The dynamics of repeated elements: Applications to the epidemiology of tuberculosis

Abstract

We propose a stepwise mutation model to describe the dynamics of DNA fingerprint variation in Mycobacterium tuberculosis. The genome of M. tuberculosis carries insertion sequences (IS6110) that are relatively stable over time periods of months but have an observable transposition rate over longer time scales. Variability in copy number and genomic location of (IS6110) can be harnessed to generate a DNA fingerprint for each strain, by digesting the genome with a restriction enzyme and using a portion of the element as a probe for Southern blots. The number of bands found for a given genome approximates the number of copies of IS6110 it carries. A large data set of such fingerprints from tuberculosis (TB) cases in San Francisco provides an observed distribution of IS6110 copy number. Implementation of the model through deterministic and stochastic simulation indicates some general features of IS͞TB dynamics. By comparing observations with outcomes of the model, we conclude that the IS͞TB system is very heterogeneous and far from equilibrium. We find that the transposition parameters have a much stronger effect than the epidemic parameters on copy number distribution. E fficient molecular methods have allowed the recent genetic characterization of parasitic agents. Such empirical work greatly enhances our understanding of the epidemiology of human diseases (1-4). These new data are the stimulus for the development of theoretical and quantitative understanding of how genetic variability among strains interacts with epidemic processes. The molecular epidemiology of tuberculosis (TB) has been well developed. The insertion sequence (IS) 6110 in the genome of Mycobacterium tuberculosis is stable on the short time scale of months, while transposing at an observable rate over longer time periods. By digesting the genome with the restriction enzyme PvuII and using a portion of the element as a probe for Southern blotting, strains can be distinguished by the resulting DNA fingerprints (2). The number of bands in each blot indicates the number of copies of IS in the isolated genome.The essential features of TB dynamics recently have been explored (5-7). Those studies take into account the various important aspects of the disease; for instance, a fraction of newly acquired infections progress to the disease immediately while the remainder enter a potentially long period of latent infection. Using estimates of epidemiological parameters from the empirical literature, those authors quantitatively characterize the length of epidemics and assess the efficacy of control strategies.Several theoretical studies have investigated transposon dynamics. Many of these are constructed for diploid genomes, particularly Drosophila (8-10). Sawyer and Hartl (11) and Moody (12) treat stochastic models of transposable elements in prokaryotes (IS elements), though without consideration of epidemic circumstances. Both studies allow a degree of horizontal transmission. The latter includes replicative transposition (increase by one copy) and deletio...

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

“…Hosts with low-copy strains might be eliminated early in studies, and sampling intervals might be chosen to be shorter for high-copy strains. Of course, these decisions are not recommended when the goal is to study population dynamics of the marker (Tanaka et al, 2000, for example) rather than to estimate rates: if high copy numbers are preferentially included, samples will no longer be random.…”

“…The Niemann data set may represent populations at a later stage of infection, during which changes might occur more slowly (Warren et al, 2002). Alternatively, there could be strain heterogeneity Tanaka et al, 2000): the strains of the Niemann data set may have less active transposases compared to the SF strains. Systematic biases in laboratory procedures may also be responsible, or changes in genotyping procedures that have occurred over time.…”

Evolutionary Relationships among Strains of Mycobacterium tuberculosis with Few Copies of IS 6110

“…In most populations, multicopy strains (with five or more copies of IS6110) form a substantial majority of isolates of M. tuberculosis (24,33,40,42). Isolates with only a few copies of IS6110 show much less polymorphism, necessitating the use of additional typing methods such as spoligotyping (20) or PGRS typing (7).…”

Tuberculosis ocular

“…La técnica de RPC anidada (nested PCR en inglés), específica para el gen MPB64, descrita por Narita y cols 56 , fue estandarizada por Madhavan y cols 43 . MPB64 es una proteína altamente inmunogénica que se encuentra en los cultivos filtrados no calentados de M. tuberculosis y algunas cepas de M. bovis BCG 59 . Se encontró que la técnica de RPC anidada fue no sólo específi-ca, sino también 10 mil veces más sensible que la RPC usando partidores de IS6110.…”