The evolution of large DNA viruses: combining genomic information of viruses and their hosts.
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DNA Viruses↗
Biomedical subjects
Edward C Holmes
Publications and source records attributed to Edward C Holmes.
The causes and consequences of HIV evolution.
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AIDS Vaccines↗
The population genetics and evolutionary epidemiology of RNA viruses.
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Animals↗
The phylogeography of human viruses.
Viruses, especially those with RNA genomes, represent ideal organisms to study the dynamics of microevolutionary change. In particular, their rapid rate of nucleotide substitution means that the epidemiological processes that shape their diversity act on the same time-scale as mutations are fixed in viral populations. Consequently, the branching structure of virus phylogenies provides a unique insight into spatial and temporal dynamics. Herein, I describe the key processes in virus phylogeography. These are generally associated with the relative rates of dispersal among populations and virus-host codivergence (vicariance), and the division between acute (short-term) and persistent (long-term) infections. These processes will be illustrated by important human viruses - HIV, dengue, rabies, polyomavirus JC and human papillomavirus - which display varying spatial and temporal structures and virus-host relationships. Key research questions for the future will also be established.
Dengue Virus↗
Selection pressures in the capsid genes of plant RNA viruses reflect mode of transmission.
To determine the selection pressures faced by RNA viruses of plants, patterns of nonsynonymous (dN) and synonymous (dS) substitution in the capsid genes of 36 viruses with differing modes of transmission were analysed. This analysis provided strong evidence that the capsid proteins of vector-borne plant viruses are subject to greater purifying selection on amino acid change than those viruses transmitted by other routes and that virus-vector interactions impose greater selective constraints than those between virus and plant host. This could be explained by specific interactions between capsid proteins and cellular receptors in the insect vectors that are necessary for successful transmission. However, contrary to initial expectations based on phylogenetic relatedness, vector-borne plant viruses are subject to weaker selective constraints than vector-borne animal viruses. The results suggest that the greater complexity involved in the transmission of circulative animal viruses compared with non-circulative plant viruses results in more intense purifying selection.
Animals↗
Distribution of surface protein variants among hyperinvasive meningococci: implications for vaccine design.
The bacterium Neisseria meningitidis is a major cause of meningitis and septicemia worldwide. Outer membrane proteins (OMPs) are candidates in the search for comprehensive meningococcal vaccines; however, the formulation of OMP vaccines is complicated by antigenic diversity, which is generated by high levels of genetic reassortment and strong positive selection in the meningococcal antigen genes. The genetic and antigenic diversity of three OMPs (FetA, PorA, and PorB) among a global collection of meningococcal isolates representative of the major hyperinvasive clonal complexes was determined. There was evidence for antigenic structuring among the three OMPs that could not be explained purely by descent. These observations violated the predictions of the clonal and epidemic clonal models of population structure but were in concordance with models of strain structure which propose that host immunity selects for nonoverlapping antigen combinations. The patterns of antigenic variant combinations suggested that an OMP-based vaccine with as few as six PorA and five FetA variant sequences could generate homologous immune responses against all 78 isolates examined.
Alleles↗
Population structure and evolution of the Bacillus cereus group.
Representative strains of the Bacillus cereus group of bacteria, including Bacillus anthracis (11 isolates), B. cereus (38 isolates), Bacillus mycoides (1 isolate), Bacillus thuringiensis (53 isolates from 17 serovars), and Bacillus weihenstephanensis (2 isolates) were assigned to 59 sequence types (STs) derived from the nucleotide sequences of seven alleles, glpF, gmk, ilvD, pta, pur, pycA, and tpi. Comparisons of the maximum likelihood (ML) tree of the concatenated sequences with individual gene trees showed more congruence than expected by chance, indicating a generally clonal structure to the population. The STs followed two major lines of descent. Clade 1 comprised B. anthracis strains, numerous B. cereus strains, and rare B. thuringiensis strains, while clade 2 included the majority of the B. thuringiensis strains together with some B. cereus strains. Other species were allocated to a third, heterogeneous clade. The ML trees and split decomposition analysis were used to assign STs to eight lineages within clades 1 and 2. These lineages were defined by bootstrap analysis and by a preponderance of fixed differences over shared polymorphisms among the STs. Lineages were named with reference to existing designations: Anthracis, Cereus I, Cereus II, Cereus III, Kurstaki, Sotto, Thuringiensis, and Tolworthi. Strains from some B. thuringiensis serovars were wholly or largely assigned to a single ST, for example, serovar aizawai isolates were assigned to ST-15, serovar kenyae isolates were assigned to ST-13, and serovar tolworthi isolates were assigned to ST-23, while other serovars, such as serovar canadensis, were genetically heterogeneous. We suggest a revision of the nomenclature in which the lineage and clone are recognized through name and ST designations in accordance with the clonal structure of the population.
Bacillus cereus↗
High-resolution phylogenetic analysis of hepatitis C virus adaptation and its relationship to disease progression.
Hepatitis C virus (HCV) persists in the majority of those infected despite host immune responses. Evidence has accrued that selectively fixed mutations in the envelope genes (E1 and E2) are associated with viral persistence, particularly those that occur within the first hypervariable region of E2 (HVR1). However, the individual amino acid residues under selection have not been identified, nor have their selection pressures been measured, despite the importance of this information for understanding disease pathogenesis and for vaccine design. We performed a high-resolution analysis of published gene sequence data from individuals undergoing acute HCV infection, employing two phylogenetic methods to determine site-specific selection pressures. Strikingly, we found a statistically significant association between the number of sites selected and disease outcome, with the fewest selected sites in fulminant HCV cases and the greatest number of selected sites in rapid progressors, reflecting the duration and intensity of the arms race between host and virus. Moreover, sites outside the HVR1 appear to play a major role in viral evolution and pathogenesis, although there was no association between viral persistence and specific mutations in E1 and E2. Our analysis therefore allows fine dissection of immune selection pressures, which may be more diverse than previously thought. Such analyses could play a similarly informative role in studies of other persistent virus infections, such as human immunodeficiency virus.
Acute Disease↗
Detection of TT virus among chimpanzees in the wild using a noninvasive technique.
Zoonotic transmission and emergence of pathogens are serious threats to endangered populations of free-ranging primate species. Recent discovery of a nonpathogenic yet highly prevalent virus in human populations, TT virus (TTV), has prompted studies into the presence of this virus among captive individuals of other species of nonhuman primates. In this study, we screened captive primate species for TTV. In addition, we provide the first data on TTV infectionin free-ranging primates by noninvasive screening of three chimpanzee (Pan troglodytes sweinfurthii) commlunities. Phylogenetic relationships between virus isolates and those previously reported from hulman popullations, captive primates, and domesticated species are inferred. Our findings are discussed with respect to potential zoonotic events that may result from increased levels of human encroachlment into wild habitats.
Animals↗
Selection-driven evolution of emergent dengue virus.
In the last four decades the incidence of dengue fever has increased 30-fold worldwide, and over half the world's population is now threatened with infection from one or more of four co-circulating viral serotypes (DEN-1 through DEN-4). To determine the role of viral molecular evolution in emergent disease dynamics, we sequenced 40% of the genome of 82 DEN-4 isolates collected from Puerto Rico over the 20 years since the onset of endemic dengue on the island. Isolates were derived from years with varying levels of DEN-4 prevalence. Over our sampling period there were marked evolutionary shifts in DEN-4 viral populations circulating in Puerto Rico; viral lineages were temporally clustered and the most common genotype at a particular sampling time often arose from a previously rare lineage. Expressed changes in structural genes did not appear to drive this lineage turnover, even though these regions include primary determinants of viral antigenic properties. Instead, recent dengue evolution can be attributed in part to positive selection on the nonstructural gene 2A (NS2A), whose functions may include replication efficiency and antigenicity. During the latest and most severe DEN-4 epidemic in Puerto Rico, in 1998, viruses were distinguished by three amino acid changes in NS2A that were fixed far faster than expected by drift alone. Our study therefore demonstrates viral genetic turnover within a focal population and the potential importance of adaptive evolution in viral epidemic expansion.
Communicable Diseases, Emerging↗
Evolution of major histocompatibility complex class I genes in Cetartiodactyls.
Previous studies of cattle MHC have suggested the presence of at least four classical class I loci. Analysis of haplotypes showed that any combination of one, two or three genes may be expressed, although no gene is expressed consistently. The aim of this study was to examine the evolutionary relationships among these genes and to study their phylogenetic history in Cetartiodactyl species, including cattle and their close relatives. A secondary aim was to determine whether recombination had occurred between any of the genes. MHC class I data sets were generated from published sequences or by polymerase chain reaction from cDNA. Phylogenetic analysis revealed that MHC class I sequences from Cetartiodactyl species closely related to cattle were distributed among the main cattle gene "groups", while those from more distantly related species were either scattered (sheep, deer) or clustered in a species-specific manner (sitatunga, giraffe). A comparison between gene and species trees showed a poor match, indicating that divergence of the MHC sequences had occurred independently from that of the hosts from which they were obtained. We also found two clear instances of interlocus recombination among the cattle MHC sequences. Finally, positive natural selection was documented at positions throughout the alpha 1 and 2 domains, primarily on those amino acids directly involved in peptide binding, although two positions in the alpha 3 domain, a region generally conserved in other species, were also shown to be undergoing adaptive evolution.
Animals↗
Epidemiology: Sexual transmission of HIV in Africa.
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Africa South of the Sahara↗
The transferrin receptor genes of Trypanosoma equiperdum are less diverse in their transferrin binding site than those of the broad-host range Trypanosoma brucei.
Trypanosoma brucei and T. equiperdum infect the mammalian bloodstream and tissues. T. brucei is transmitted by tsetse flies between an extremely large range of mammals in sub-Saharan Africa. In contrast, T. equiperdum is restricted to equines, where it is transmitted as a venereal disease. Both species evade immune destruction by changing their variant surface glycoprotein (VSG), encoded in a telomeric VSG expression site. T. brucei has about 20 VSG expression sites, and it has been proposed that their genetic diversity plays a role in host adaptation. Two expression site-associated genes ESAG6 and ESAG7, encode variable transferrin receptor subunits allowing trypanosomes to internalize polymorphic transferrin molecules from different mammals. We investigated if there was a correlation between the size of the trypanosome host range and the degree of ESAG6 genetic diversity. Both T. equiperdum and T. brucei appear to have approximately similar numbers of ESAG6, however, the genetic diversity of the ESAG6 family varies in the two species. We sequenced 114 T. equiperdum ESAG6 genomic clones, resulting in the isolation of 10 T. equiperdum ESAG6 variants. The T. equiperdum ESAG6 genes were less genetically diverse than those of T. brucei in regions known to play a role in transferrin binding. This indicates that ESAG6 genetic diversity playing a role in host adaptation could have been lost in the absence of selection pressure. There was also evidence of positive selection ( d(N) /d(S) = approximately 5) acting on other ESAG6 regions not involved in transferrin binding, perhaps due to antigenic variation of these surface molecules.
Amino Acid Sequence↗
Error thresholds and the constraints to RNA virus evolution.
RNA viruses are often thought of as possessing almost limitless adaptability as a result of their extreme mutation rates. However, high mutation rates also put a cap on the size of the viral genome by establishing an error threshold, beyond which lethal numbers of deleterious mutations accumulate. Herein, I argue that a lack of genomic space means that RNA viruses will be subject to important evolutionary constraints because specific sequences are required to encode multiple and often conflicting functions. Empirical evidence for these constraints, and how they limit viral adaptability, is now beginning to accumulate. Documenting the constraints to RNA virus evolution has important implications for predicting the emergence of new viruses and for improving therapeutic procedures.
Adaptation, Biological↗
Origins, evolution, and vector/host coadaptations within the genus Flavivirus.
Although viruses in the genus Flavivirus share complex antigenic interrelationships, they can be divided into four phylogenetic/ecological groups: two mosquito-borne groups, a tick-borne group, and nonvectored viruses. These divisions largely reflect the selective constraints imposed on the viruses by the vertebrate hosts, the invertebrate vectors, and the associated ecologies. Phylogenetic trees based on the flavivirus genetic sequence show characteristic branching patterns that reflect these groupings. This review describes the evolution and possible origins of individual flaviviruses, correlating ecological and epidemiological characteristics with their phylogenies and geographic dispersal. It will also become apparent that many of the phylogenetic lineages that define species diverged relatively recently, and the subsequent dispersal and epidemiology of these viruses have therefore been significantly influenced by increasing human population densities and activities such as recreation, urbanization, land reclamation, transportation, and deforestation. This review also considers some of the likely implications of persistent/chronic infections in relation to virus dispersal and recombination between related flaviviruses on phylogenetic analysis and vaccine development strategies.
Adaptation, Physiological↗
The extent of codon usage bias in human RNA viruses and its evolutionary origin.
Revealing the determinants of codon usage bias is central to the understanding of factors governing viral evolution. Herein, we report the results of a survey of codon usage bias in a wide range of genetically and ecologically diverse human RNA viruses. This analysis showed that the overall extent of codon usage bias in RNA viruses is low and that there is little variation in bias between genes. Furthermore, the strong correlation between base and dinucleotide composition and codon usage bias suggested that mutation pressure rather than natural (translational) selection is the most important determinant of the codon bias observed. However, we also detected correlations between codon usage bias and some characteristics of viral genome structure and ecology, with increased bias in segmented and aerosol-transmitted viruses and decreased bias in vector-borne viruses. This suggests that translational selection may also have some influence in shaping codon usage bias.
Base Composition↗
Comparative population dynamics of mosquito-borne flaviviruses.
Among the members of the genus Flavivirus are several important human pathogens, including the dengue (DEN) and Japanese encephalitis (JE) viruses. From the analysis of gene sequence data of samples of these virus populations it is possible to infer phylogenetic relationships, which in turn can yield important epidemiological information, including their demographic history in humans. In this study, we use a recently developed method, based on coalescent theory, to infer the population dynamics of a variety of mosquito-borne flaviviruses. Our study involves the testing of alternative hypotheses, the estimation of confidence intervals around demographic model parameter values, and the placing of the maximum likelihood (ML) demographic model into a "real time" epidemiological history. We reveal that all the Flavivirus populations studied are growing at an exponential rate, with the rates of population growth of dengue virus serotypes 2 and 3 increasing rapidly in the recent past, and that of Japanese encephalitis virus changing from constant population size to exponential growth within the last century. We therefore demonstrate that the use of these coalescent methods may be extremely valuable in monitoring responses to interventions such as vaccination or vector control.
Arboviruses↗
The origin, emergence and evolutionary genetics of dengue virus.
Dengue is one of the most important emerging viruses, posing a threat to one-third of the global human population. Herein we show how the comparative analysis of gene sequence data has shed light on the origin and spread of dengue virus, as well as on the evolutionary processes that structure its genetic diversity. This reveals that dengue virus has a relatively recent evolutionary history, with the four serotypes originating approximately 1000 years ago and only establishing endemic transmission in humans in the last few hundred years. However, its place of origin remains uncertain as does the extent of genetic and phenotypic diversity present in the sylvatic (primate) transmission cycle. Although there is some evidence that viral strains differ in key phenotypic features such as virulence, and for positive selection at immunologically important sites, it seems likely that stochastic processes also play a major role in shaping viral genetic diversity, with lineage extinction a common occurrence. A more complete understanding of the evolution and epidemiology of dengue virus, particularly with respect to the aetiology of severe disease, will require large-scale prospective studies and the comparative analysis of complete genome sequences.
Animals↗