Pan-genomic epidemiology of tuberculosis: dnraveling the genetic diversity of mycobacterium tuberculosis clinical isolates

Abstract

Genomic epidemiology has significantly advanced our understanding of tuberculosis (TB) by providing standards to define sub-lineages, drug resistance patterns, and transmission groups (TGs). However, this approach has its limitations, primarily its reliance on a single reference genome, which fails to capture valuable genetic information present in diverse Mycobacterium tuberculosis complex (MTBC) lineages. Moreover, the underrepresentation of specific geographical regions, notably Mexico, in defining these standards has hindered the identification of region-specific disease markers. In this study, we embark on a comprehensive exploration of the genetic diversity of MTBC across regions, sub-lineages, and TGs, marking a shift from genomic epidemiology to pan-genomic epidemiology in TB research. Our research unfolds across three distinct sections, each addressing a critical facet of our overarching project. First, we contribute to an extended dataset of Mycobacterium tuberculosis (Mtb) clinical isolates from TB patients in various Mexican states, utilizing a whole-genome sequencing (WGS)-based strategy (Chapter 2). We illustrate the distribution of sub-lineages and drug resistance patterns in the country, revealing significant disparities between phenotypic and genotypic drug resistance profiles. In the subsequent section (Chapter 3), we present the groundbreaking discovery of TGs across different Mexican states and identify the primary risk factors associated with these groups. These findings underscore the urgency of enhancing national TB surveillance and monitoring in Mexico, ultimately aiding in the effective management of the disease. In the third and final section of our study (Chapter 4), we broaden our perspective, transitioning from a genomic to a pan-genomic approach. We compile the most extensive MTBC pangenome to date, encompassing 7,034 Mtb genomes from diverse global locations. This comprehensive analysis deciphers the structure of the Mtb pangenome and uncovers specific genes associated with unique traits. Our study addresses the intricate landscape of TB, providing novel insights into genetic diversity, transmission dynamics, and innovative approaches to comprehending this persistent global health challenge