Mutation of Mycobacterium tuberculosis and Implications for Using Whole-Genome Sequencing for Investigating Recent Tuberculosis Transmission

Abstract

Tuberculosis (TB) control programs use whole-genome sequencing (WGS) of Mycobacterium tuberculosis (Mtb) for detecting and investigating TB case clusters. Existence of few genomic differences between Mtb isolates might indicate TB cases are the result of recent transmission. However, the variable and sometimes long duration of latent infection, combined with uncertainty in the Mtb mutation rate during latency, can complicate interpretation of WGS results. To estimate the association between infection duration and single nucleotide polymorphism (SNP) accumulation in the Mtb genome, we first analyzed pairwise SNP differences among TB cases from Los Angeles County, California, with strong epidemiologic links. We found that SNP distance alone was insufficient for concluding that cases are linked through recent transmission. Second, we describe a well-characterized cluster of TB cases in California to illustrate the role of genomic data in conclusions regarding recent transmission. Longer presumed latent periods were inconsistently associated with larger SNP differences. Our analyses suggest that WGS alone cannot be used to definitively determine that a case is attributable to recent transmission. Methods for integrating clinical, epidemiologic, and genomic data can guide conclusions regarding the likelihood of recent transmission, providing local public health practitioners with better tools for monitoring and investigating TB transmission.

A precision overview of genomic resistance screening in isolates ofMycobacterium tuberculosisusing web-based bioinformatics tools

“…Furthermore, we showed a relatively high transmission rate (54/88, 61.4%). These results differ from previous local studies where a low transmission rate was reported when using MIRU-VNTR (38,39) or using WGS for the localities of Valencia (24%) (40) and Los Angeles (25%) (41). This could be due to a large percentage of cluster of two isolates (43.8%) in our results or the highest SNPs umbral used in other studies (15 SNPs).…”

Genomic epidemiology of Mycobacterium bovis infection in sympatric badger and cattle populations in Northern Ireland

“…Owing to the low rate of molecular evolution observed in M. bovis, the phylogenetic methods we employ lack the resolution over shorter outbreak time scales to identify such amplification events and inform on their impact. Indeed, this latter point is an even more broadly salient one -it is recognized that it is difficult to elucidate transmission dynamics for monomorphic pathogens with low rates of evolution using genomic data alone [5], as has been noted before for another member of the MTBC, M. tuberculosis [61,78].…”

“…Indeed, this latter point is an even more broadly salient one – it is recognized that it is difficult to elucidate transmission dynamics for monomorphic pathogens with low rates of evolution using genomic data alone [5], as has been noted before for another member of the MTBC, M. tuberculosis [61, 78].…”

The Mycobacterium tuberculosis genome at 25 years: lessons and lingering questions

“…Indeed, there has been a trend in the United States to limit LTBI testing by tuberculin skin test or interferon-γ release assay to select high-risk groups ( 117 ). Interestingly, recent work using WGS to address the matter of recent versus remote infection found that longer latency times do not necessarily correlate with SNP distance — a finding that calls into question the reliability of genomic determinants in estimating the recency of infection ( 118 ). Additional studies using high sequencing depth to query M. tuberculosis mutation rates in human patients, particularly during paucibacillary states, may refine the relationship between the rate of M. tuberculosis mutation acquisition and latency time to enhance epidemiological tracking tools.…”