Comparative Genomics Shows Differences in the Electron Transport and Carbon Metabolic Pathways ofMycobacterium africanumrelative toMycobacterium tuberculosisand suggests an adaptation to low oxygen tension

Abstract

Pathways of Mycobacterium africanum relative to Mycobacterium tuberculosis and suggests an 3 adaptation to low oxygen tension 4 5 Summary: 27 The geographically restricted M. africanum lineages (MAF) are primarily found in West Africa, where 28 they account for a significant proportion of tuberculosis. Despite this phenomenon, little is known 29 about the co-evolution of these ancient lineages with West Africans. MAF and M. tuberculosis sensu 30 stricto lineages (MTB) differ in their clinical, in vitro and in vivo characteristics for reasons not fully 31 understood. Therefore, we compared genomes of 289 MAF and 205 MTB clinical isolates from the 32 6 main human-adapted M. tuberculosis complex lineages, for mutations in their Electron Transport 33 Chain and Central Carbon Metabolic pathway in an attempt to explain these metabolic differences. 34 Furthermore, we determined, in silico, whether each mutation could affect the function of genes 35 encoding enzymes in these pathways. 36 We found more potentially deleterious mutations in these pathways in MAF lineages compared to 37 MTB lineages. Additionally, we found that convergent evolution in these pathways occurred 38 between MAF and some MTB lineages. 39 Generally, our findings show further differences between MAF and MTB lineages that may have 40 contributed to the MAF clinical-and growth phenotype and may indicate potential adaptation of 41 MAF lineages to a distinct ecological niche, that we suggest may include areas characterized by low 42 oxygen tension. 43 44 Running title: The M. africanum respiratory chain and carbon metabolic pathway 45 46 Transport, Carbon Metabolism 48 49 50 51 3 1 Introduction 52 The Mycobacterium tuberculosis complex (MTBC) consists of a group of human-adapted ecotypes-53 Mycobacterium tuberculosis sensu stricto, Mycobacterium africanum, Mycobacterium canetti and 54 animal-adapted ecotypes (1-4). There are seven known MTBC lineages (L) associated with particular 55 geographic regions and adapted to specific human populations. These are the five lineages that 56 make up M. tuberculosis sensu stricto (lineages 1-4 and lineage 7) and the two M. africanum lineages 57 (lineages 5 and 6). Africa uniquely has a representation of all seven lineages. 58 MTBC strains from the seven lineages differ on average by about 1200 single nucleotide 59 polymorphisms (5), with clear distinction between MAF and MTB lineages (6-8). 60 MTB Lineages 2 and 4 are more widespread geographically, more pathogenic and more 61 transmissible, while MAF Lineages are exclusively found in West Africa and less transmissible (5, 9, 62 10). Clinically, MTB L4 is relatively more virulent than MAF L6 as evidenced by significantly faster 63 progression, in contacts of infectious cases, to active disease (11). MAF lineages are associated with 64 extrapulmonary disease and MAF L6 more commonly causes disease in immunocompromised 65 persons and those with lower Body Mass Index, implying a more opportunistic pathogen (10, 12). 66 Furthermore, MAF L5 a...

Phylogenomics ofMycobacterium africanumreveals a new lineage and a complex evolutionary history

“…L5 and L6 differ substantially from the other lineages of the MTBC with respect to metabolism and in vitro growth (10,11). Several mutations in different genes of the electron transport chain and central carbon metabolic pathway can explain metabolic differences between L5 and L6 and the other lineages (12). L5 and L6 are also less virulent than other lineages in animal models, and appear to transmit less efficiently in clinical settings (13,14).…”