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Evidence for the contribution of point mutations to vlsE variation and for apparent constraints on the net accumulation of sequence changes in vlsE during infection with Lyme disease spirochetes.

ABSTRACT: In the Lyme disease spirochetes, both the ospE and vlsE gene families have been demonstrated to undergo sequence variation during infection. To further investigate the mechanisms associated with the generation of vls variation, single-nucleotide polymorphism and subsequent DNA sequence analyses were performed on the vlsE gene and its paralog, BBJ51, a related gene with a frameshift mutation. These analyses focused on a series of postinfection clonal populations obtained from mice infected with Borrelia burgdorferi B31MIpc or its clonal derivative, B31MIc53. vlsE, but not BBJ51, was found to undergo sequence changes during infection. Consistent with that reported previously (J.-R. Zhang et al., Cell 89:275-285, 1997) many of the sequence changes appear to have arisen through gene conversion events and to be localized to the variable regions of vlsE. However, analysis of the vlsE nucleotide sequences revealed that some sequence changes were the result of point mutations, as these changes did not have potential contributing sources in the vls cassettes. To determine if sequence changes accumulate in vlsE over long-term infection, the vlsE genes of clonal populations recovered after 7 months of infection in mice were analyzed. While new sequence changes developed, a significant number of these changes resulted in the restoration of the vlsE sequence of the original infecting clone. In addition, we noted that some positions within the variable regions (VR) are stable even though the cassettes possess residues that could contribute to sequence variation through gene conversion. These analyses suggest that the total number of amino acid sequence changes that can be maintained by VlsE levels off during infection. In summary, in this report we demonstrate that the development of point mutations serves as a second mechanism by which vlsE sequence variation can be generated and that the capacity for vlsE variation, while still significant, is less than previously postulated.

SUBMITTER: Sung SY

PROVIDER: S-EPMC99662 | biostudies-literature | 2001 Oct

REPOSITORIES: biostudies-literature

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Evidence for the contribution of point mutations to vlsE variation and for apparent constraints on the net accumulation of sequence changes in vlsE during infection with Lyme disease spirochetes.

Sung S Y SY McDowell J V JV Marconi R T RT

Journal of bacteriology 20011001 20

In the Lyme disease spirochetes, both the ospE and vlsE gene families have been demonstrated to undergo sequence variation during infection. To further investigate the mechanisms associated with the generation of vls variation, single-nucleotide polymorphism and subsequent DNA sequence analyses were performed on the vlsE gene and its paralog, BBJ51, a related gene with a frameshift mutation. These analyses focused on a series of postinfection clonal populations obtained from mice infected with B ...[more]

PMID: 11566983

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Project description:Borrelia burgdorferi, the etiological agent of Lyme disease, persists in nature through an enzootic cycle consisting of a vertebrate host and an Ixodes tick vector. The sequence motifs modified by two well-characterized restriction/modification (R/M) loci of B. burgdorferi type strain B31 were recently described, but the methylation profiles of other Lyme disease Borrelia bacteria have not been characterized. Here, the methylomes of B. burgdorferi type strain B31 and 7 clonal derivatives, along with B. burgdorferi N40, B. burgdorferi 297, B. burgdorferi CA-11, B. afzelii PKo, B. afzelii BO23, and B. garinii PBr, were defined through PacBio single-molecule real-time (SMRT) sequencing. This analysis revealed 9 novel sequence motifs methylated by the plasmid-encoded restriction/modification enzymes of these Borrelia strains. Furthermore, while a previous analysis of B. burgdorferi B31 revealed an epigenetic impact of methylation on the global transcriptome, the current data contradict those findings; our analyses of wild-type B. burgdorferi B31 revealed no consistent differences in gene expression among isogenic derivatives lacking one or more restriction/modification enzymes. IMPORTANCE The principal causative agent of Lyme disease in humans in the United States is Borrelia burgdorferi, while B. burgdorferi, B. afzelii, and B. garinii, collectively members of the Borrelia burgdorferi sensu lato species complex, cause Lyme disease in Europe and Asia. Two plasmid-encoded restriction/modification systems have been shown to limit the genetic transformation of B. burgdorferi type strain B31 with foreign DNA, but little is known about the restriction/modification systems of other Lyme disease Borrelia bacteria. This paper describes the methylation motifs present on genomic DNAs of multiple B. burgdorferi, B. afzelii, and B. garinii strains. Contrary to a previous report, we did not find evidence for an epigenetic impact on gene expression by methylation. Knowledge of the motifs recognized and methylated by the restriction/modification enzymes of Lyme disease Borrelia will facilitate molecular genetic investigations of these important human pathogens. Additionally, the similar motifs methylated by orthologous restriction/modification systems of Lyme disease Borrelia bacteria and the presence of these motifs within recombinogenic loci suggest a biological role for these ubiquitous restriction/modification systems in horizontal gene transfer.

Dataset Information

Evidence for the contribution of point mutations to vlsE variation and for apparent constraints on the net accumulation of sequence changes in vlsE during infection with Lyme disease spirochetes.

Publications

Evidence for the contribution of point mutations to vlsE variation and for apparent constraints on the net accumulation of sequence changes in vlsE during infection with Lyme disease spirochetes.

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