Multiple Introductions of Mycobacterium tuberculosis Lineage 2–Beijing Into Africa Over Centuries

Rutaihwa, Liliana K.; Menardo, Fabrizio; Stucki, David; Gygli, Sebastian M.; Ley, Serej D.; Malla, Bijaya; Feldmann, Julia; Borrell, Sònia; Beisel, Christian; Middelkoop, Keren; Carter, E. Jane; Diero, Lameck; Ballif, Marie; Jugheli, Levan; Reither, Klaus; Fenner, Lukas; Brites, Daniela; Gagneux, Sébastien

doi:10.3389/fevo.2019.00112

Cited by 41 publications

(45 citation statements)

References 70 publications

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“…Our findings would suggest the frequency of Lineage 2–Beijing in Tanzania, like in most parts of the continent except for South Africa [39,40] to be relatively low, despite the long-standing African-Asian contacts [40]. Evidence from recent studies show that Lineage 2–Beijing was only recently introduced into Africa [13,41].…”

Section: Discussionmentioning

confidence: 73%

Insights into the genetic diversity of Mycobacterium tuberculosis in Tanzania

et al. 2019

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Background Human tuberculosis (TB) is caused by seven phylogenetic lineages of the Mycobacterium tuberculosis complex (MTBC), Lineage 1–7. Recent advances in rapid genotyping of MTBC based on single nucleotide polymorphisms (SNP), allow for phylogenetically robust strain classification, paving the way for defining genotype-phenotype relationships in clinical settings. Such studies have revealed that, in addition to host and environmental factors, strain variation in the MTBC influences the outcome of TB infection and disease. In Tanzania, such molecular epidemiological studies of TB however are scarce in spite of a high TB burden. Methods and findings Here we used SNP-typing to characterize a nationwide collection of 2,039 MTBC clinical isolates representative of 1.6% of all new and retreatment TB cases notified in Tanzania during 2012 and 2013. Four lineages, namely Lineage 1–4 were identified within the study population. The distribution and frequency of these lineages varied across regions but overall, Lineage 4 was the most frequent (n = 866, 42.5%), followed by Lineage 3 (n = 681, 33.4%) and 1 (n = 336, 16.5%), with Lineage 2 being the least frequent (n = 92, 4.5%). We found Lineage 2 to be independently associated with female sex (adjusted odds ratio [aOR] 2.14; 95% confidence interval [95% CI] 1.31 – 3.50, p = 0.002) and retreatment cases (aOR 1.67; 95% CI 0.95 – 2.84, p = 0. 065) in the study population. We found no associations between MTBC lineage and patient age or HIV status. Our sublineage typing based on spacer oligotyping on a subset of Lineage 1, 3 and 4 strains revealed the presence of mainly EAI, CAS and LAM families. Finally, we detected low levels of multidrug resistant isolates among a subset of 144 retreatment cases. Conclusions This study provides novel insights into the MTBC lineages and the possible influence of pathogen–related factors on the TB epidemic in Tanzania.

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Section: Discussionmentioning

confidence: 73%

Insights into the genetic diversity of Mycobacterium tuberculosis in Tanzania

et al. 2019

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“…Since the publication of the MTB reference genome [6], whole genome sequence (WGS) data of MTB strains is becoming available at increasing speed, and especially in the last five years, studies using large WGS data sets allowed for precise estimates of the MTB genetic diversity and of the molecular clock rate. Phylogenetic analyses with a molecular clock have been used to estimate the timing of the introduction of MTB clades to particular geographic regions, the divergence time of the MTB lineages, and the age of the most recent common ancestor (MRCA) of the MTB complex [7–13]. Clock models, together with phylodynamic models in a Bayesian setting have been used to characterize tuberculosis epidemics by determining the time at which outbreaks began and ended [14–18], establishing the time of origin and spread of drug resistant clades [11, 14, 19–20], and correlating population dynamics with historical events [9, 12, 20, 21–22].…”

Section: Introductionmentioning

confidence: 99%

“…While many of the studies inferring evolutionary rates for MTB reported support for a molecular clock [10–11, 13–14, 16, 18, 20, 22], some found a lack of clocklike structure [7, 17–18], and others assumed a molecular clock without testing whether the data had a temporal structure [9, 12, 15, 19, 21]. In all studies where the calibration was based on the sampling time (tip-dating), the clock rate estimates spanned roughly an order of magnitude around 10 −7 nucleotide changes per site per year.…”

Section: Introductionmentioning

confidence: 99%

“…Studies based on WGS and tip-dating found some differences in the clock rate of different lineages: some lineage 2 (L2) data sets [20] were found to have a faster clock rate compared to lineage 4 (L4) data sets [11, 14, 16, 21], while others showed lower clock rates, comparable with L4 [13, 18]. Studies based on aDNA produced slightly lower clock rate estimates [8, 10] compared to studies based on modern strains, thus suggesting support for the phenomenon of time dependency of clock rates in MTB [25–26].…”

Section: Introductionmentioning

confidence: 99%

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The molecular clock of Mycobacterium tuberculosis

et al. 2019

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The molecular clock and its phylogenetic applications to genomic data have changed how we study and understand one of the major human pathogens, Mycobacterium tuberculosis (MTB), the etiologic agent of tuberculosis. Genome sequences of MTB strains sampled at different times are increasingly used to infer when a particular outbreak begun, when a drug-resistant clone appeared and expanded, or when a strain was introduced into a specific region. Despite the growing importance of the molecular clock in tuberculosis research, there is a lack of consensus as to whether MTB displays a clocklike behavior and about its rate of evolution. Here we performed a systematic study of the molecular clock of MTB on a large genomic data set (6,285 strains), covering different epidemiological settings and most of the known global diversity. We found that sampling times below 15–20 years were often insufficient to calibrate the clock of MTB. For data sets where such calibration was possible, we obtained a clock rate between 1x10-8 and 5x10-7 nucleotide changes per-site-per-year (0.04–2.2 SNPs per-genome-per-year), with substantial differences between clades. These estimates were not strongly dependent on the time of the calibration points as they changed only marginally when we used epidemiological isolates (sampled in the last 40 years) or three ancient DNA samples (about 1,000 years old) to calibrate the tree. Additionally, the uncertainty and the discrepancies in the results of different methods were sometimes large, highlighting the importance of using different methods, and of considering carefully their assumptions and limitations.

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“…Current genome data show that the MTBC is comprised of the five human-adapted lineages representing M. tuberculosis sensu stricto (L1-4 and L7), two other humanadapted lineages traditionally referred to as M. africanum (L5-6) and at least nine animal-adapted lineages 6 . Africa is the only continent where all MTBC lineages are present, suggesting that the MTBC emerged from a common ancestor therein and then expanded to the rest of the world following human migrations 3,[7][8][9][10] . However, the genomic traits of this common ancestor and the region from which this expansion took place in Africa remain unknown.…”

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A sister lineage of the Mycobacterium tuberculosis complex discovered in the African Great Lakes region

et al. 2020

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The human-and animal-adapted lineages of the Mycobacterium tuberculosis complex (MTBC) are thought to have expanded from a common progenitor in Africa. However, the molecular events that accompanied this emergence remain largely unknown. Here, we describe two MTBC strains isolated from patients with multidrug resistant tuberculosis, representing an as-yet-unknown lineage, named Lineage 8 (L8), seemingly restricted to the African Great Lakes region. Using genome-based phylogenetic reconstruction, we show that L8 is a sister clade to the known MTBC lineages. Comparison with other complete mycobacterial genomes indicate that the divergence of L8 preceded the loss of the cobF genome region-involved in the cobalamin/vitamin B12 synthesis-and gene interruptions in a subsequent common ancestor shared by all other known MTBC lineages. This discovery further supports an East African origin for the MTBC and provides additional molecular clues on the ancestral genome reduction associated with adaptation to a pathogenic lifestyle.

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Multiple Introductions of Mycobacterium tuberculosis Lineage 2–Beijing Into Africa Over Centuries

Cited by 41 publications

References 70 publications

Insights into the genetic diversity of Mycobacterium tuberculosis in Tanzania

Insights into the genetic diversity of Mycobacterium tuberculosis in Tanzania

The molecular clock of Mycobacterium tuberculosis

A sister lineage of the Mycobacterium tuberculosis complex discovered in the African Great Lakes region

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