Biomedical subjects

Mark M Tanaka

Publications and source records attributed to Mark M Tanaka.

11 recordsLinked to original sources

PubMed2006

Detecting emerging strains of tuberculosis by using spoligotypes.

The W-Beijing strain of tuberculosis has been identified in many molecular epidemiological studies as being particularly prevalent. This identification has been made possible through the development of a number of genotyping technologies including spoligotyping. Highly prevalent genotypes associated with outbreaks, such as the W-Beijing strain, are implicitly regarded as fast spreading. Here we present a quantitative method to identify "emerging" strains, those that are spreading faster than the background rate inferred from spoligotype data. The approach uses information about the mutation process specific to spoligotypes, combined with a model of both transmission and mutation. The core principle is that if two comparable strains have the same number of isolates, then the strain with fewer inferred mutation events must have spread faster if the mutation process is common. Applying this method to four different data sets, we find not only the W-Beijing strain, but also a number of other strains, to be emerging in this sense. Importantly, the strains that are identified as emerging are not simply those with the largest number of cases. The use of this method should facilitate the targeting of individual genotypes in intervention programs.

Animals↗

PubMed2006

An evaluation of indices for quantifying tuberculosis transmission using genotypes of pathogen isolates.

BACKGROUND: Infectious diseases are often studied by characterising the population structure of the pathogen using genetic markers. An unresolved problem is the effective quantification of the extent of transmission using genetic variation data from such pathogen isolates. METHODS: It is important that transmission indices reflect the growth of the infectious population as well as account for the mutation rate of the marker and the effects of sampling. That is, while responding to this growth rate, indices should be unresponsive to the sample size and the mutation rate. We use simulation methods taking into account both the mutation and sampling processes to evaluate indices designed to quantify transmission of tuberculosis. RESULTS: Previously proposed indices generally perform inadequately according to the above criteria, with the partial exception of the recently proposed Transmission-Mutation Index. CONCLUSION: Any transmission index needs to take into account mutation of the marker and the effects of sampling. Simple indices are unlikely to capture the full complexity of the underlying processes.

Computer Simulation↗

PubMed2006

Using approximate Bayesian computation to estimate tuberculosis transmission parameters from genotype data.

Tuberculosis can be studied at the population level by genotyping strains of Mycobacterium tuberculosis isolated from patients. We use an approximate Bayesian computational method in combination with a stochastic model of tuberculosis transmission and mutation of a molecular marker to estimate the net transmission rate, the doubling time, and the reproductive value of the pathogen. This method is applied to a published data set from San Francisco of tuberculosis genotypes based on the marker IS6110. The mutation rate of this marker has previously been studied, and we use those estimates to form a prior distribution of mutation rates in the inference procedure. The posterior point estimates of the key parameters of interest for these data are as follows: net transmission rate, 0.69/year [95% credibility interval (C.I.) 0.38, 1.08]; doubling time, 1.08 years (95% C.I. 0.64, 1.82); and reproductive value 3.4 (95% C.I. 1.4, 79.7). These figures suggest a rapidly spreading epidemic, consistent with observations of the resurgence of tuberculosis in the United States in the 1980s and 1990s.

Algorithms↗

PubMed2005

Optimal replication of poliovirus within cells.

We construct a mathematical model of the within-cell replication of poliovirus, a prototypic RNA virus, and use realistic parameter estimates to describe the increase of copy number of the viral genome. Our initial model is essentially an exponential growth model; we also consider modifications of this model to account for resource utilization. The saturation of viral replication dynamics observed in experimental systems can be explained in terms of heavy resource use by the virus. We then use our models to consider the conditions under which the growth of poliovirus is optimized. Intriguingly, if poliovirus has optimized its replication within cells, the predicted ratio of positive to negative strands is close to what is actually observed. We interpret our findings in terms of the evolution of life-history traits.

Animals↗

PubMed2005

Methods of quantifying and visualising outbreaks of tuberculosis using genotypic information.

Genotypic data from pathogenic isolates are often used to measure the extent of infectious disease transmission. These methods include phylogenetic reconstruction and the evaluation of clustering indices. The first aim of this paper is to critique current methods used to analyse genotypic data from molecular epidemiological studies of tuberculosis. In particular, by not accounting for the mutation rate of markers, errors arise in making inferences about outbreaks based on genotypic information. The second aim is to suggest a new way to represent genotypic data visually, involving graphs and trees. We also discuss some interpretations and modifications of existing indices. Although our focus is tuberculosis, the methods we discuss are generally applicable to any directly transmissible clonal pathogen.

Cluster Analysis↗

PubMed2005

Norovirus recombination in ORF1/ORF2 overlap.

Norovirus (NoV) genogroups I and II (GI and GII) are now recognized as the predominant worldwide cause of outbreaks of acute gastroenteritis in humans. Three recombinant NoV GII isolates were identified and characterized, 2 of which are unrelated to any previously published recombinant NoV. Using data from the current study, published sequences, database searches, and molecular techniques, we identified 23 recombinant NoV GII and 1 recombinant NoV GI isolates. Analysis of the genetic relationships among the recombinant NoV GII isolates identified 9 independent recombinant sequences; the other 14 strains were close relatives. Two of the 9 independent recombinant NoV were closely related to other recombinants only in the polymerase region, and in a similar fashion 1 recombinant NoV was closely related to another only in the capsid region. Breakpoint analysis of recombinant NoV showed that recombination occurred in the open reading frame (ORF)1/ORF2 overlap. We provide evidence to support the theory of the role of subgenomic RNA promoters as recombination hotspots and describe a simple mechanism of how recombination might occur in NoV.

Caliciviridae Infections↗

PubMed2004

Evidence for positive selection on Mycobacterium tuberculosis within patients.

BACKGROUND: While the pathogenesis and epidemiology of tuberculosis are well studied, relatively little is known about the evolution of the infectious agent Mycobacterium tuberculosis, especially at the within-host level. The insertion sequence IS6110 is a genetic marker that is widely used to track the transmission of tuberculosis between individuals. This and other markers may also facilitate our understanding of the disease within patients. RESULTS: This article presents three lines of evidence supporting the action of positive selection on M. tuberculosis within patients. The arguments are based on a comparison between empirical findings from molecular epidemiology, and population genetic models of evolution. Under the hypothesis of neutrality of genotypes, 1) the mutation rate of the marker IS6110 is unusually high, 2) the time it takes for substitutions to occur within patients is too short, and 3) the amount of polymorphism within patients is too low. CONCLUSIONS: Empirical observations are explained by the action of positive selection during infection, or alternatively by very low effective population sizes. I discuss the possible roles of antibiotic treatment, the host immune system and extrapulmonary dissemination in creating opportunities for positive selection.

DNA, Bacterial↗

PubMed2004

The control of copy number of IS6110 in Mycobacterium tuberculosis.

Insertion sequence (IS) elements are bacterial genes that are able to transpose to different locations in the genome. These elements are often used in molecular epidemiology as genetic markers that track the spread of pathogens. Transposable elements have frequently been described as "selfish DNA" because they facilitate their own transposition, causing damage when they insert into coding regions, while contributing little if anything to the bacterial host. According to this hypothesis, the expansion of copy number of insertion sequences is opposed by negative selection against high copy numbers. From an alternative point of view, we might expect IS elements to intrinsically regulate transposition within cells, thereby limiting damage to their bacterial host. Here, we report evidence that the copy number of IS6110 in Mycobacterium tuberculosis is controlled by selection against the element. We first construct 12 different models of marker change resulting from a combination of possible transposition functions and selective regimes. We then compute the Akaike Information Criterion for each model to identify the models that best explain data consisting of serial isolates of M. tuberculosis genotyped with IS6110. We find that the best performing models all include selection against the accumulation of copies. Specifically, our analysis points to the interaction of separate copies of the element causing lethal effects. We discuss the implications of these findings for genome evolution and molecular epidemiology.

DNA Transposable Elements↗

PubMed2003

Estimating change rates of genetic markers using serial samples: applications to the transposon IS6110 in Mycobacterium tuberculosis.

In infectious disease epidemiology, it is useful to know how quickly genetic markers of pathogenic agents evolve while inside hosts. We propose a modular framework with which these genotype change rates can be estimated. The estimation scheme requires a model of the underlying process of genetic change, a detection scheme that filters this process into observable quantities, and a monitoring scheme that describes the timing of observations. We study a linear "birth-shift-death" model for change in transposable element genotypes, obtaining maximum-likelihood estimators for various detection and monitoring schemes. The method is applied to serial genotypes of the transposon IS6110 in Mycobacterium tuberculosis. The estimated birth rate of 0.0161 (events per copy of the transposon per year) and death rate of 0.0108 are both significantly larger than the estimated shift rate of 0.0018. The sum of these estimates, which corresponds to a "half-life" of 2.4 years for a typical strain that has 10 copies of the element, substantially exceeds a previous estimate of 0.0135 total changes per copy per year. We consider experimental design issues that enable the precision of estimates to be improved. We also discuss extensions to other markers and implications for molecular epidemiology.

DNA Transposable Elements↗

PubMed2003

The evolution of mutator genes in bacterial populations: the roles of environmental change and timing.

Recent studies have found high frequencies of bacteria with increased genomic rates of mutation in both clinical and laboratory populations. These observations may seem surprising in light of earlier experimental and theoretical studies. Mutator genes (genes that elevate the genomic mutation rate) are likely to induce deleterious mutations and thus suffer an indirect selective disadvantage; at the same time, bacteria carrying them can increase in frequency only by generating beneficial mutations at other loci. When clones carrying mutator genes are rare, however, these beneficial mutations are far more likely to arise in members of the much larger nonmutator population. How then can mutators become prevalent? To address this question, we develop a model of the population dynamics of bacteria confronted with ever-changing environments. Using analytical and simulation procedures, we explore the process by which initially rare mutator alleles can rise in frequency. We demonstrate that subsequent to a shift in environmental conditions, there will be relatively long periods of time during which the mutator subpopulation can produce a beneficial mutation before the ancestral subpopulations are eliminated. If the beneficial mutation arises early enough, the overall frequency of mutators will climb to a point higher than when the process began. The probability of producing a subsequent beneficial mutation will then also increase. In this manner, mutators can increase in frequency over successive selective sweeps. We discuss the implications and predictions of these theoretical results in relation to antibiotic resistance and the evolution of mutation rates.

Bacteria↗

PubMed2002

Coevolution of pathogens and cultural practices: a new look at behavioral heterogeneity in epidemics.

The effect of heterogeneity within populations on the spread of infectious diseases has been a recent focus of research. Such heterogeneity may be, for example, spatial, temporal or behavioral in form. Generally, models that include population subdivision have assumed that individuals are permanently assigned to given behavioral states represented by the subpopulations. We consider a simple epidemic model in which a behavioral trait affects disease transmission, and this trait may be transferred among hosts as a consequence of social interaction. This creates a situation where the frequencies of different behavioral traits and disease states as well as their associations may change over time. We consider the impact of the culturally transmitted trait on the criterion for initial spread of the disease. We also explore the evolution of cultural traits in response to pathogen dynamics and show some conditions under which behavioral traits that reduce transmission evolve. We find that behaviors increasing the risk of infection can also evolve when they are inherently favored or when there is sufficient clustering of contacts between like behaviors.

Communicable Diseases↗