Bibliographic record
Abstract
Mycobacterium tuberculosis and Mycobacterium avium subsp. paratuberculosis (MAP) are important human and animal pathogens, respectively. Previous studies indicate that these two host-adapted pathogenic species have emerged from closely-related environmental strains that rarely cause disease. Through comparative genomic studies, our research group has observed a common, biphasic pattern of evolution that independently gave rise to these pathogenic species, characterized by gene acquisition via horizontal gene transfer (HGT), followed by gene deletion. As HGT is an important mechanism for bacteria to integrate novel genetic material into their genomes, yet was considered until recently to not occur in mycobacteria, we are particularly interested in its evolutionary significance in this genus. Our hypothesis is that the acquisition of virulence factors via HGT contributed to the emergence of these two professional pathogens. In this thesis, I aim to identify and characterize genomic differences between these two host-adapted mycobacterial pathogens and their genetically-closest environmental counterparts, using both a genome-wide discovery approach and targeted investigation of a candidate locus identified through genomic studies. In the example of MAP, use of transposon (Tn) mutagenesis mediated genome-wide screen showed MAP-specific genes are under-represented in genes required for growth in vitro, but over-represented for in vivo survival. One of the MAP-specific genes, MAP3776c, is required for full fitness in vivo. MAP3776c belongs to a 5-gene MAP-specific genomic island, LSPP15 (MAP3776-2c) that we experimentally showed codes for an iron acquisition system. As MAP has long been recognized as a siderophore auxotroph, our genomic analysis reveals that the acquisition of LSPP15 provides MAP with an alternative machinery for MAP to acquire metals such as iron in vivo. Applying this paradigm to the study of M. tuberculosis, we showed that many currently-accepted virulence factors of this organism are shared with M. kansasii, an environmental mycobacterium incapable of human-to-human transmission. This observation prompted us to pursue functional characterization of a M. tuberculosis-specific gene pair, akin to our MAP LSPP15 study. The introduction of the M. tuberculosis genes, Rv3377c-78c, into M. kansasii, resulted in the production in M. kansasii of tuberculosinol-adenosine, providing proof-of-principle that one can model in the laboratory discrete steps in the emergence of M. tuberculosis from an environmental ancestor. Overall these findings provide independent lines of evidence that HGT events have contributed to the parallel emergence of these important pathogenic mycobacteria. This work is expected to stimulate further investigations that characterize the unique virulence attributes that define pathogenic mycobacteria of medical and veterinary relevance.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".