05 - mmbr.00062 18 s0003

Deciphering within-host microevolution of Mycobacterium
tuberculosis through whole genome sequencing: the

phenotypic impact and way forward
Ley SDa, de Vos Ma, Van Rie Ab*, Warren RMa*#
a
DST-NRF Centre of Excellence for Biomedical Tuberculosis Research; South African Medical Research
Council Centre for Tuberculosis Research; Division of Molecular Biology and Human Genetics, Faculty of
Medicine and Health Sciences, Stellenbosch University, Cape Town.
b
Department of Epidemiology and Social Medicine, Faculty of Medicine and Health Sciences, University
of Antwerp, Belgium
# corresponding author: rw1@sun.ac.za
* shared senior last authors
SUPPLEMENTAL MATERIAL
Dataset S1: Patient and isolate data extracted from the included publications
see separate file
Dataset S2: Comparison of genes found to micro-evolve within the host
see separate file
1
Table S1: Search strategy and electronic databases screened
07.08.2018 PubMed No. of hits

search order/strategy
tuberculosis[MeSH terms] OR tuberculosis OR TB OR mycobacterium
(DP = 2010 - present) tuberculosis[MeSH terms] OR mycobacterium tuberculosis OR Mtb OR M.
AND tuberculosis 69044
((full genome OR complete genome OR entire genome OR next generation OR whole
1 AND genome OR deep OR genome) AND (sequenc*)) OR NGS OR WGS 2203
within-host OR within host OR within patient OR within-patient OR intra patient OR
1 AND 2 AND intra-patient OR in patient OR single patient OR during treatment 1043
NOT PT= review AND serial* OR consecutive OR multiple OR several OR follow up OR emerg* OR
1 AND 2 AND 3 AND acquired OR acquisition 314
07.08.2018 Web of Science Core Collection [v 5.29] No. of hits

search order/strategy For all searches only hits published between 2010 - 2018 included
tuberculosis[MeSH terms] OR tuberculosis OR TB OR mycobacterium
tuberculosis[MeSH terms] OR mycobacterium tuberculosis OR Mtb OR M.
1 tuberculosis 84340
((full genome OR complete genome OR entire genome OR next generation OR whole
within 1 genome OR deep OR genome) AND (sequenc*)) OR NGS OR WGS 2056
within-host OR within host OR within patient OR within-patient OR intra patient OR
within 1 AND 2 intra-patient OR in patient OR single patient OR during treatment 437
serial* OR consecutive OR multiple OR several OR follow up OR emerg* OR
within 1 AND 2 AND 3 acquired OR acquisition 210
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4
Table S2: Inclusion and exclusion criteria for the comparison of micro-evolved loci between studies
Included in
gene analysis
Author & Reference (yes/no) Data set used Reason for exclusion
1 Saunders et al (1) yes SNVs within article
2 Comas et al (2) yes Suppl. Table 2 SNVs from in vitro single colonies excluded (see inclusion criteria)
3 Walker et al (3) no SNVs between serial isolates not described
4 Sun et al (4) yes Table S2
5 Farhat et al (5) yes Suppl. Table 17; IDs 6 - 13
6 Bryant et al (6) yes Suppl. Table 1
SNVs could not be assigned to specific isolates, so unclear which ones are
7 Clark et al (7) no from serials and which ones from non-serial isolates
Yellow highlighted genes in Table S1 (Patient A) and Table S3 Table S5 (Patient C) excluded as exogenous re-infection, not within-patient
8 Merker et al (8) yes (Patient B) microevolution
Only nucleotide change indicated, but no gene name or loci (Table 2). Within
9 Pérez-Lago et al (9) no main text only 2 genes mentioned.
10 Eldholm et al (10) yes Suppl. Table 13059_2014_490_MOESM1_ESM.xlsx
Suppl. Tables indicate relapse associated SNVs, but these are not necessarily
all SNVs detected between pairs. Data not assignable to specific isolate (i.e.
11 Guerra-Assunçao et al (11) no gain/loss, present in both isolates of a patient?)
Complete set of SNVs between paired isolates only given for Case 2; no
12 Witney et al (12) yes Table A1; only data of Case 2 heterozygous SNVs though…
13 Guerra-Assunçao et al (13) no Same data than Guerra-Assunçao et al (11)
14 Black et al (14) yes Table 5 SNV between in vitro grown single colonies excluded (see inclusion criteria)
Meta-analysis of data sets of Merker et al, Sun et al and Eldholm et al (4, 8,
15 O'Neill et al (15) no 10)
16 Stinear et al (16) yes Suppl. Table 1
17 Pérez-Lago et al (17) no No high confidence SNVs detected between serial isolates
18 Bloemberg et al (18) no Drug resistance-conferring mutations only
Suppl. Table S1 A excluded, as these SNVs did not appear de novo or
19 Liu et al (19) yes Suppl. Table S1 B disappear completely over time (see inclusion criteria)
Only a sub-set of drug resistance-conferring mutations analyzed and reported;
20 Silva Feliciano et al (20) no unclear if these are all SNVs detected or not.
5
Included in
gene analysis
Author & Reference (yes/no) Data set used Reason for exclusion
Not ALL SNVs compared to reference reported, but all de novo emerged or
21 Korhonen et al (21) yes Suppl. Table disappeared SNVs reported
22 Faksri et al (22) yes SNVs described in main text
23 Ssengooba et al (23) yes additional file 2 Parallel isolates (sputum and blood)
24 Zhang et al (24) no Only SNVs in the genes gyrA and gyrB reported
Only drug resistance-conferring and compensatory mutations indicated, but no
25 Casali et al (25) no other SNVs between serial isolates
26 Lieberman et al (26) yes Parallel isolates across several anatomical sites
27 Wollenberg et al (27) no Drug resistance-conferring mutations only
28 Datta et al (28) yes Suppl.Tables 2, 3 and 4
29 Manson et al (29) no Drug resistance-conferring mutations only
30 Dheda et al (30) no No SNVs reported
31 Witney et al (31) yes Table 4
SNVs present at all timepoints of a patient were excluded (see inclusion
32 Trauner et al (32) yes Additional File 3_v-SNPs criteria)
33 Navarro et al (33) yes Table 1 SNVs from in vitro single colonies excluded (see inclusion criteria)
34 Nsofor et al (34) no Drug resistance-conferring mutations only
35 Senghore et al (35) no Drug resistance-conferring mutations and compensatory mutations only
36 Leung et al (36) yes Table 5 Only Sanger sequencing confirmed SNVs included
37 Herranz et al (37) yes Supplementary table 1
SNPs not assignable to specific patient, but as all patients have parallel/serial
Suppl. Table e6: SNPs gained at t= 1 isolates, and reported SNPs are all SNPs gained during treatment, still
38 Dheda et al (38) yes All new non-synonymous SNPs included in analysis

6
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5 5 5 5 5 5 5 5
6 6 6 6 6 6 6 6
= = + + + 7 7 7
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Table S4: Genes micro-evolving in more than two studies
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Deciphering within-host microevolution of Mycobacterium

tuberculosis through whole genome sequencing: the

Ley SDa, de Vos Ma, Van Rie Ab*, Warren RMa*#

Medicine and Health Sciences, Stellenbosch University, Cape Town.

# corresponding author: rw1@sun.ac.za

* shared senior last authors

see separate file

Dataset S2: Comparison of genes found to micro-evolve within the host

see separate file

07.08.2018 PubMed No. of hits

07.08.2018 Web of Science Core Collection [v 5.29] No. of hits

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otherwise stable genetic background. J Infect 62:212–217.

a retrospective observational study. Lancet Infect Dis 13:137–146.

convergent positive selection in drug-resistant Mycobacterium tuberculosis. Nat Genet 45:1183–1189.

Clin Microbiol 53:1473–1483.

in a high prevalence area. eLife 4.

Mycobacterium tuberculosis isolates. BMC Genomics 16:857.

a Massive Outbreak. J Clin Microbiol 53:3423–3429.

Tuberculosis Outbreak in London: A Retrospective Observational Study. PLOS Med 13:e1002137.

host dissemination of HIV-associated Mycobacterium tuberculosis. Nat Med.

Need for Region-Specific Diagnostics. Clin Infect Dis 64:1494–1501.

efficacy. Genome Biol 18:71.

Tuberculosis Patients in Shanghai, China. Sci Rep 7:7691.

Nigeria. PloS One 12:e0184510.

Front Cell Infect Microbiol 7:478.

Reactivations and Transmissions Involving Multiple Hosts. Front Microbiol 8:2661.

genomes. Tuberc Edinb Scotl 91:8–13.

tuberculosis. Eur Respir J 50.

You might also like

Ley SDa, de Vos Ma, Van Rie Ab, Warren RMa#

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