Abstract
BackgroundThe PE and PPE multigene families of Mycobacterium tuberculosis comprise about 10% of the coding potential of the genome. The function of the proteins encoded by these large gene families remains unknown, although they have been proposed to be involved in antigenic variation and disease pathogenesis. Interestingly, some members of the PE and PPE families are associated with the ESAT-6 (esx) gene cluster regions, which are regions of immunopathogenic importance, and encode a system dedicated to the secretion of members of the potent T-cell antigen ESAT-6 family. This study investigates the duplication characteristics of the PE and PPE gene families and their association with the ESAT-6 gene clusters, using a combination of phylogenetic analyses, DNA hybridization, and comparative genomics, in order to gain insight into their evolutionary history and distribution in the genus Mycobacterium.ResultsThe results showed that the expansion of the PE and PPE gene families is linked to the duplications of the ESAT-6 gene clusters, and that members situated in and associated with the clusters represent the most ancestral copies of the two gene families. Furthermore, the emergence of the repeat protein PGRS and MPTR subfamilies is a recent evolutionary event, occurring at defined branching points in the evolution of the genus Mycobacterium. These gene subfamilies are thus present in multiple copies only in the members of the M. tuberculosis complex and close relatives. The study provides a complete analysis of all the PE and PPE genes found in the sequenced genomes of members of the genus Mycobacterium such as M. smegmatis, M. avium paratuberculosis, M. leprae, M. ulcerans, and M. tuberculosis.ConclusionThis work provides insight into the evolutionary history for the PE and PPE gene families of the mycobacteria, linking the expansion of these families to the duplications of the ESAT-6 (esx) gene cluster regions, and showing that they are composed of subgroups with distinct evolutionary (and possibly functional) differences.
Highlights
The proline-glutamic acid (PE) and proline-proline-glutamic acid (PPE) multigene families of Mycobacterium tuberculosis comprise about 10% of the coding potential of the genome
Phylogenetic reconstruction of the evolutionary history of the PE and PPE gene families suggests that the first pair of these genes were initially inserted into the ESAT-6 gene cluster region 1, and have subsequently been duplicated along with the regions (Figure 11)
The evolutionary history predicted by the phylogenetic trees suggests that the highly duplicated PE_PGRS subfamily and subsequently the PPE-major polymorphic tandem repeat (MPTR) subfamily have originated from a duplication from ESAT-6 gene cluster region 5
Summary
The PE and PPE multigene families of Mycobacterium tuberculosis comprise about 10% of the coding potential of the genome. Some members of the PE and PPE families are associated with the ESAT-6 (esx) gene cluster regions, which are regions of immunopathogenic importance, and encode a system dedicated to the secretion of members of the potent T-cell antigen ESAT-6 family. The PE and PPE gene families of M. tuberculosis encode large multi-protein families (99 and 69 members, respectively) of unknown function [12,13]. These protein families comprise about 10% of the coding potential of the genome of M. tuberculosis [12]. The PPE family contains a highly conserved, but unique, N-terminal domain of approximately 180 amino acids, with a proline-proline-glutamic acid (PPE) motif at positions 7–9 (Figure 2A) [12]. The C-terminal domains of both of these protein families are of variable size and sequence and frequently contain repeat sequences of different copy numbers [14]
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