Insights into the Complexity of a Dormant <i>Mycobacterium tuberculosis</i> Cluster Once Transmission Is Resumed

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ABSTRACT

Genotyping tools help identify the complexity in Mycobacterium tuberculosis transmission clusters. We carried out a thorough analysis of the epidemiological and bacteriological complexity of a cluster in Almería, Spain. The cluster, initially associated with Moroccan migrants and with no secondary cases identified in 4 years, then reappeared in Spanish-born individuals. In one case, two Mycobacterium tuberculosis clonal variants were identified. We reanalyzed the cluster, supported by the characterization of multiple cultured isolates and respiratory specimens, whole-genome sequencing, and epidemiological case interviews. Our findings showed that the cluster, which was initially thought to have restarted activity with just a single case harboring a small degree of within-host diversity, was in fact currently growing due to coincidental reactivation of past exposures, with clonal diversity transmitted throughout the cluster. In one case, within-host diversity was amplified, probably due to prolonged diagnostic delay.

IMPORTANCE The precise study of the dynamics of tuberculosis transmission in socio-epidemiologically complex scenarios may require more thorough analysis than the standard molecular epidemiology strategies. Our study illustrates the epidemiological and bacteriological complexity present in a transmission cluster in a challenging epidemiological setting with a high proportion of migrant cases. The combination of whole-genome sequencing, refined and refocused epidemiological interviews, and in-depth analysis of the bacterial composition of sputa and cultured isolates was crucial in order to correctly reinterpret the true nature of this cluster. Our global approach allowed us to reinterpret correctly the unnoticed epidemiological and bacteriological complexity involved in the Mycobacterium tuberculosis transmission event under study, which had been overlooked by the usual molecular epidemiology approaches.

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Most cited references 28

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A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3.

Pablo E. Cingolani, Adrian E. Platts, Le Lily Wang … (2012)

We describe a new computer program, SnpEff, for rapidly categorizing the effects of variants in genome sequences. Once a genome is sequenced, SnpEff annotates variants based on their genomic locations and predicts coding effects. Annotated genomic locations include intronic, untranslated region, upstream, downstream, splice site, or intergenic regions. Coding effects such as synonymous or non-synonymous amino acid replacement, start codon gains or losses, stop codon gains or losses, or frame shifts can be predicted. Here the use of SnpEff is illustrated by annotating ~356,660 candidate SNPs in ~117 Mb unique sequences, representing a substitution rate of ~1/305 nucleotides, between the Drosophila melanogaster w(1118); iso-2; iso-3 strain and the reference y(1); cn(1) bw(1) sp(1) strain. We show that ~15,842 SNPs are synonymous and ~4,467 SNPs are non-synonymous (N/S ~0.28). The remaining SNPs are in other categories, such as stop codon gains (38 SNPs), stop codon losses (8 SNPs), and start codon gains (297 SNPs) in the 5'UTR. We found, as expected, that the SNP frequency is proportional to the recombination frequency (i.e., highest in the middle of chromosome arms). We also found that start-gain or stop-lost SNPs in Drosophila melanogaster often result in additions of N-terminal or C-terminal amino acids that are conserved in other Drosophila species. It appears that the 5' and 3' UTRs are reservoirs for genetic variations that changes the termini of proteins during evolution of the Drosophila genus. As genome sequencing is becoming inexpensive and routine, SnpEff enables rapid analyses of whole-genome sequencing data to be performed by an individual laboratory.

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Fast and accurate long-read alignment with Burrows–Wheeler transform

Heng Li, Richard Durbin (2010)

Motivation: Many programs for aligning short sequencing reads to a reference genome have been developed in the last 2 years. Most of them are very efficient for short reads but inefficient or not applicable for reads >200 bp because the algorithms are heavily and specifically tuned for short queries with low sequencing error rate. However, some sequencing platforms already produce longer reads and others are expected to become available soon. For longer reads, hashing-based software such as BLAT and SSAHA2 remain the only choices. Nonetheless, these methods are substantially slower than short-read aligners in terms of aligned bases per unit time. Results: We designed and implemented a new algorithm, Burrows-Wheeler Aligner's Smith-Waterman Alignment (BWA-SW), to align long sequences up to 1 Mb against a large sequence database (e.g. the human genome) with a few gigabytes of memory. The algorithm is as accurate as SSAHA2, more accurate than BLAT, and is several to tens of times faster than both. Availability: http://bio-bwa.sourceforge.net Contact: rd@sanger.ac.uk

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From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline.

Geraldine Auwera, Mauricio Carneiro, Christopher Hartl … (2013)

This unit describes how to use BWA and the Genome Analysis Toolkit (GATK) to map genome sequencing data to a reference and produce high-quality variant calls that can be used in downstream analyses. The complete workflow includes the core NGS data processing steps that are necessary to make the raw data suitable for analysis by the GATK, as well as the key methods involved in variant discovery using the GATK.

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Author and article information

Contributors

Laura Pérez-Lago:

ORCID: https://orcid.org/0000-0001-5249-7619

Darío García de Viedma:

ORCID: https://orcid.org/0000-0003-3647-7110

S. Wesley Long: Role: Editor

Journal

Journal ID (nlm-ta): Microbiol Spectr

Journal ID (iso-abbrev): Microbiol Spectr

Journal ID (publisher-id): spectrum

Title: Microbiology Spectrum

Publisher: American Society for Microbiology (1752 N St., N.W., Washington, DC )

ISSN (Electronic): 2165-0497

Publication date (Electronic, pub): 19 January 2022

Publication date (Electronic, collection): Jan-Feb 2022

Publication date PMC-release: 19 January 2022

Volume: 10

Issue: 1

Electronic Location Identifier: e01381-21

Affiliations

[a ] Servicio de Microbiología Clínica y Enfermedades Infecciosas, Hospital General Universitario Gregorio Marañóngrid.410526.4, , Madrid, Spain

[b ] Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain

[c ] Complejo Hospitalario Torrecárdenas, Almería, Spain

[d ] CIBER Enfermedades Respiratorias (CIBERES), Madrid, Spain

[e ] Departamento de Medicina, Universidad Complutense, Madrid, Spain

Houston Methodist Hospital

Author notes

Laura Pérez-Lago and Darío García de Viedma contributed equally to this article. Author order was determined by the corresponding author after negotiation.

The authors declare no conflict of interest.

Author information

Patricia Muñoz https://orcid.org/0000-0001-5706-5583

Laura Pérez-Lago https://orcid.org/0000-0001-5249-7619

Darío García de Viedma https://orcid.org/0000-0003-3647-7110

Article

Publisher ID: 01381-21 Publisher ID: spectrum.01381-21

DOI: 10.1128/spectrum.01381-21

PMC ID: 8768656

PubMed ID: 35044196

SO-VID: 13210395-dd32-4f1d-bd11-8faf5dce5638

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

History

Date received : 25 August 2021

Date accepted : 13 December 2021

Page count

supplementary-material: 1, Figures: 3, Tables: 2, Equations: 0, References: 28, Pages: 9, Words: 5843

Funding

Funded by: ISCIII;

Award ID: CPII20/00001

Award Recipient : Darío Garcia de Viedma Award Recipient : Laura Pérez-Lago

Funded by: Junta de Andalucía (Andalusian Board);

Award ID: PI0488-2017

Award Recipient : Miguel Jose Martinez-Lirola

Funded by: ERANet-LAC (TRANS-TB-TRANS Project);

Award ID: ELAC2015 (T08-0664)

Award Recipient : Darío Garcia de Viedma

Funded by: IFARHU-SENACYT;

Award ID: 216-2017

Award Recipient : Fermin Acosta

Custom metadata

cover-date January/February 2022

Keywords: tuberculosis,cluster,transmission,reactivation,within-host diversity,clonal complexity,mycobacterium tuberculosis

Data availability:

Keywords: tuberculosis, cluster, transmission, reactivation, within-host diversity, clonal complexity, mycobacterium tuberculosis

Insights into the Complexity of a Dormant Mycobacterium tuberculosis Cluster Once Transmission Is Resumed

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ABSTRACT

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TKD - Transmission Kikuchi Diffraction

Most cited references 28

A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3.

Fast and accurate long-read alignment with Burrows–Wheeler transform

From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline.

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Author notes

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