Sunday, January 18, 2009

The origin of syphilis: a phylogenetic approach

K.N. Harper, P.S. Ocampo, B.M. Steiner, R.W. George, M.S. Silverman, S. Bolotin, A. Pillay, N.J. Saunders, and G.J. Armelagos. (2008). On the origin of the treponematoses: A phylogenetic approach. PLoS Neglected Tropical Diseases 2(1):e148.

The first recorded outbreak of syphilis occurred in Europe in 1495, a few years after Columbus sailed the ocean blue. Was syphilis a New World disease newly introduced into Europe by Columbus and his crew, or was it an Old World disease that simply was not noticed until 1495? A study from Harper and colleagues published last January described a molecular genetic analysis that may have yielded important clues hidden within the genetic material of Treponema pallidum.

The authors first examined the evolutionary relationships among Treponema pallidum strains from subspecies pertenue, endemicum, and pallidum, which are responsible for the diseases yaws, bejel, and syphilis, respectively. The small collection of strains or their DNA was obtained from different patients throughout the past century. The tree illustrated below (Figure 3 of Harper et al.) was constructed from the alignment of 70 SNPs (single nucleotide polymorphisms) and 12 indels (insertions/deletions). The branching pattern indicates that pertenue emerged the earliest. Subspecies endemicum later emerged from pertenue, and pallidum, the agent of syphilis, arose most recently.
The authors also obtained scrapings from yaws skin lesions on two aboriginal children living deep in the rainforests of Guyana. Since these children were members of a population that had been living for generations with minimal contact with the rest of the world, these pertenue strains may be closely related to those present in the Americas before the European explorers arrived. Unfortunately, the samples collected by the authors had degraded extensively by the time the DNA was extracted for analysis. Consequently, the two Guyanan strains could not be included in the phylogenetic analysis shown above; only regions encompassing 17 of the 70 SNPs could be sequenced from the degraded DNA. Nevertheless, they went ahead and aligned the 17 nucleotides with those from the strains used to construct the phylogenetic tree. The alignment revealed that among the nonveneral strains (pertenue and endemicum), only the Guyanan strains had as many as 4 nucleotides that were identical to those of the pallidum strains.

The world map illustrated below (Figure 4 of Harper et al.) depicts the path of sequence changes in the 4 SNPs among the Treponema strains. The dots mark the geographic source of each strain used in the analysis. The red and green colors demark areas of endemicity of the nonvenereal diseases yaws and bejel, respectively, around the year 1900. The map shows that T. pallidum first appeared as pertenue in the Old World and gave rise to the endemicum subspecies, which migrated with humans to the Middle East and Europe. The Old World pertenue or endemicum strain then eventually gave rise to the New World pertenue strain as humans crossed the Bering Land Bridge and spread throughout the Americas. The sequence identity of the Guyanan strains with the pallidum strains at all 4 positions is consistent with the New World strain being introduced back into the Old World as a progenitor of today's syphilis-causing pallidum strains, which are now found worldwide. Clinical evidence also supports the New World model: the nonvenereal skin lesions in the Guyanan yaws patients resembled syphilis chancres rather than the typical skin lesions found with yaws.I do not believe that the results presented in the paper support the New World origin of syphilis. As Harper et al. state in the Discussion of the paper, the close evolutionary relationship of the South American pertenue strains with the pallidum (syphilis) strains is based on a mere four nucleotides. Still, the authors concluded that pallidum arose from a descendant of the New World pertenue that was brought to Europe by Columbus. However, the results do not rule out the possibility that pallidum and New World pertenue strains evolved independently from a common ancestor, such as the "unknown" strain illustrated in the map. The New World strains would need to be included in the phylogenetic tree to distinguish the two possibilities. It was unfortunate that the entire set of 70 SNPs and 12 indels could not be examined in the Guyanan strains.

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