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Background  The presence of four mammalian cell entry ( mce ) operons in  Mycobacterium tuberculosis  suggests the essentiality of the functions of the genes in these operons. The differential expression of the four  mce  operons in different phases of  in vitro  growth and in infected animals reported earlier from our laboratory further justifies the apparent redundancy for these genes in the genome.  Here we investigate the extent of polymorphism in eight genes in the  mce1  and  mce4  operons of  M. tuberculosis  from four standard reference strains (H37Rv, H37Ra, LVS (Low Virulent Strain) and BCG) and 112 clinical isolates varying in their drug susceptibility profile, analysed by direct sequencing and Sequenom MassARRAY platform.    Results  We discovered 20 single nucleotide polymorphisms (SNPs) in the two operons. The comparative analysis of the genes of  mce1  and  mce4  operons revealed that  yrbE1A  [ Rv0167 ] was most polymorphic in  mce1  operon while  yrbE4A  [ Rv3501c ] and  lprN  [ Rv3495c ] had the highest number of SNPs in the  mce4  operon. Of 20 SNPs, 12 were found to be nonsynonymous and were further analysed for their pathological relevance to  M. tuberculosis  using web servers PolyPhen and PMut, which predicted five deleterious nonsynonymous SNPs. A mutation from proline to serine at position 359 of the native Mce1A protein was most deleterious as predicted by both PolyPhen and PMut servers. Energy minimization of the structure of native Mce1A protein and mutated protein was performed using InsightII. The mutated Mce1A protein showed structural changes that could account for the effects of this mutation.    Conclusions  Our results show that SNPs in the coding sequences of  mce1  and  mce4  operons in clinical isolates can be significantly high. Moreover,  mce4  operon is significantly more polymorphic than  mce1  operon (p < 0.001). However, the frequency of nonsynonymous substitutions is higher in  mce1  operon and synonymous substitutions are more in  mce4  operon.  In silico  modeling predict that nonsynonymous SNP at  mce1A  [ Rv0169 ], a virulence gene could play a pivotal role in causing functional changes in  M. tuberculosis  that may reflect upon the biology of the bacteria.

bmc microbiology

Single nucleotide polymorphism in the genes of mce1 and mce4 operons of Mycobacterium tuberculosis: analysis of clinical isolates and standard reference strains