addition, we reveal the climatic factors that drive patterns of arbovirus distribution and, by doing so, provide a more complete understanding of arbovirus seasonality, which in turn will improve the risk assessment of these viruses.
PMCID: PMC4239014  PMID: 25412443
9.  Host-Specific Parvovirus Evolution in Nature Is Recapitulated by In Vitro Adaptation to Different Carnivore Species 
PLoS Pathogens  2014;10(11):e1004475.
Canine parvovirus (CPV) emerged as a new pandemic pathogen of dogs in the 1970s and is closely related to feline panleukopenia virus (FPV), a parvovirus of cats and related carnivores. Although both viruses have wide host ranges, analysis of viral sequences recovered from different wild carnivore species, as shown here, demonstrated that >95% were derived from CPV-like viruses, suggesting that CPV is dominant in sylvatic cycles. Many viral sequences showed host-specific mutations in their capsid proteins, which were often close to sites known to control binding to the transferrin receptor (TfR), the host receptor for these carnivore parvoviruses, and which exhibited frequent parallel evolution. To further examine the process of host adaptation, we passaged parvoviruses with alternative backgrounds in cells from different carnivore hosts. Specific mutations were selected in several viruses and these differed depending on both the background of the virus and the host cells in which they were passaged. Strikingly, these in vitro mutations recapitulated many specific changes seen in viruses from natural populations, strongly suggesting they are host adaptive, and which were shown to result in fitness advantages over their parental virus. Comparison of the sequences of the transferrin receptors of the different carnivore species demonstrated that many mutations occurred in and around the apical domain where the virus binds, indicating that viral variants were likely selected through their fit to receptor structures. Some of the viruses accumulated high levels of variation upon passage in alternative hosts, while others could infect multiple different hosts with no or only a few additional mutations. Overall, these studies demonstrate that the evolutionary history of a virus, including how long it has been circulating and in which hosts, as well as its phylogenetic background, has a profound effect on determining viral host range.
Author Summary
Canine parvovirus (CPV) is an important example of a viral pathogen that evolved by cross-species transmission and mutation to initiate a disease pandemic. Carnivore parvoviruses infect many species, and their passage in different hosts may select mutations that facilitate host jumping; for example, natural passage of CPV in raccoons may have facilitated its adaptation to dogs. Conversely, some raccoon-adapted viruses are non-infectious to dogs, illustrating that host range barriers exist among different carnivores. Here we demonstrate that these barriers can be overcome by only a few mutations in the virus that likely alter host receptor binding, and that host adaptation can differ dramatically among very similar viruses. Importantly, we also show that passage of viruses in cell cultures of different hosts results in mutations at the same sites that vary in nature and confer fitness increases, strongly suggesting that they are adaptively important. These findings demonstrate that parvoviruses may cross species barriers to infect less susceptible hosts through single or only a few mutations, and that differences in the genetic background, host range, and/or evolutionary history of the viruses influence their propensity to jump hosts. Overall, these discoveries help reveal the mechanisms that control host switching and viral emergence.
PMCID: PMC4223063  PMID: 25375184
10.  Contact Heterogeneity, Rather Than Transmission Efficiency, Limits the Emergence and Spread of Canine Influenza Virus 
PLoS Pathogens  2014;10(10):e1004455.
Host-range shifts in influenza virus are a major risk factor for pandemics. A key question in the study of emerging zoonoses is how the evolution of transmission efficiency interacts with heterogeneity in contact patterns in the new host species, as this interplay influences disease dynamics and prospects for control. Here we use a synergistic mixture of models and data to tease apart the evolutionary and demographic processes controlling a host-range shift in equine H3N8-derived canine influenza virus (CIV). CIV has experienced 15 years of continuous transfer among dogs in the United States, but maintains a patchy distribution, characterized by sporadic short-lived outbreaks coupled with endemic hotspots in large animal shelters. We show that CIV has a high reproductive potential in these facilities (mean R0 = 3.9) and that these hotspots act as refugia from the sparsely connected majority of the dog population. Intriguingly, CIV has evolved a transmission efficiency that closely matches the minimum required to persist in these refugia, leaving it poised on the extinction/invasion threshold of the host contact network. Corresponding phylogenetic analyses show strong geographic clustering in three US regions, and that the effective reproductive number of the virus (Re) in the general dog population is close to 1.0. Our results highlight the critical role of host contact structure in CIV dynamics, and show how host contact networks could shape the evolution of pathogen transmission efficiency. Importantly, efficient control measures could eradicate the virus, in turn minimizing the risk of future sustained transmission among companion dogs that could represent a potential new axis to the human-animal interface for influenza.
Author Summary
Influenza virus infects a range of vertebrate hosts, including domesticated animals as well as humans. Some of the most serious influenza pandemics in humans have involved host range shifts, when an influenza virus jumps from one host species to another. Importantly, however, host range shifts do not always cause pandemics. Rather, epidemiological patterns tend to be unpredictable in new host species, causing disease patterns that change over space and time. In this paper, we analyze epidemiological and evolutionary dynamics of canine influenza virus (CIV), which jumped to dogs in the late 1990s from an equine strain (EIV) prevalent in horses. We show that the epidemiology and evolution of CIV is strongly influenced by heterogeneous patterns of infectious contact among dogs in the US. A few large populations in metropolitan animal shelters serve as reservoirs for CIV, but the virus cannot be maintained for long in smaller facilities or in the companion dog population without input from the larger shelters, which represent disease hotspots. These hotspot dynamics give a clear picture of what can happen in the time between the beginning of a host range shift and the onset of a possible pandemic, allowing more targeted strategies for control and eradication.
PMCID: PMC4207809  PMID: 25340642
11.  What can we predict about viral evolution and emergence? 
Current opinion in virology  2012;3(2):180-184.
Predicting the emergence of infectious diseases has been touted as one of the most important goals of biomedical science, with an array of funding schemes and research projects. However, evolutionary biology generally has a dim view of prediction, and there is a danger that erroneous predictions will mean a misuse of resources and undermine public confidence. Herein, I outline what can be realistically predicted about viral evolution and emergence, argue that any success in predicting what may emerge is likely to be limited, but that forecasting how viruses might evolve and spread following emergence is more tractable. I also emphasize that a properly grounded research program in disease prediction must involve a synthesis of ecological and genetic perspectives.
PMCID: PMC3626763  PMID: 23273851
12.  Emergence of a Highly Pathogenic Avian Influenza Virus from a Low-Pathogenic Progenitor 
Journal of Virology  2014;88(8):4375-4388.
Avian influenza (AI) viruses of the H7 subtype have the potential to evolve into highly pathogenic (HP) viruses that represent a major economic problem for the poultry industry and a threat to global health. However, the emergence of HPAI viruses from low-pathogenic (LPAI) progenitor viruses currently is poorly understood. To investigate the origin and evolution of one of the most important avian influenza epidemics described in Europe, we investigated the evolutionary and spatial dynamics of the entire genome of 109 H7N1 (46 LPAI and 63 HPAI) viruses collected during Italian H7N1 outbreaks between March 1999 and February 2001. Phylogenetic analysis revealed that the LPAI and HPAI epidemics shared a single ancestor, that the HPAI strains evolved from the LPAI viruses in the absence of reassortment, and that there was a parallel emergence of mutations among HPAI and later LPAI lineages. Notably, an ultradeep-sequencing analysis demonstrated that some of the amino acid changes characterizing the HPAI virus cluster were already present with low frequency within several individual viral populations from the beginning of the LPAI H7N1 epidemic. A Bayesian phylogeographic analysis revealed stronger spatial structure during the LPAI outbreak, reflecting the more rapid spread of the virus following the emergence of HPAI. The data generated in this study provide the most complete evolutionary and phylogeographic analysis of epidemiologically intertwined high- and low-pathogenicity viruses undertaken to date and highlight the importance of implementing prompt eradication measures against LPAI to prevent the appearance of viruses with fitness advantages and unpredictable pathogenic properties.
IMPORTANCE The Italian H7 AI epidemic of 1999 to 2001 was one of the most important AI outbreaks described in Europe. H7 viruses have the ability to evolve into HP forms from LP precursors, although the mechanisms underlying this evolutionary transition are only poorly understood. We combined epidemiological information, whole-genome sequence data, and ultradeep sequencing approaches to provide the most complete characterization of the evolution of HPAI from LPAI viruses undertaken to date. Our analysis revealed that the LPAI viruses were the direct ancestors of the HPAI strains and identified low-frequency minority variants with HPAI mutations that were present in the LPAI samples. Spatial analysis provided key information for the design of effective control strategies for AI at both local and global scales. Overall, this work highlights the importance of implementing rapid eradication measures to prevent the emergence of novel influenza viruses with severe pathogenic properties.
PMCID: PMC3993777  PMID: 24501401
13.  Niakha virus: A novel member of the family Rhabdoviridae isolated from phlebotomine sandflies in Senegal 
Virology  2013;444(0):80-89.
Members of the family Rhabdoviridae have been assigned to eight genera but many remain unassigned. Rhabdoviruses have a remarkably diverse host range that includes terrestrial and marine animals, invertebrates and plants. Transmission of some rhabdoviruses often requires an arthropod vector, such as mosquitoes, midges, sandflies, ticks, aphids and leafhoppers, in which they replicate. Herein we characterize Niakha virus (NIAV), a previously uncharacterized rhabdovirus isolated from phebotomine sandflies in Senegal. Analysis of the 11,124 nt genome sequence indicates that it encodes the five common rhabdovirus proteins with alternative ORFs in the M, G and L genes. Phylogenetic analysis of the L protein indicate that NIAV’s closest relative is Oak Vale rhabdovirus, although in this analysis NIAV is still so phylogenetically distinct that it might be classified as distinct from the eight currently recognized Rhabdoviridae genera. This observation highlights the vast, and yet not fully recognized diversity, of this family.
PMCID: PMC3755043  PMID: 23773405
Niakha virus (NIAV); Rhabdoviridae; phlebotomine sandflies; complement fixation; West Africa
14.  Evolution of Bovine Ephemeral Fever Virus in the Australian Episystem 
Journal of Virology  2014;88(3):1525-1535.
Bovine ephemeral fever virus (BEFV) is an arthropod-borne rhabdovirus that causes a debilitating disease of cattle in Africa, Asia, and Australia; however, its global geodynamics are poorly understood. An evolutionary analysis of G gene (envelope glycoprotein) ectodomain sequences of 97 BEFV isolates collected from Australia during 1956 to 2012 revealed that all have a single common ancestor and are phylogenetically distinct from BEFV sampled in other geographical regions. The age of the Australian clade is estimated to be between 56 and 65 years, suggesting that BEFV has entered the continent on few occasions since it was first reported in 1936 and that the 1955-1956 epizootic was the source of all currently circulating viruses. Notably, the Australian clade has evolved as a single genetic lineage across the continent and at a high evolutionary rate of ∼10−3 nucleotide substitutions/site/year. Screening of 66 isolates using monoclonal antibodies indicated that neutralizing antigenic sites G1, G2, and G4 have been relatively stable, although variations in site G3a/b defined four antigenic subtypes. A shift in an epitope at site G3a, which occurred in the mid-1970s, was strongly associated with a K218R substitution. Similarly, a shift at site G3b was associated primarily with substitutions at residues 215, 220, and 223, which map to the tip of the spike on the prefusion form of the G protein. Finally, we propose that positive selection on residue 215 was due to cross-reacting neutralizing antibody to Kimberley virus (KIMV).
PMCID: PMC3911615  PMID: 24227855
15.  The Effect of Gene Overlapping on the Rate of RNA Virus Evolution 
Molecular Biology and Evolution  2013;30(8):1916-1928.
Gene overlapping is widely employed by RNA viruses to generate genetic novelty while retaining a small genome size. However, gene overlapping also increases the deleterious effect of mutations as they affect more than one gene, thereby reducing the evolutionary rate of RNA viruses and hence their adaptive capacity. Although there is general agreement on the benefits of gene overlapping as a mechanism of genomic compression for rapidly evolving organisms, its effect on the pace of RNA virus evolution remains a source of debate. To address this issue, we collected sequence data from 117 instances of gene overlapping across 19 families, 30 genera, and 55 species of RNA viruses. On these data, we analyzed how genetic distances, selective pressures, and the distribution of RNA secondary structures and conserved protein functional domains vary between overlapping (OV) and nonoverlapping (NOV) regions. We show that gene overlapping generally results in a decrease in the rate of RNA virus evolution through a reduction in the frequency of synonymous mutations. However, this effect is less pronounced in genes with a terminal rather than an internal gene overlap, which might result from a greater proportion of protein functional conserved domains in NOV than in OV regions, in turn reducing the number of nonsynonymous mutations in the former. Overall, our analyses clarify the role of gene overlapping as a modulator of the evolutionary rates exhibited by RNA viruses and shed light on the factors that shape the genetic diversity of this important group of pathogens.
PMCID: PMC3708502  PMID: 23686658
overlapping genes; rate of evolution; RNA viruses; comparative genomics
16.  Extensive diversity of Rickettsiales bacteria in two species of ticks from China and the evolution of the Rickettsiales 
Bacteria of the order Rickettsiales (Alphaproteobacteria) are obligate intracellular parasites that infect species from virtually every major eukaryotic lineage. Several rickettsial genera harbor species that are significant emerging and re-emerging pathogens of humans. As species of Rickettsiales are associated with an extremely diverse host range, a better understanding of the historical associations between these bacteria and their hosts will provide important information on their evolutionary trajectories and, particularly, their potential emergence as pathogens.
Nine species of Rickettsiales (two in the genus Rickettsia, three in the genus Anaplasma, and four in the genus Ehrlichia) were identified in two species of hard ticks (Dermacentor nuttalli and Hyalomma asiaticum) from two geographic regions in Xinjiang through genetic analyses of 16S rRNA, gltA, and groEL gene sequences. Notably, two lineages of Ehrlichia and one lineage of Anaplasma were distinct from any known Rickettsiales, suggesting the presence of potentially novel species in ticks in Xinjiang. Our phylogenetic analyses revealed some topological differences between the phylogenies of the bacteria and their vectors, which led us to marginally reject a model of exclusive bacteria-vector co-divergence.
Ticks are an important natural reservoir of many diverse species of Rickettsiales. In this work, we identified a single tick species that harbors multiple species of Rickettsiales, and uncovered extensive genetic diversity of these bacteria in two tick species from Xinjiang. Both bacteria-vector co-divergence and cross-species transmission appear to have played important roles in Rickettsiales evolution.
PMCID: PMC4236549  PMID: 25073875
Co-divergence; Evolution; Phylogeny; Rickettsiales bacteria; Ticks; Vectors
17.  Novel non-parametric models to estimate evolutionary rates and divergence times from heterochronous sequence data 
Early methods for estimating divergence times from gene sequence data relied on the assumption of a molecular clock. More sophisticated methods were created to model rate variation and used auto-correlation of rates, local clocks, or the so called “uncorrelated relaxed clock” where substitution rates are assumed to be drawn from a parametric distribution. In the case of Bayesian inference methods the impact of the prior on branching times is not clearly understood, and if the amount of data is limited the posterior could be strongly influenced by the prior.
We develop a maximum likelihood method – Physher – that uses local or discrete clocks to estimate evolutionary rates and divergence times from heterochronous sequence data. Using two empirical data sets we show that our discrete clock estimates are similar to those obtained by other methods, and that Physher outperformed some methods in the estimation of the root age of an influenza virus data set. A simulation analysis suggests that Physher can outperform a Bayesian method when the real topology contains two long branches below the root node, even when evolution is strongly clock-like.
These results suggest it is advisable to use a variety of methods to estimate evolutionary rates and divergence times from heterochronous sequence data. Physher and the associated data sets used here are available online at
PMCID: PMC4222489  PMID: 25055743
18.  Correction: The Role of Selection in Shaping Diversity of Natural M. tuberculosis Populations 
PLoS Pathogens  2013;9(8):10.1371/annotation/cff22061-44d5-4301-b853-41702d160203.
PMCID: PMC3779277
19.  Genome Scale Evolution of Myxoma Virus Reveals Host-Pathogen Adaptation and Rapid Geographic Spread 
Journal of Virology  2013;87(23):12900-12915.
The evolutionary interplay between myxoma virus (MYXV) and the European rabbit (Oryctolagus cuniculus) following release of the virus in Australia in 1950 as a biological control is a classic example of host-pathogen coevolution. We present a detailed genomic and phylogeographic analysis of 30 strains of MYXV, including the Australian progenitor strain Standard Laboratory Strain (SLS), 24 Australian viruses isolated from 1951 to 1999, and three isolates from the early radiation in Britain from 1954 and 1955. We show that in Australia MYXV has spread rapidly on a spatial scale, with multiple lineages cocirculating within individual localities, and that both highly virulent and attenuated viruses were still present in the field through the 1990s. In addition, the detection of closely related virus lineages at sites 1,000 km apart suggests that MYXV moves freely in geographic space, with mosquitoes, fleas, and rabbit migration all providing means of transport. Strikingly, despite multiple introductions, all modern viruses appear to be ultimately derived from the original introductions of SLS. The rapidity of MYXV evolution was also apparent at the genomic scale, with gene duplications documented in a number of viruses. Duplication of potential virulence genes may be important in increasing the expression of virulence proteins and provides the basis for the evolution of novel functions. Mutations leading to loss of open reading frames were surprisingly frequent and in some cases may explain attenuation, but no common mutations that correlated with virulence or attenuation were identified.
PMCID: PMC3838154  PMID: 24067966
20.  Frequent Cross-Species Transmission of Parvoviruses among Diverse Carnivore Hosts 
Journal of Virology  2013;87(4):2342-2347.
Although parvoviruses are commonly described in domestic carnivores, little is known about their biodiversity in nondomestic species. A phylogenetic analysis of VP2 gene sequences from puma, coyote, gray wolf, bobcat, raccoon, and striped skunk revealed two major groups related to either feline panleukopenia virus (“FPV-like”) or canine parvovirus (“CPV-like”). Cross-species transmission was commonplace, with multiple introductions into each host species but, with the exception of raccoons, relatively little evidence for onward transmission in nondomestic species.
PMCID: PMC3571474  PMID: 23221559
21.  Differing Epidemiological Dynamics of Influenza B Virus Lineages in Guangzhou, Southern China, 2009-2010 
Journal of Virology  2013;87(22):12447-12456.
The epidemiological and evolutionary dynamics of the two cocirculating lineages of influenza B virus, Victoria and Yamagata, are poorly understood, especially in tropical or subtropical areas of Southeast Asia. We performed a phylogenetic analysis of the hemagglutinin (HA) and neuraminidase (NA) sequences of influenza B viruses isolated in Guangzhou, a southern Chinese city, during 2009 to 2010 and compared the demographic and clinical features of infected patients. We identified multiple viral introductions of Victoria strains from both Chinese and international sources, which formed two phylogenetically and antigenically distinct clades (Victoria 1 and 2), some of which persisted between seasons. We identified one dominant Yamagata introduction from outside China during 2009. Our phylogenetic analysis reveals the occurrence of reassortment events among the Victoria and Yamagata lineages and also within the Victoria lineage. We found no significant difference in clinical severity by influenza B lineage, with the exceptions that (i) the Yamagata lineage infected older people than either Victoria lineage and (ii) fewer upper respiratory tract infections were caused by the Victoria 2 than the Victoria 1 clade. Overall, our study reveals the complex epidemiological dynamics of different influenza B lineages within a single geographic locality and has implications for vaccination policy in southern China.
PMCID: PMC3807886  PMID: 24027322
22.  Comparative Analysis of the Complete Genome Sequence of the California MSW Strain of Myxoma Virus Reveals Potential Host Adaptations 
Journal of Virology  2013;87(22):12080-12089.
Myxomatosis is a rapidly lethal disease of European rabbits that is caused by myxoma virus (MYXV). The introduction of a South American strain of MYXV into the European rabbit population of Australia is the classic case of host-pathogen coevolution following cross-species transmission. The most virulent strains of MYXV for European rabbits are the Californian viruses, found in the Pacific states of the United States and the Baja Peninsula, Mexico. The natural host of Californian MYXV is the brush rabbit, Sylvilagus bachmani. We determined the complete sequence of the MSW strain of Californian MYXV and performed a comparative analysis with other MYXV genomes. The MSW genome is larger than that of the South American Lausanne (type) strain of MYXV due to an expansion of the terminal inverted repeats (TIRs) of the genome, with duplication of the M156R, M154L, M153R, M152R, and M151R genes and part of the M150R gene from the right-hand (RH) end of the genome at the left-hand (LH) TIR. Despite the extreme virulence of MSW, no novel genes were identified; five genes were disrupted by multiple indels or mutations to the ATG start codon, including two genes, M008.1L/R and M152R, with major virulence functions in European rabbits, and a sixth gene, M000.5L/R, was absent. The loss of these gene functions suggests that S. bachmani is a relatively recent host for MYXV and that duplication of virulence genes in the TIRs, gene loss, or sequence variation in other genes can compensate for the loss of M008.1L/R and M152R in infections of European rabbits.
PMCID: PMC3807925  PMID: 23986601
23.  Migratory Flyway and Geographical Distance are Barriers to the Gene Flow of Influenza Virus among North American Birds 
Ecology letters  2011;15(1):24-33.
Despite the importance of migratory birds in the ecology and evolution of avian influenza virus (AIV), there is a lack of information on the patterns of AIV spread at the intra-continental scale. We applied a variety of statistical phylogeographic techniques to a plethora of viral genome sequence data to determine the strength, pattern, and determinants of gene flow in AIV sampled from wild birds in North America. These analyses revealed a clear isolation-by-distance of AIV among sampling localities. In addition, we show that phylogeographic models incorporating information on the avian flyway of sampling proved a better fit to the observed sequence data than those specifying homogeneous or random rates of gene flow among localities. In sum, these data strongly suggest that the intra-continental spread of AIV by migratory birds is subject to major ecological barriers, including spatial distance and avian flyway.
PMCID: PMC3228906  PMID: 22008513
avian influenza; phylogeography; evolution; gene flow; ecological barriers; flyways; spatial distance
24.  The emergence and evolution of the novel epidemic norovirus GII.4 variant Sydney 2012 
Virology  2013;0:106-113.
Norovirus is the leading cause of acute gastroenteritis with most infections caused by GII.4 variants. To understand the evolutionary processes that contribute to the emergence of GII.4 variants, we examined the molecular epidemiology of norovirus-associated acute gastroenteritis in Australia and New Zealand from 893 outbreaks between 2009 and 2012. Throughout the study GII.4 New Orleans 2009 was predominant; however, during 2012 it was replaced by an emergent GII.4 variant, Sydney 2012. An evolutionary analysis of capsid gene sequences was performed to determine the origins and selective pressures driving the emergence of these recently circulating GII.4 variants. This revealed that both New Orleans 2009 and Sydney 2012 share a common ancestor with GII.4 Apeldoorn 2007. Furthermore, pre-epidemic ancestral variants of each virus were identified up to two years before their pandemic emergence. Adaptive changes at known blockade epitopes in the viral capsid were also identified that likely contributed to their emergence.
PMCID: PMC3984403  PMID: 24503072
Norovirus; Gastroenteritis; Emergence; Evolution; Sydney 2012
25.  Recombination Is Associated with an Outbreak of Novel Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Viruses in China 
Journal of Virology  2013;87(19):10904-10907.
In 2009 to 2010, there was a marked increase in the number of infections with highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) in China. Through phylogenetic analysis, we show that viruses from this outbreak originated from a single recombination event, illustrating the potential importance of this process for disease emergence.
PMCID: PMC3807407  PMID: 23885071

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