Abstract
Homoplastic mutations are mutations independently occurring in different clades of an organism. The homoplastic changes may be a result of convergence evolution due to selective pressures. Reports on the analysis of homoplastic mutations in Mycobacterium tuberculosis have been limited. Here we characterized the distribution of homoplastic single nucleotide polymorphisms (SNPs) among genomes of 1,170 clinical M. tuberculosis isolates. They were present in all functional categories of genes, with pe/ppe gene family having the highest ratio of homoplastic SNPs compared to the total SNPs identified in the same functional category. Among the pe/ppe genes, the homoplastic SNPs were common in a relatively small number of homologous genes, including ppe18, the protein of which is a component of a promising candidate vaccine, M72/AS01E. The homoplastic SNPs in ppe18 were particularly common among M. tuberculosis Lineage 1 isolates, suggesting the need for caution in extrapolating the results of the vaccine trial to the population where L1 is endemic in Asia. As expected, homoplastic SNPs strongly associated with drug resistance. Most of these mutations are already well known. However, a number of novel mutations associated with streptomycin resistance were identified, which warrants further investigation. A SNP in the intergenic region upstream of Rv0079 (DATIN) was experimentally shown to increase transcriptional activity of the downstream gene, suggesting that intergenic homoplastic SNPs should have effects on the physiology of the bacterial cells. Our study highlights the potential of homoplastic mutations to produce phenotypic changes. Under selective pressure and during interaction with the host, homoplastic mutations may confer advantages to M. tuberculosis and deserve further characterization.
Highlights
Mycobacterium tuberculosis (Mtb) is a successful human-adapted species that has undergone long-term coevolution with its human host[1]
The homoplastic single nucleotide polymorphisms (SNPs) were identified in 1,170 clinical isolates, with 480, 521, 11 and 158 isolates belonging to L1 to L4, respectively. 1,229 homoplastic SNPs were identified in 5 isolates or more. 1,121 SNPs (91%) were in the coding sequences of 589 annotated genes and 108 SNPs in intergenic regions (Table 1 and Supplementary Table S1)
As we used the genomes of the H37Rv strain, belonging to L4.9, as the reference for identifying SNPs, the numbers of total identified SNPs would depend on the lineages of the studied isolates, which might correlate with the numbers of homoplastic SNPs
Summary
Mycobacterium tuberculosis (Mtb) is a successful human-adapted species that has undergone long-term coevolution with its human host[1]. Several studies have demonstrated associations between Mtb lineages with demographic profiles, geographic distribution, transmission capacity, pathogenesis, cytokine induction, and drug resistance[6,8,9,10].Once a strong association has been established, it may be explained through the identification of genotype-specific mutations, in coding or intergenic regions[11,12,13]. Some phenotypes, such as drug resistance, usually occur in several phylogenetic lineages. The functional effect of a homoplastic mutation in a regulatory region was experimentally examined in this study
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