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Andrew Rambaut

Publications and source records attributed to Andrew Rambaut.

At least 37 records · Page 2Linked to original sources
PubMed2005

The evolutionary dynamics of endogenous retroviruses.

Endogenous retroviruses (ERVs) are vertically transmitted intragenomic elements derived from integrated retroviruses. ERVs can proliferate within the genome of their host until they either acquire inactivating mutations or are lost by recombinational deletion. We present a model that unifies current knowledge of ERV biology into a single evolutionary framework. The model predicts the possible long-term outcomes of retroviral germline infection and can account for the variable patterns of observed ERV genetic diversity. We hope the model will provide a useful framework for understanding ERV evolution, enabling the testing of evolutionary hypotheses and the estimation of parameters governing ERV proliferation.

Endogenous Retroviruses↗
PubMed2005

Molecular footprint of drug-selective pressure in a human immunodeficiency virus transmission chain.

Known human immunodeficiency virus (HIV) transmission histories are invaluable models for investigating the evolutionary and transmission dynamics of the virus and to assess the accuracy of phylogenetic reconstructions. Here we have characterized an HIV-1 transmission chain consisting of nine infected patients, almost all of whom were treated with antiviral drugs at later stages of infection. Partial pol and env gp41 regions of the HIV genome were directly sequenced from plasma viral RNA for at least one sample from each patient. Phylogenetic analyses in pol using likelihood methods inferred an evolutionary history not fully compatible with the known transmission history. This could be attributed to parallel evolution of drug resistance mutations resulting in the incorrect clustering of multidrug-resistant virus. On the other hand, a fully compatible phylogenetic tree was reconstructed from the env sequences. We were able to identify and quantify the molecular footprint of drug-selective pressure in pol using maximum likelihood inference under different codon substitution models. An increased fixation rate of mutations in the HIV population of the multidrug-resistant patient was demonstrated using molecular clock modeling. We show that molecular evolutionary analyses, guided by a known transmission history, can reveal the presence of confounding factors like natural selection and caution should be taken when accurate descriptions of HIV evolution are required.

Anti-HIV Agents↗
PubMed2004

Comparative population dynamics of HIV-1 subtypes B and C: subtype-specific differences in patterns of epidemic growth.

The human immunodeficiency virus (HIV) pandemic continues to grow at an alarming rate, with a further 5 million new infections in 2003. Some 3.5 million of these were in sub-Saharan Africa, where approximately 70% of the world's HIV-positive population resides. In contrast, the spread of HIV in high-income countries has slowed since its discovery in the 1980s, and in regions such as Western Europe prevalence has decreased. Here, we employ coalescent methods to compare the epidemic growth rates of two subtypes of HIV-1 with differing epidemiological profiles: subtype C, which is dominant in sub-Saharan Africa and associated with heterosexual transmission, and subtype B, the main cause of AIDS in Western Europe and North America, and which was primarily transmitted through homosexual sex and injecting drug use. We show that although both subtypes emerged at approximately the same time ( approximately 1960), they have widely differing patterns of exponential population growth. At its current growth rate the epidemic of subtype C in sub-Saharan Africa is doubling every 2.4 years, which is approximately half the rate observed during the early stages of the subtype B epidemic in Western Europe and North America. However, the subtype C growth rate is still 5-10 times greater than that estimated for the blood-borne hepatitis C virus, supporting the hypothesis that sexual transmission has been primarily responsible for the HIV epidemic in sub-Saharan Africa.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Rise and fall of the Beringian steppe bison.

The widespread extinctions of large mammals at the end of the Pleistocene epoch have often been attributed to the depredations of humans; here we present genetic evidence that questions this assumption. We used ancient DNA and Bayesian techniques to reconstruct a detailed genetic history of bison throughout the late Pleistocene and Holocene epochs. Our analyses depict a large diverse population living throughout Beringia until around 37,000 years before the present, when the population's genetic diversity began to decline dramatically. The timing of this decline correlates with environmental changes associated with the onset of the last glacial cycle, whereas archaeological evidence does not support the presence of large populations of humans in Eastern Beringia until more than 15,000 years later.

Alaska↗
PubMed2004

Viral evolution and the emergence of SARS coronavirus.

The recent appearance of severe acute respiratory syndrome coronavirus (SARS-CoV) highlights the continual threat to human health posed by emerging viruses. However, the central processes in the evolution of emerging viruses are unclear, particularly the selection pressures faced by viruses in new host species. We outline some of the key evolutionary genetic aspects of viral emergence. We emphasize that, although the high mutation rates of RNA viruses provide them with great adaptability and explain why they are the main cause of emerging diseases, their limited genome size means that they are also subject to major evolutionary constraints. Understanding the mechanistic basis of these constraints, particularly the roles played by epistasis and pleiotropy, is likely to be central in explaining why some RNA viruses are more able than others to cross species boundaries. Viral genetic factors have also been implicated in the emergence of SARS-CoV, with the suggestion that this virus is a recombinant between mammalian and avian coronaviruses. We show, however, that the phylogenetic patterns cited as evidence for recombination are more probably caused by a variation in substitution rate among lineages and that recombination is unlikely to explain the appearance of SARS in humans.

Databases, Nucleic Acid↗
PubMed2004

Origin of AIDS: contaminated polio vaccine theory refuted.

Despite strong evidence to the contrary, speculation continues that the AIDS virus, human immunodeficiency virus type 1 (HIV-1), may have crossed into humans as a result of contamination of the oral polio vaccine (OPV). This 'OPV/AIDS theory' claims that chimpanzees from the vicinity of Stanleyville--now Kisangani in the Democratic Republic of Congo--were the source of a simian immunodeficiency virus (SIVcpz) that was transmitted to humans when chimpanzee tissues were allegedly used in the preparation of OPV. Here we show that SIVcpz is indeed endemic in wild chimpanzees of this region but that the circulating virus is phylogenetically distinct from all strains of HIV-1, providing direct evidence that these chimpanzees were not the source of the human AIDS pandemic.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Phylogenetic reconstruction of a known HIV-1 CRF04_cpx transmission network using maximum likelihood and Bayesian methods.

The CRF04_cpx strains of HIV-1 accounts for approximately 2-10% of the infected population in Greece, across different transmission risk groups. CRF04_cpx was the lineage documented in an HIV-1 transmission network in Thessalonica, northern Greece. Most of the transmissions occurred through unprotected heterosexual contacts between 1989 and 1993. Blood samples were available for six patients, obtained 6-10 years later, except for one patient sampled in 1991. Our objective was to examine whether the transmission history is compatible with the evolutionary tree of the virus, in partial gag, partial env, and partial gag+env. The inferred phylogenetic tree obtained using maximum likelihood and Bayesian methods in partial gag+env was much closer to the transmission tree than that using either env or gag separately. Our findings suggest that the epidemiological relationships among patients who have been infected by a common source correspond almost exactly to the evolutionary trees of the virus, given that enough phylogenetic signal is present in the alignment. Moreover, we found evidence that recombination is not the most parsimonious explanation for the phylogenetic incongruence between gag and env. For patients with known infection dates, the estimated dates of the coalescent events obtained using molecular clock calculations based on a newly developed Bayesian method in gag + env were in agreement with the actual infection dates.

Bayes Theorem↗
PubMed2004

Analysis of the medium (M) segment sequence of Guaroa virus and its comparison to other orthobunyaviruses.

Guaroa virus (GROV), a segmented virus in the genus Orthobunyavirus, has been linked to the Bunyamwera serogroup (BUN) through cross-reactivity in complement fixation assays of S segment-encoded nucleocapsid protein determinants, and also to the California serogroup (CAL) through cross-reactivity in neutralization assays of M segment-encoded glycoprotein determinants. Phylogenetic analysis of the S-segment sequence supported a closer relationship to the BUN serogroup for this segment and it was hypothesized that the serological reaction may indicate genome-segment reassortment. Here, cloning and sequencing of the GROV M segment are reported. Sequence analysis indicates an organization similar to that of other orthobunyaviruses, with genes in the order GN-NSm-Gc, and mature proteins generated by protease cleavage at one, and by signalase at possibly three, sites. A potential role of motifs that are more similar to CAL than to BUN virus sequences with respect to the serological reaction is discussed. No discernable evidence for reassortment was identified.

Amino Acid Sequence↗
PubMed2004

The molecular population genetics of HIV-1 group O.

HIV-1 group O originated through cross-species transmission of SIV from chimpanzees to humans and has established a relatively low prevalence in Central Africa. Here, we infer the population genetics and epidemic history of HIV-1 group O from viral gene sequence data and evaluate the effect of variable evolutionary rates and recombination on our estimates. First, model selection tools were used to specify suitable evolutionary and coalescent models for HIV group O. Second, divergence times and population genetic parameters were estimated in a Bayesian framework using Markov chain Monte Carlo sampling, under both strict and relaxed molecular clock methods. Our results date the origin of the group O radiation to around 1920 (1890-1940), a time frame similar to that estimated for HIV-1 group M. However, group O infections, which remain almost wholly restricted to Cameroon, show a slower rate of exponential growth during the twentieth century, explaining their lower current prevalence. To explore the effect of recombination, the Bayesian framework is extended to incorporate multiple unlinked loci. Although recombination can bias estimates of the time to the most recent common ancestor, this effect does not appear to be important for HIV-1 group O. In addition, we show that evolutionary rate estimates for different HIV genes accurately reflect differential selective constraints along the HIV genome.

Bayes Theorem↗
PubMed2003

Inference of viral evolutionary rates from molecular sequences.

The processes of mutation and nucleotide substitution contribute to the observed variability in virulence, transmission and persistence of viral pathogens. Since most viruses evolve many times faster than their human hosts, we are in the unusual position of being able to measure these processes directly by comparing viral genes that have been isolated and sequenced at different points in time. The analysis of such data requires the use of specific statistical methods that take into account the shared ancestry of the sequences and the randomness inherent in the process of nucleotide substitution. In this paper we describe the various statistical methods for estimating evolutionary rates, which can be classified into three general approaches: linear regression, maximum likelihood, and Bayesian inference. We discuss the advantages and shortcomings of each approach and illustrate their use through the analysis of two example viruses; human immunodeficiency virus type 1 and dengue virus serotype 4. Reliable estimates of viral substitution rates have many important applications in population genetics and phylogenetics, including dating evolutionary events and divergence times, estimating demographic parameters such as population size and generation time, and investigating the effect of natural selection on molecular evolution.

Base Sequence↗
PubMed2003

Inferring the rate and time-scale of dengue virus evolution.

Dengue is often referred to as an emerging disease because of the rapid increases in incidence and prevalence that have been observed in recent decades. To understand the rate at which genetic diversification occurs in dengue virus and to infer the time-scale of its evolution, we employed a maximum likelihood method that uses information about times of virus sampling to estimate the rate of molecular evolution in a large number of viral envelope (E) gene sequences and to place bounds around the dates of appearance of all serotypes and specific genotypes. Our analysis reveals that dengue virus generally evolves according to a molecular clock, although some serotype-specific and genotype-specific rate differences were observed, and that its origin is more recent than previously suggested, with the virus appearing approximately 1,000 years ago. Furthermore, we estimate that the zoonotic transfer of dengue from sylvatic (monkey) to sustained human transmission occurred between 125 and 320 years ago, that the current global genetic diversity in the four serotypes of dengue virus only appeared during the past century, and that the recent rise in genetic diversity can be loosely correlated both to human activities such as population growth, urbanization, and mass transport and to the emergence of dengue hemorrhagic fever as a major disease problem.

Animals↗
PubMed2002

Inferring confidence sets of possibly misspecified gene trees.

The problem of inferring confidence sets of gene trees is discussed without assuming that the substitution model or the branching pattern of any of the investigated trees is correct. In this case, widely used methods to compare genealogies can give highly contradicting results. Here, three methods to infer confidence sets that are robust against model misspecification are compared, including a new approach based on estimating the confidence in a specific tree using expected-likelihood weights. The power of the investigated methods is studied by analysing HIV-1 and mtDNA sequence data as well as simulated sequences. Finally, guidelines for choosing an appropriate method to compare multiple gene trees are provided.

Animals↗
PubMed2002

Rates of molecular evolution in RNA viruses: a quantitative phylogenetic analysis.

The study of rates of nucleotide substitution in RNA viruses is central to our understanding of their evolution. Herein we report a comprehensive analysis of substitution rates in 50 RNA viruses using a recently developed maximum likelihood phylogenetic method. This analysis revealed a significant relationship between genetic divergence and isolation time for an extensive array of RNA viruses, although more rate variation was usually present among lineages than would be expected under the constraints of a molecular clock. Despite the lack of a molecular clock, the range of statistically significant variation in overall substitution rates was surprisingly narrow for those viruses where a significant relationship between genetic divergence and time was found, as was the case when synonymous sites were considered alone, where the molecular clock was rejected less frequently. An analysis of the ecological and genetic factors that might explain this rate variation revealed some evidence of significantly lower substitution rates in vector-borne viruses, as well as a weak correlation between rate and genome length. Finally, a simulation study revealed that our maximum likelihood estimates of substitution rates are valid, even if the molecular clock is rejected, provided that sufficiently large data sets are analyzed.

Amino Acid Substitution↗
PubMed2002

Testing the relationship between morphological and molecular rates of change along phylogenies.

Molecular evolution has been considered to be essentially a stochastic process, little influenced by the pace of phenotypic change. This assumption was challenged by a study that demonstrated an association between rates of morphological and molecular change estimated for "total-evidence" phylogenies, a finding that led some researchers to challenge molecular date estimates of major evolutionary radiations. Here we show that Omland's (1997) result is probably due to methodological bias, particularly phylogenetic nonindependence, rather than being indicative of an underlying evolutionary phenomenon. We apply three new methods specifically designed to overcome phylogenetic bias to 13 published phylogenetic datasets for vertebrate taxa, each of which includes both morphological characters and DNA sequence data. We find no evidence of an association between rates of molecular and morphological rates of change.

Animals↗