Phylogenomics of Mycobacterium africanum reveals a new lineage and a complex evolutionary history

Abstract

Human tuberculosis (TB) is caused by members of the Mycobacterium tuberculosis complex (MTBC). The MTBC comprises several human-adapted lineages known as M. tuberculosis sensu stricto, as well as two lineages (L5 and L6) traditionally referred to as Mycobacterium africanum . Strains of L5 and L6 are largely limited to West Africa for reasons unknown, and little is known of their genomic diversity, phylogeography and evolution. Here, we analysed the genomes of 350 L5 and 320 L6 strains, isolated from patients from 21 African countries, plus 5 related genomes that had not been classified into any of the known MTBC lineages. Our population genomic and phylogeographical analyses showed that the unclassified genomes belonged to a new group that we propose to name MTBC lineage 9 (L9). While the most likely ancestral distribution of L9 was predicted to be East Africa, the most likely ancestral distribution for both L5 and L6 was the Eastern part of West Africa. Moreover, we found important differences between L5 and L6 strains with respect to their phylogeographical substructure and genetic diversity. Finally, we could not confirm the previous association of drug-resistance markers with lineage and sublineages. Instead, our results indicate that the association of drug resistance with lineage is most likely driven by sample bias or geography. In conclusion, our study sheds new light onto the genomic diversity and evolutionary history of M. africanum , and highlights the need to consider the particularities of each MTBC lineage for understanding the ecology and epidemiology of TB in Africa and globally.

Toward a Phage Cocktail for Tuberculosis: Susceptibility and Tuberculocidal Action of Mycobacteriophages against Diverse Mycobacterium tuberculosis Strains

“…However, L6 strains are found in limited geographical regions and represent only a small minority of all tuberculosis infections (23); however, early clinical trials may need to avoid the regions where L6 strains are prevalent. There are additional lineages we have not yet tested, including L7, L8, and L9, although L7 is also rare and is restricted to Ethiopia, and both L8 and L9 have been reported from very few individual patients (25,29). It would also be helpful to examine a much broader set of clinical isolates and more drug-resistant strains, especially those in lineages L2, and L4, which are more diverse, more virulent, and more likely to become drug resistant (30).…”

Analysis of Mycobacterium africanum in the last 17 years in Aragon identifies a specific location of IS6110 in Lineage 6

“…This gene was studied in the Beijing lineage as a possible cause of a major number of SNPs related to resistance 43 . It has been observed that L6 has a higher variability in its genome in comparison to L5, which could be related to a higher mutation rate 44 , 45 . MutT2 is involved in DNA repair, therefore the mutation detected in the mutT2 promoter could increase the polymorphisms in L6 strains 46 .…”

Mycobacterium tuberculosis complex lineage 5 exhibits high levels of within-lineage genomic diversity and differing gene content compared to the type strain H37Rv

“…One genome was from a Benin isolate [PcbL5Ben; sequenced in this study, National Center for Biotechnology Information (NCBI) accession PRJNA641267], one from an isolate from The Gambia (PcbL5Gam, WBB1453_11-00429-1) [1] and one from Nigeria (PcbL5Nig, WBB1454_IB091-1) [1]. These genomes also represent disparate parts of L5's diversity, representing a broad range of L5 sub-lineages, as recently defined [6]. The previously published reference/complete genomes H37Rv (L4) (NC_000962.3) [39,40,49], L6 (GM041182, GenBank accession: FR878060.1, GCF_0001593225.1_ ASM159322v1) [50] and M. bovis (AF2122/97, accession: LT708304.1) [51] were also included.…”