Abstract
Mycobacterium tuberculosis (Mtb) lineage 1 (L1) contributes considerably to the disease morbidity. While whole genome sequencing (WGS) is increasingly used for studying Mtb, our understanding of genetic diversity of L1 remains limited. Using phylogenetic analysis of WGS data from endemic range in Asia and Africa, we provide an improved genotyping scheme for L1. Mapping deletion patterns of the 68 direct variable repeats (DVRs) in the CRISPR region of the genome onto the phylogeny provided supporting evidence that the CRISPR region evolves primarily by deletion, and hinted at a possible Southeast Asian origin of L1. Both phylogeny and DVR patterns clarified some relationships between different spoligotypes, and highlighted the limited resolution of spoligotyping. We identified a diverse repertoire of drug resistance mutations. Altogether, this study demonstrates the usefulness of WGS data for understanding the genetic diversity of L1, with implications for public health surveillance and TB control. It also highlights the need for more WGS studies in high-burden but underexplored regions.
Highlights
Mycobacterium tuberculosis (Mtb) is classified into 9 lineages[1,2,3], with lineages 1–4 (L1–L4) being widely distributed around the world
Spoligotyping is another widely used genotyping method, with data available from most countries. It evaluates the presence of 43 out of 68 genomic segments called direct variable repeats (DVRs) located in the CRISPR region, called the Direct Repeat (DR) region[12]. This scheme classifies Mtb strains with deletions at DVR39–42, 44 and 48 as the East African Indian (EAI) genotype, which is equivalent to lineage 1 (L1)
whole genome sequencing (WGS) data of 1,764 M. tuberculosis (Mtb) L1 isolates from Asia, Oceania and Africa were obtained until November 2020
Summary
Mycobacterium tuberculosis (Mtb) is classified into 9 lineages[1,2,3], with lineages 1–4 (L1–L4) being widely distributed around the world. High burden countries such as the Philippines and India, each of which has several hundred thousand L1-infected patients each y ear[4] Spoligotyping is another widely used genotyping method, with data available from most countries. It evaluates the presence of 43 out of 68 genomic segments called direct variable repeats (DVRs) located in the CRISPR region, called the Direct Repeat (DR) region[12]. This scheme classifies Mtb strains with deletions at DVR39–42, 44 and 48 as the East African Indian (EAI) genotype, which is equivalent to L1. The information is useful for evaluating TB burden and for understanding of the evolutionary history and pathogenesis, with implications for TB control
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