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Detection a new Mycobacterium tuberculosis complex modern L2  taxon based on SNPs in the Rv2983 and fgd1 gene

M Antar-Soutou(1,2) G Senelle(3) Z Awad(4) F Mougari(4) C Guyeux(3) E Cambau(1,4) C Sola(1,5)

1:Inserm, IAME, UMR1137, Université Paris Cité; 2:Laboratoire National de Référence pour la Tuberculose, Laboratoire Rodolphe Mérieux du Liban, Faculté de Pharmacie, Université Saint-Joseph de Beyrouth, Beyrouth; 3:FEMTO-ST Institute, UMR 6174, Université Franche-Comté; 4:Service de mycobactériologie spécialisée et de référence, Laboratoire associé du Centre national de référence des mycobactéries et résistance des mycobactéries aux antituberculeux, APHP GHU Nord Université Paris Cité, Hôpital Bichat; 5:Université Paris Saclay, Gif-sur-Yvette, France

Rv2983 and fgd1 are involved into pretomanid and delamanid metabolism, both drugs used in new treatment schemes for multidrug resistant tuberculosis (MDR-TB). We look at the sequences of these two genes in different lineages of Mycobacterium tuberculosis complex  using NCBI SRAs and the pipeline TB-Annotator v2.4, which compiles 112,373 SRAs. Based on the Rv2983 sequence, we grouped 46 SRAs that share the SNP SPDI NC_000962.3:3339291:A:C. These 46 SRAs share also another unique SNP on fgd1 at SPDI NC_000962.3:491741:T:C. These genomes were retrospectively tracked back to 20 Bioprojects, most of  them concerning MTBC isolates from China (n=14), Canada (British Columbia, n=1)  or unknown (n=31). We built a maximum likelihood phylogenetic tree with RAxML on these SRAs and others taken as representative of the L2 diversity. The tree shows these SRAs in a new terminal leaf.  The taxon was named as L2-CC-2983-I59L. This branch is structured into two sub-branches C1 (n=3) and C2 (n=43). It belongs to a modern L2 sublineage but does not enter into any existing taxonomical classification. We are now investigating the potential loss of function of these two gene products (Rv2983, fgd1). It is likely that the detection of this Rv2983-fgd1 variant antedates the use of pretomanid and delamanid, and just grew to a detectable epidemic signal recently, in relation to the existence of a yet undescribed chinese historical TB genomic diversity reservoir. In conclusions, we describe a new sublineage 2 cluster, made-up of 46 SRAs, that will require search for fitness advantage outside the drug resistance selection.

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