Substantial molecular evolution and mutation rates in prolonged latent Mycobacterium tuberculosis infection in humans

Lillebæk, Troels; Norman, Anders; Rasmussen, Erik Michael; Marvig, Rasmus Lykke; Folkvardsen, Dorte Bek; Andersen, Anita Sylvest; Jelsbak, Lars

doi:10.1016/j.ijmm.2016.05.017

Cited by 35 publications

(29 citation statements)

References 28 publications

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“…These two studies yielded similar rate estimates, despite including data from very different time periods. The substitution rate estimates of ∼5 × 10 −8 substitutions/site/year (s/s/y) obtained in these aDNA studies are slightly lower than estimates from epidemiologic studies and other studies based on contemporaneous sampling, all of which produced rate estimates around 0.7 × 10 −7 -1.3 × 10 −7 s/s/y, corresponding to 0.3-0.5 substitutions/genome/ year (6,(13)(14)(15)(16)(17)(18).…”

contrasting

confidence: 65%

Armed conflict and population displacement as drivers of the evolution and dispersal of Mycobacterium tuberculosis

Eldholm

Pettersson

Brynildsrud

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The "Beijing" Mycobacterium tuberculosis (Mtb) lineage 2 (L2) is spreading globally and has been associated with accelerated disease progression and increased antibiotic resistance. Here we performed a phylodynamic reconstruction of one of the L2 sublineages, the central Asian clade (CAC), which has recently spread to western Europe. We find that recent historical events have contributed to the evolution and dispersal of the CAC. Our timing estimates indicate that the clade was likely introduced to Afghanistan during the 1979-1989 Soviet-Afghan war and spread further after population displacement in the wake of the American invasion in 2001. We also find that drug resistance mutations accumulated on a massive scale in Mtb isolates from former Soviet republics after the fall of the Soviet Union, a pattern that was not observed in CAC isolates from Afghanistan. Our results underscore the detrimental effects of political instability and population displacement on tuberculosis control and demonstrate the power of phylodynamic methods in exploring bacterial evolution in space and time.

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contrasting

confidence: 65%

Armed conflict and population displacement as drivers of the evolution and dispersal of Mycobacterium tuberculosis

Eldholm

Pettersson

Brynildsrud

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

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“…Also, given previously reported mutation rates in MTB, usually within the range of 0.25–0.5 SNPs per genome per year, the accumulation of SNPs in the intrapatient variants is much higher than expected. It suggests a higher tendency to acquire variability by this strain, but we must also leave open the possibility that part of that variability could have been acquired during the latency period, as it has been suggested elsewhere (Lillebaek et al, 2016). …”

Section: Discussionmentioning

confidence: 54%

In-Depth Characterization and Functional Analysis of Clonal Variants in a Mycobacterium tuberculosis Strain Prone to Microevolution

et al. 2017

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The role of clonal complexity has gradually been accepted in infection by Mycobacterium tuberculosis (MTB), although analyses of this issue are limited. We performed an in-depth study of a case of recurrent MTB infection by integrating genotyping, whole genome sequencing, analysis of gene expression and infectivity in in vitro and in vivo models. Four different clonal variants were identified from independent intrapatient evolutionary branches. One of the single-nucleotide polymorphisms in the variants mapped in mce3R, which encodes a repressor of an operon involved in virulence, and affected expression of the operon. Competitive in vivo and in vitro co-infection assays revealed higher infective efficiency for one of the clonal variants. A new clonal variant, which had not been observed in the clinical isolates, emerged in the infection assays and showed higher fitness than its parental strain. The analysis of other patients involved in the same transmission cluster revealed new clonal variants acquired through novel evolutionary routes, indicating a high tendency toward microevolution in some strains that is not host-dependent. Our study highlights the need for integration of various approaches to advance our knowledge of the role and significance of microevolution in tuberculosis.

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“…If this relationship exists -for example if latent cases both do not transmit and do not accumulate SNPs (Colangeli et al 2014) -then low SNP differences could correspond to fewer intermediate hosts despite long elapsed times. This is an implicit assumption of a SNP-only method; while it may be correct it is a strong assumption, and there is evidence that mutation rates in latency are not reduced compared to active disease (Ford et al 2011;Lillebaek et al 2016).…”

Section: Discussionmentioning

confidence: 99%

Beyond the SNP threshold: identifying outbreak clusters using inferred transmissions

Stimson

Gardy

Mathema

et al. 2018

Preprint

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Whole genome sequencing (WGS) is increasingly used to aid the understanding of pathogen transmission. A first step in analysing WGS data is usually to define "transmission clusters", sets of cases that are potentially linked by direct transmission. This is often done by including two cases in the same cluster if they are separated by fewer SNPs than a specified threshold. However, there is little agreement as to what an appropriate threshold should be. We propose a probabilistic alternative, suggesting that the key inferential target for transmission clusters is the number of transmissions separating cases. We characterise this by combining the number of SNP differences and the length of time over which those differences have accumulated, using information about case timing, molecular clock and transmission processes. Our framework has the advantage of allowing for variable mutation rates across the genome and can incorporate other epidemiological data. We use two tuberculosis studies to illustrate the impact our approach: with British Columbia data by using spatial divisions; with Republic of Moldova data by incorporating antibiotic resistance. Simulation results indicate that our transmission-based method is better at identifying direct transmissions than a SNP threshold, with dissimilarity between clusterings of on average 0.27 bits compared to 0.37 bits for the SNP threshold method and 0.84 bits for randomly permuted data. These results show that it is likely to outperform the SNP threshold where clock rates are variable and sample collection times are spread out. We implement the method in the R package transcluster.

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Substantial molecular evolution and mutation rates in prolonged latent Mycobacterium tuberculosis infection in humans

Cited by 35 publications

References 28 publications

Armed conflict and population displacement as drivers of the evolution and dispersal of Mycobacterium tuberculosis

Armed conflict and population displacement as drivers of the evolution and dispersal of Mycobacterium tuberculosis

In-Depth Characterization and Functional Analysis of Clonal Variants in a Mycobacterium tuberculosis Strain Prone to Microevolution

Beyond the SNP threshold: identifying outbreak clusters using inferred transmissions

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