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Title: Rate heterogeneity in the evolution of Helicobacter pylori and the behavior of homoplasious sites

Author
item Meinersmann, Richard - Rick
item ROMERO-GALLO, JUDITH - VANDERBILT UNIVERSITY
item BLASER, MARTIN - NEW YORK UNIVERSITY

Submitted to: Infection, Genetics and Evolution
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/11/2008
Publication Date: 4/18/2008
Citation: Meinersmann, R.J., Romero-Gallo, J.G., Blaser, M.J. 2008. Rate heterogeneity in the evolution of Helicobacter pylori and the behavior of homoplasious sites. Infection, Genetics and Evolution. 8(5):593-602.

Interpretive Summary: Bacteria change frequently by mutation and also by incorporation of DNA from related bacteria into their genes, a process known as lateral gene transfer (LGT). When the ancestral relationships of families of bacteria are put together, a condition of the analysis known as a homoplasy may be seen. A homoplasy can occur when there are multiple mutations at a specific site on the genome or if an LGT has occurred. Many scientists believe that LGT occurs more often than mutation, mostly because it takes fewer changes to create the homoplasies by this mechanism. However, when we analyzed data on a gene from Helicobacter pylori, the bacteria that causes human stomach ulcers and is known to change more rapidly than most types of bacteria, it was noted that sites that were identifiable as homoplasies had an excess of a type of change, called transitions, that was not compatible with LGT. This type of excess transitions had never been documented before and it was unknown if they could be explained by a very high rate of mutations. A computer program that was designed to simulate evolution with or without LGT was employed to create model data. When this data was analyzed it was seen that the natural data from H. pylori most closely fit with data without recombination. Other parameters were analyzed that showed compatibility with multiple mutations at certain sites with natural selection limiting mutations at critical sites. Our analyses suggest that the rate of LGT is likely to be much lower than currently estimated.

Technical Abstract: Helicobacter pylori are bacteria with substantial strain-to-strain variability. Although frequent recombination events have been proposed as contributing to the variability, the effects of nucleotide substitution rate heterogeneities on the reconstruction of H. pylori genealogies have not been studied. We analyzed the substitution pattern of a housekeeping gene, a homologue of the ribonuclease reductase gene (rnr), to characterize rate heterogeneities between 11 H. pylori isolates. Evidence of limited recombination was demonstrated by the Sawyer’s runs test, but the homoplasy test and site-by-site compatibility tests indicated frequent recombination events. Within the 1935 nucleotide gene, 292 sites were polymorphic with an average pair-wise difference of 5.01%. Xia’s distances for amino acids at nonsynonymous codon substitution sites were smaller at homoplasious sites than at sites that were not homoplasious. Transitions were significantly more common among homoplasious than among non-homoplasious nucleotide substitutions. Computer simulations of evolution with or without recombination were performed and indicated the transition/transversion ratio is expected to be higher in more cases in homoplasious sites with no recombination. Analyses of the H. pylori rnr genealogy does not show a random tree despite evidence of recombination and shows base substitution behaviors that are characteristic of both recombination and substitution saturation at some sites. Similar evidence was seen in analyses of sequences in the H. pylori multilocus sequence-typing database.