|Sensabaugh, George -|
Submitted to: BMC Research Notes
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: December 14, 2011
Publication Date: January 20, 2012
Citation: Brunelle, B.W., Sensabaugh, G.F. 2012. Nucleotide and phylogenetic analyses of the Chlamydia trachomatis ompA gene indicates it is a hotspot for mutation. BMC Research Notes [serial online]. 5(53). Available: http://www.biomedcentral.com/1756-0500/5/53/abstract. Interpretive Summary: Chlamydia trachomatis is the most frequent bacterial sexually transmitted disease in the United States, as well as the leading cause of infectious blindness worldwide. The ompA gene of C. trachomatis encodes a protein that constitutes the main target of the host immune system. There is a high level of nucleotide variability in the ompA gene among strains of C. trachomatis, and this helps the bacteria avoid the host immune response. It is unknown, however, if the increase in nucleotide variability is generated by a regular level of mutation in the gene, or if there is a mechanism that increases the mutation rate in the gene. We investigated the rate of nucleotide changes in the ompA gene from a collection of C. trachomatis isolates and determined that the ompA gene has an elevated rate of mutation. This is significant as this increases the diversity of the strains and promotes evasion of host immune detection.
Technical Abstract: Background: Serovars of the human pathogen Chlamydia trachomatis occupy one of three specific tissue niches. Genomic analyses indicate that the serovars have a phylogeny congruent with their pathobiology and have an average substitution rate of less than one nucleotide per kilobase. The ompA gene, however, has a phylogenetic association that is not congruent with tissue tropism and has a degree of nucleotide variability much higher than other loci in the genome. The ompA gene encodes the major surface-exposed antigenic determinant, and thus is important for virulence and fitness. It is unknown if the increase in nucleotide diversity observed in the ompA gene has been shaped only by positive selection and recombination, or if there is a localized increase in mutations. Results: Nucleotide diversity and phylogenetic relationships of the five constant and four variable domains of the ompA gene, as well as the loci surrounding the ompA gene, were examined for each serovar. The loci flanking the ompA gene demonstrated that nucleotide diversity increased monotonically as ompA is approached and that their gene trees are not congruent with either ompA or tissue tropism. The variable domains of the ompA gene have a very high level of non-synonymous changes, which is expected as these regions encode the surface-exposed epitopes and are under positive selection. However, the synonymous changes are clustered in the variable regions compared to the constant domains; if hitchhiking were to account for the increase in synonymous changes, it should be more evenly distributed across the gene. Recombination also cannot entirely account for this increase as the phylogenetic relationships of the constant and variable domains are congruent with each other. Conclusions: The high synonymous substitution rate that has been observed within the variable domains of ompA appears to be due to an increase in mutations within this region, while the increase in nucleotide substitution rate and the lack of any phylogenetic congruence in the regions flanking ompA are characteristic motifs of gene conversion. Together, the increased mutation rates, positive selection, and recombination in the ompA gene result in the high degree of variability observed, promoting evasion of host immune detection.