Genetic diversity, drug resistance, and transmission patterns of tuberculosis based on whole-genome sequencing in Almaty, Kazakhstan

Tuberculosis, particularly multidrug-resistant TB (MDR-TB), remains a major public health concern in Kazakhstan, where 26% of new TB cases are MDR, far exceeding the global average. To better understand the genetic diversity, drug resistance, and transmission dynamics of <i>Mycobacterium tuberculosis</i> in Kazakhstan, we conducted a retrospective study at the National Scientific Center of Phthisiopulmonology in Almaty from 2023 to 2024. Whole-genome sequencing (WGS) was performed on 272 culture-confirmed TB isolates collected from patients across the country. Phylogenetic analysis revealed the predominance of Lineage 2 (East Asian genotype, 72.4%) and Lineage 4 (Euro-American genotype, 26.8%). Drug resistance profiling identified 29.0% of isolates as MDR-TB, of which 3.3% were classified as pre-XDR and 0.7% as XDR. The most frequently observed resistance-associated mutations were <i>katG</i> S315T (99.2%) and <i>rpoB</i> S450L (91.1%). Cluster analysis using a ≤ 12 SNP threshold identified 22 genomic clusters involving 80 isolates (29.4%), indicating recent and possibly ongoing transmission. Spatial mapping showed that nearly 60% of clusters spanned multiple regions, while others were highly localized, suggesting household or close-contact transmission. A Mantel correlogram test revealed a statistically significant correlation between geographic and genomic SNP distances in Almaty and Almaty Region (r = 0.0634, <i>p</i> = 0.041) within the first distance class (average 5 km, range 0-8 km). These findings suggest that patients living in close proximity are more likely to carry genetically similar strains. As distance increases, geographic proximity becomes less predictive of transmission, with other factors-such as mobility, shared environments, or healthcare contact-likely playing a greater role. Our findings underscore the need to integrate WGS into national TB control programs to guide targeted interventions, enhance surveillance, and curb the spread of drug-resistant TB strains across Kazakhstan.