The mutational signatures of poor treatment outcomes on the drug-susceptible Mycobacterium tuberculosis genome
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, China
- National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, China
- School of Public Health, Public Health Research Institute of Renmin Hospital, Wuhan University, China
- Department of Epidemiology and Biostatistics,School of Public Health, Xinjiang Medical University, China
- Instituto Venezolano de Investigaciones Cientificas (IVIC), Venezuela
Figures
Figure 1
Sample origin and genetic structure of Mycobacterium tuberculosis.
(A) Geographic location of the samples analyzed and study cohort characteristics. (B) The phylogenetic tree of 3196 drug-susceptible tuberculosis strains. The different colors on the branches …
Figure 2 with 4 supplements
Generation of the functional mutation set.
(A) Manhattan plots of genome-wide association study (GWAS) for fixed single nucleotide polymorphisms (SNPs) associated with poor treatment outcomes. The dashed red line highlights the …
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Figure 2—source data 1
GWAS identified fixed SNPs.
- https://cdn.elifesciences.org/articles/84815/elife-84815-fig2-data1-v2.docx
Figure 2—figure supplement 1
Manhattan plots of unfixed single nucleotide polymorphisms (SNPs) associated with poor treatment outcomes.
The top 50 unfixed mutations were annotated with the gene. The dashed red line highlights the Bonferroni-corrected threshold (p=4.82 × 10–6).
Figure 2—figure supplement 2
Gene expression (log2FPKM) from RNA-seq after drug exposure and hypoxia.
Figure 2—figure supplement 3
Within-host frequency distribution of genome-wide association study (GWAS)-identified unfixed mutations.
Figure 2—figure supplement 4
Manhattan plot of genome-wide association study (GWAS) analysis based on the Malawi dataset.
The dashed red line highlights the Bonferroni-corrected threshold (p=2.66 × 10–6).
Figure 3
Bacterial whole-genome mutation features between patients with different treatment outcomes.
(A) The proportion of six mutation types in all fixed and unfixed mutations (t-test, mean range: mean ± SE). (B) Distribution of total unfixed mutations and nonsynonymous unfixed mutations across …
Figure 4
Effects of genome-wide association study (GWAS) identified mutations on tuberculosis treatment outcomes.
(A) Univariable and multivariable logistic regression on the risk factors for poor treatment outcomes. (B) Nomogram for predicting the probability of poor treatment outcomes. (C) ROC curves are …
Author response image 1
Schematics of false positive filter in three single colonies.
The density plot above the scatter plot shows the distribution of mutation depth while the plot to the right of the scatter plot shows the distribution of mutation frequency. The first row shows the …
Tables
Author response table 1
Comparison of the ratio of strains carrying the GWAS-identified fixed mutation in different lineages.
| L2 | L4 | P-value | L2 | L4 | P-value | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| Rv0051 Q149H | Yes | 5 | 5 | 0.13F | ctpB E345K | Yes | 27 | 15 | 0.14 | |
| No | 2368 | 818 | No | 2346 | 808 | |||||
| Rv0260c T72I | Yes | 41 | 22 | 0.09 | Rv0648 P454S | Yes | 87 | 42 | 0.07 | |
| No | 2332 | 801 | No | 2286 | 781 | |||||
| Rv1248c *1232S | Yes | 87 | 43 | 0.05 | Rv1747 T191A | Yes | 94 | 66 | <0.001 | |
| No | 2286 | 780 | No | 2279 | 757 | |||||
| otsB1 G559D | Yes | 14 | 9 | 0.14 | cobN A751V | Yes | 98 | 60 | <0.001 | |
| No | 2359 | 814 | No | 2275 | 763 | |||||
| Rv2164c D233G | Yes | 96 | 46 | 0.06 | dlaT V55A | Yes | 94 | 50 | 0.01 | |
| No | 2277 | 777 | No | 2279 | 773 | |||||
| Rv3168 E308* | Yes | 17 | 9 | 0.30 | metA G146D | Yes | 106 | 50 | 0.07 | |
| No | 2356 | 814 | No | 2267 | 773 | |||||
| metA E149G | Yes | 104 | 56 | 0.01 | papA1 I497T | Yes | 5 | 1 | 1F | |
| No | 2273 | 763 | No | 2368 | 822 |
Author response table 2
Comparison of the ratios of strains carrying at least one GWAS-identified fixed mutation from relapse cases with strains from all other patients.
| GWAS-identified mutations | P-value | |||
|---|---|---|---|---|
| Yes | No | |||
| Relapse | Yes | 13 | 34 | P < 0.001 |
| No | 241 | 2908 |
Author response table 3
Comparison of the ratio of strains carrying at least one GWAS-identified fixed mutation from the relapse cases with strains from patients with other poor treatment outcomes.
| GWAS-identified mutations | P-value | |||
|---|---|---|---|---|
| Yes | No | |||
| Relapse | Yes | 13 | 34 | P = 0.422 |
| No | 9 | 35 |
