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

Group-theoretic models of the inversion process in bacterial genomes

The variation in genome arrangements among bacterial taxa is largely due to the process of inversion. Recent studies indicate that not all inversions are equally probable, suggesting, for instance, that shorter inversions are more frequent than longer, and those that move the terminus of replication are less probable than those that do not. Current methods for establishing the inversion distance between two bacterial genomes are unable to incorporate such information. In this paper we suggest a group-theoretic framework that in principle can take these constraints into account. In particular, we show that by lifting the problem from circular permutations to the affine symmetric group, the inversion distance can be found in polynomial time for a model in which inversions are restricted to acting on two regions. This requires the proof of new results in group theory, and suggests a vein of new combinatorial problems concerning permutation groups on which group theorists will be needed to collaborate with biologists. We apply the new method to inferring distances and phylogenies for published Yersinia pestis data.Comment: 19 pages, 7 figures, in Press, Journal of Mathematical Biolog

Maximum likelihood estimates of pairwise rearrangement distances

Accurate estimation of evolutionary distances between taxa is important for many phylogenetic reconstruction methods. In the case of bacteria, distances can be estimated using a range of different evolutionary models, from single nucleotide polymorphisms to large-scale genome rearrangements. In the case of sequence evolution models (such as the Jukes-Cantor model and associated metric) have been used to correct pairwise distances. Similar correction methods for genome rearrangement processes are required to improve inference. Current attempts at correction fall into 3 categories: Empirical computational studies, Bayesian/MCMC approaches, and combinatorial approaches. Here we introduce a maximum likelihood estimator for the inversion distance between a pair of genomes, using the group-theoretic approach to modelling inversions introduced recently. This MLE functions as a corrected distance: in particular, we show that because of the way sequences of inversions interact with each other, it is quite possible for minimal distance and MLE distance to differently order the distances of two genomes from a third. This has obvious implications for the use of minimal distance in phylogeny reconstruction. The work also tackles the above problem allowing free rotation of the genome. Generally a frame of reference is locked, and all computation made accordingly. This work incorporates the action of the dihedral group so that distance estimates are free from any a priori frame of reference.Comment: 21 pages, 7 figures. To appear in the Journal of Theoretical Biolog

Models of deletion for visualizing bacterial variation: an application to tuberculosis spoligotypes

<p>Abstract</p> <p>Background</p> <p>Molecular typing methods are commonly used to study genetic relationships among bacterial isolates. Many of these methods have become standardized and produce portable data. A popular approach for analyzing such data is to construct graphs, including phylogenies. Inferences from graph representations of data assist in understanding the patterns of transmission of bacterial pathogens, and basing these graph constructs on biological models of evolution of the molecular marker helps make these inferences. Spoligotyping is a widely used method for genotyping isolates of <it>Mycobacterium tuberculosis </it>that exploits polymorphism in the direct repeat region. Our goal was to examine a range of models describing the evolution of spoligotypes in order to develop a visualization method to represent likely relationships among <it>M. tuberculosis </it>isolates.</p> <p>Results</p> <p>We found that inferred mutations of spoligotypes frequently involve the loss of a single or very few adjacent spacers. Using a second-order variant of Akaike's Information Criterion, we selected the Zipf model as the basis for resolving ambiguities in the ancestry of spoligotypes. We developed a method to construct graphs of spoligotypes (which we call spoligoforests). To demonstrate this method, we applied it to a tuberculosis data set from Cuba and compared the method to some existing methods.</p> <p>Conclusion</p> <p>We propose a new approach in analyzing relationships of <it>M. tuberculosis </it>isolates using spoligotypes. The spoligoforest recovers a plausible history of transmission and mutation events based on the selected deletion model. The method may be suitable to study markers based on loci of similar structure from other bacteria. The groupings and relationships in the spoligoforest can be analyzed along with the clinical features of strains to provide an understanding of the evolution of spoligotypes.</p

First molecular phylogenetic insights into the evolution of Eriocaulon (Eriocaulaceae, Poales)

Eriocaulon is a genus of c. 470 aquatic and wetland species of the monocot plant family Eriocaulaceae. It is widely distributed in Africa, Asia and America, with centres of species richness in the tropics. Most species of Eriocaulon grow in wetlands although some inhabit shallow rivers and streams with an apparent adaptive morphology of elongated submerged stems. In a previous molecular phylogenetic hypothesis, Eriocaulon was recovered as sister of the African endemic genus Mesanthemum. Several regional infrageneric classifications have been proposed for Eriocaulon. This study aims to critically assess the existing infrageneric classifications through phylogenetic reconstruction of infrageneric relationships, based on DNA sequence data of four chloroplast markers and one nuclear marker. There is little congruence between our molecular results and previous morphology-based infrageneric classifications. However, some similarities can be found, including Fyson’s sect. Leucantherae and Zhang’s sect. Apoda. Further phylogenetic studies, particularly focusing on less well sampled regions such as the Neotropics, will help provide a more global overview of the relationships in Eriocaulon and may enable suggesting the first global infrageneric classification

A Very Hot, High Redshift Cluster of Galaxies: More Trouble for Omega_0 = 1

We have observed the most distant (z=0.829) cluster of galaxies in the Einstein Extended Medium Sensitivity Survey, with the ASCA and ROSAT satellites. We find an X-ray temperature of 12.3 +3.1/-2.2 keV for this cluster, and the ROSAT map reveals significant substructure. The high temperature of MS1054-0321 is consistent with both its approximate velocity dispersion, based on the redshifts of 12 cluster members we have obtained at the Keck and the Canada-France-Hawaii telescopes, and with its weak lensing signature. The X-ray temperature of this cluster implies a virial mass ~ 7.4 x 10^14 h^-1 solar masses, if the mean matter density in the universe equals the critical value, or larger if Omega_0 < 1. Finding such a hot, massive cluster in the EMSS is extremely improbable if clusters grew from Gaussian perturbations in an Omega_0 = 1 universe. Combining the assumptions that Omega_0 = 1 and that the intial perturbations were Gaussian with the observed X-ray temperature function at low redshift, we show that the probability of this cluster occurring in the volume sampled by the EMSS is less than a few times 10^{-5}. Nor is MS1054-0321 the only hot cluster at high redshift; the only two other $z > 0.5$ EMSS clusters already observed with ASCA also have temperatures exceeding 8 keV. Assuming again that the initial perturbations were Gaussian and Omega_0 = 1, we find that each one is improbable at the < 10^{-2} level. These observations, along with the fact that these luminosities and temperatures of the high-$z$ clusters all agree with the low-z L_X-T_X relation, argue strongly that Omega_0 < 1. Otherwise, the initial perturbations must be non-Gaussian, if these clusters' temperatures do indeed reflect their gravitational potentials.Comment: 20 pages, 4 figures, To appear in 1 Aug 1998 ApJ (heavily revised version of original preprint

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

The Formation of Massive Cluster Galaxies

We present composite 3.6 and 4.5 micron luminosity functions for cluster galaxies measured from the Spitzer Deep, Wide-Field Survey (SDWFS) for 0.3<z<2. We compare the evolution of m* for these luminosity functions to models for passively evolving stellar populations to constrain the primary epoch of star formation in massive cluster galaxies. At low redshifts (z < 1.3) our results agree well with models with no mass assembly and passively evolving stellar populations with a luminosity-weighted mean formation redshift zf=2.4 assuming a Kroupa initial mass function (IMF). We conduct a thorough investigation of systematic biases that might influence our results, and estimate systematic uncertainites of Delta zf=(+0.16-0.18) (model normalization), Delta zf=(+0.40-0.05) (alpha), and Delta zf=(+0.30-0.45) (choice of stellar population model). For a Salpeter type IMF, the typical formation epoch is thus strongly constrained to be z ~2-3. Higher formation redshifts can only be made consistent with the data if one permits an evolving IMF that is bottom-light at high redshift, as suggested by van Dokkum et al 2008. At high redshift (z > 1.3) we also witness a statistically significant (>5sigma) disagreement between the measured luminosity function and the continuation of the passive evolution model from lower redshifts. After considering potential systematic biases that might influence our highest redshift data points, we interpret the observed deviation as potential evidence for ongoing mass assembly at this epoch.Comment: 17 pages, 14 figures, accepted for publication in Ap

Regulation of meiotic prophase arrest in mouse oocytes by GPR3, a constitutive activator of the Gs G protein

The arrest of meiotic prophase in mouse oocytes within antral follicles requires the G protein Gs and an orphan member of the G protein–coupled receptor family, GPR3. To determine whether GPR3 activates Gs, the localization of Gαs in follicle-enclosed oocytes from Gpr3+/+ and Gpr3−/− mice was compared by using immunofluorescence and GαsGFP. GPR3 decreased the ratio of Gαs in the oocyte plasma membrane versus the cytoplasm and also decreased the amount of Gαs in the oocyte. Both of these properties indicate that GPR3 activates Gs. The follicle cells around the oocyte are also necessary to keep the oocyte in prophase, suggesting that they might activate GPR3. However, GPR3-dependent Gs activity was similar in follicle-enclosed and follicle-free oocytes. Thus, the maintenance of prophase arrest depends on the constitutive activity of GPR3 in the oocyte, and the follicle cell signal acts by a means other than increasing GPR3 activity