Syphillis and the Early Peopling of America

A A spring-shaped bacteria belonging to the genus Treponema causes several diseases in humans, one of them is well known for the devastating effects it produced in humans until the advent of antibiotics: syphilis. It is also the only venereal treponemal disease, because the other three (yaws, bejel and pinta) are transmitted via oral and⁄or skin contact.

Today's post will look into the treponemal diseases to see if it can help us gauge when America was peopled and if any of our more distant ancestors made it to the New World before Homo sapiens did.

Treponemal disease

There are four different varieties of the spirochete Treponema bacteria, and each one causes a different disease: T. carateum provokes pinta, T. pallidum subsp. endemicum causes bejel, also known as endemic or non-venereal syphilis, T. pallidum subsp. pertenue leads to yaws and T. pallidum subsp. pallidum is the cause of venereal syphilis (it is pictured above).

The interesting part is that they are morphologically and serologically identical and the genetic variability between them is very small (0.2% between yaws and syphillis) so this makes it very hard to distinguish between them (there are no specific serological tests to pinpoint the type of infection affecting individuals) [3].

The genetic sequencing of all the subspecies of T pallidum (except one, the vector of Pinta, T. carateum -more on this below) shows that ther are five genogroups which do not identify "discrete organisms for each treponemal disease [instead] there may in fact be a genetic continuum of the pathogenic Treponema, individual components of which affect pathogenesis in an individual host in concert with social or environmental factors that influence routes of transmission and disease manifestations." [3].

In other words, they are virtually identical but are assumed to be different "subspecies" because they appear in different geographical areas around the world and produce manifest themselves in different manners and virulence.

The range of each "subspecies" is the following: Pinta is quite rare and was found in Central and South America. Yaws appears across Central and Western Africa, Southeast Asia, New Guinea, Northern Australia, Indonesia and the coastal regions of tropical Central and South America. Endemic Syphilis is found in the Middle East, the Balkans, South Central Asia, North Africa and central Australia. Venereal Syphilis, is global.

A genetic analysis

The controversy over the origin of these diseases continues: Is venereal syphillis an American disease or did it originate in the Old World?, how are the different subspecies related? The modern tools of genetics will be able to settle these issues once more information is obtained and analysed. However initial studies by Harper et al, 2008 [5](which regrettably do not include the analysis of Pinta) have reached some interesting conclusions:

• A maximum likelihood tree placed all of the T. pallidum subspecies (strains) within a single clade showing their very close relationship in comparison to other Treponemes which infect primates.
• Two of the subspecies subsp. pallidum (venereal syphillis) and subsp. endemicum (endemic or non-venereal syphillis) grouped seprately from the subsp. pertenue (yaws).
• The different strains within subsp. pertenue are closer to the root of the tree, meaning that it is the "oldest" lineage in the family, the ancestral population to all other subspecies.
• pertenue (yaws) and endemicum (non-venereal syphillis or bejel) are genetically closer to each other than to the venereal strain subsp. pallidum. The paper [5] obviously interprets this as meaning that venereal syphillis is caused by the youngest strain (the one that "diverged most recently" [5])

The geographic distribution of the diseases is used together with the Treponemal gdp gene sequences for each subspecies to try to elucidate the realtionship and origin of each strain. The following map which I have adapted from figure 4 in [5] shows the reasonable proposal of Harper et al., (2008) [5]:

Global distribution of Treponemal diseases and their origin. Adapted from [5]

The map is based on the assumption that the Old World yaws is the ancestral form, and that the gdp gene's GATG sequence is the basal one. As the map above shows (red shaded regions are those with different varieties of yaws), this ancestral form is found in Southeast Asia and Africa. I added the Pinta strain, in pink, in America, absent in the original map because it is relevant as we will see below.

This strain mutates into another variety of yaws, only found in Africa, with the GATA sequence (in other word the final "G" mutates to "A").

It also mutates by switching the second "A" for a "G", becoming GGTG in Eurasia and North Africa, becoming the vector for Endemic Syphillis (shaded green on the map).

This ties in with the close genetic distance between the endemicum and pertenue subspecies mentioned further up.

The interesting part is that the American variety of yaws has a very distinct sequence, removed by three mutations from the Eurasian GGTG or the African GATA, the Amerindian yaws sequence is: AGGA which is also the same sequence found in the pallidum subspecies!, the one that causes venereal syphillis. In other words it seems to prove that this disease appeared in America as a more virulent strain of yaws.

It is a pity that the agent causing Pinta was not sequenced, it probably lies somewhere in between the Eurasian strain (for endemic syphillis) and the Amerindian yaws strain.

The paper proposes that this three mutation gap between New World yaws (and venereal syphillis sequence) and the Old World sequences is split into two steps: they place a hypothetical intermediate strain one mutation away from either the African or the Eurasian strains (GGTA) and this strain with two mutations becomes the AGGA Amerindian one:

"The pattern of substitutions suggest that a hypothetical intermediate strain, arising from either the group II subsp. pertenue strains [African yaws] or endemicum strains [Eurasian endemic syphillis], once existed and was a progenitor to both New World subsp. pertenue[yaws] and to all subsp. pallidum [venereal syphillis] strains. This data also suggests that the New World subsp. pertenue strains belong to a group distinct from the Old World subsp. pertenue strains, occupying a phylogenetic position somewhere between Old World non-venereal strains and modern subsp. pallidum strains." [5]

The authors conclude that " a T. pallidum strain from the Americas was introduced back into the Old World, probably as a result of the European exploration of the Americas, becoming the progenitor of modern syphilis-causing strains. Third, modern subsp. pallidum [venereal syphillis causing] strains disseminated from Europe to the rest of the world." [5].

I do believe that the tree is coherent and the sequence propsed is also adequate, I also agree that the venereal syphillis is the most recent strain to appear, my doubts are, as always, on the issue of the dates assigned to these events. The paper does not make any conjectures regarding dates it merely indicates that the Amerindian strains "diverged most recently, indicating that they emerged relatively recently in human history" [5], which if in line with mainstream science means any time between the discovery of America in 1492 AD and 16,000 ya -the date that Asians are supposed to have entered America from Beringia.

These findings are supported by another paper (Melo et al., 2010) [1] which statistically tests three scenarios and concluded:

1. A recent emergence of venereal syphilis. This rececent (500 years ago) origin is found "utterly unlikely, be it in the New or the Old World". [1] This time span was chosen because the first reports of the epidemic of syphilis which quickly spanned Europe, are from 1495. By the way, this epidemic reached India in Portuguese ships (1498) and Japan (1510), killing thousands. The disease seemed to mutate to a more benign and slower-killing strain.
2. An Homo erectus origin. Treponematoses have been plaguing our ancestors at least since the days of H. erectus. But it is not likely that the strain that caused it is one of the contemporary ones. It is probably due to "ancestral forms still unknown". [1] I differ, but we will go into that later.
3. If it emerged in the Americas between 16,500 and 5,000 years ago. They find it the most likely alternative. We will discuss it below.

The dates. As usual the paper is based on the orthodox dates for the "time of the first colonization of the Americas", which is set at 16,500 years. The other date of 5 kya is based on "the oldest probable evidence of venereal syphilis in the world." [1].

What would they have concluded if instead of 16.5 kya they had used 75 kya or 100 kya? Later we will try to work it out.

Melo et al., using this 16.5 - 5 ky time range conclude that they could not reject the hypothesis based on the mutation rates of treponemes, which is "compatible with those observed in other bacteria" (see my comments below). They are cautious however because there are "claims of precolumbian venereal syphilis outside the Americas [to be] taken into account", so they conclude that "the place of origin remains unsolved." [1].

In other words, it could have originated in Asia and moved from there into America and also remained in Asia or, originated in Asia and only moved into America or, finally, appeared exclusively in the New World and reached the Old World after the voyages of Columbus in 1492.

What do ancient remains tell us?

Since Pinta leaves no skeletal marks, we cannot say much about its prevalence in the past. The other forms of treponemal diseases do leave very distinct marks on the bones and can be identified (though as usual, there is always some disagreement between experts).

The paelopahtological studies. Amerindian remains dating back to 7,000 years ago [5] show that treponemal disease afflicted the natives. There are some disputed and isolated cases of pre-Columbian treponemal disease in the Old World [5].

Melo et al., 2010 [1] review these studies and finds that "treponemal diseases in general were well established in pre-Columbian times all over the world. The oldest dates we are aware of refer to bejel in Sudan 15,000 yBP, yaws in Florida some 7,900 yBP, and treponematosis in Peru more than 8,000 yBP" as well as those from Indian Knoll in the U.S. (5,300 yBP) and Colombia (5,000 yBP) with osseous evidences of venereal syphilis in the whole World, and in my opinion support an Amerindian origin of this disease. [1]

Checking the calculations

Melo et al., [1] assumed that the venereal syphillis subspecies split from the others, in America between 16.5 and 5 kya, and then calculated that the most recent common ancestor for the human treponeme group lived 77.4 kya (this is their 95%HPD), which means that H. erectus did not have a "modern" human kind of treponeme. This time frame allows for Old World dispersal of yaws and endemic syphillis as well as an American or Asian origin of venereal syphillis.

Which is very neat and tidy. But why did they dismiss the appearance of treponematosis in H. erectus? Well, I have gone over their Table 2 several times and believe that there is a mistake in the table: the other two tables give the MRCA for venereal syphilis as younger than the whole group, but this table has syphilis as older than the yaws - bejel subspecies, which contradicts the conclusions of Harper et al., [5] mentioned above, where yaws mutated into venereal syphilis. The text itself mentions 175,000 years as the MRCA for one of the subspecies but the table says 1.75 My... it is confusing! What is clear is that the age of these bacteria would be similar to that of H. erectus and the authors conclude that the microbial mutation rate would be too slow, so this hypothesis is discarded.

I am inclined to believe that the date may be in fact older than 16 kya. Looking at Table 4, the oldest date of 77.4 ky for all human treponemes is linked to a 12.5 ky date for the subsp. pallidum. Roughly 6.2 times greater than the MRCA for venereal syphilis.

If we assume that human treponematosis appeared 300 kya, the venereal strain would have appeared: 300/6.2 = 48 kya in America, which is in line with some of the oldest (not accepted by orthodoxy) sites in the Americas. This would imply a Neanderthal origin for these diseases. Extrapolating further, if it appeared 1.6 Mya among Homoe erectus, then syphilis would have appeared 258 kya, also, among Neanderthals. Or maybe among East Asian H. erectus.

Looking at the map and the temporal sequence suggested by Harper et al. the following scenario seems plausible and maybe even probable:

• Since the oldest genetic sequence is found in Africa and Southeast Asia, we can assume an African origin and an out of Africa Migration of this oldest sequnce, with the first OoA migrants: H. erectus.
  The coastal route along the Indian Ocean towards Indonesia is actually where this subspecies prevails and it is identical to the territories once occupied by Homo erectus. It also coincides with the Y chromosome haplogroup C range, which I have suggested mirrors the OoA migration of H. erectus.
• Those who remained in Africa mutated into a second clade of yaws, and it is still found there, and only there.
• The Asian variant carried by H. erectus mutated into the bejel or endemic syphilis kind, found only in Eurasia and North Africa (maybe due to a back-migration). When did this take place? Was it among H. erectus? Denisovans? Neanderthals? Surprisingly this green area is very similar to the range occupied by Neanderthals. The Australian patch may reflect a Denisovan admixture.
• Then these people moved into America, where the mutations leading to the American pinta (whose sequence is not known, but I bet will be found to be intermediate between the Eurasian bejel and the Amerindian yaws) arose. Very likely the Neanderthals took it into America and there it mutated again, into the Amerindian yaws - venereal syphilis kind.
• Perhaps it was quite lethal in America, maybe Neanderthal carried the benign kind. Absent in the Old World, when Columbus' crew took it back to Europe, it spawned a colossal epidemic.

See Second part and conclusion of this post.

Pinta

Pinta which is said to be caused by Treponema carateum is quite unique among all the Treponemal diseases because it is the least aggressive one and only causes changes in the color of the skin of those afflicted with it. [5]

It is also unique because it is an exclusively American disease. But it has become rare: at one time it was endemic in the Caribbean, Central America and Northern South America, now it is hard to find. [5]

I included it in the map above (pink shaded region), because it is quite interesting in its distribution: it is in the region where haplogroup C (Y chromosome) is found in America, Colombia, Ecuador, Mexico.

Paleopathological studies of Pinta are not possible because it leaves no visible lesions on the bones (like the other treponemal diseases do), so it is quite elusive!

The problem is that there is no pinta available for study: "no strains of this organism are available" [3], so it could not be sequenced. Additionally, "Treponema carateum is the etiological agent of pinta, although no isolates of this organism are known to exist" [4], the actual bacteria has not been collected and stored in any lab!

It was "Once found in Central and South America, this mild disease is characterized solely by alterations in skin color.[...] no strains or samples of T. carateum survive. Furthermore, it is uncertain whether the disease pinta still exists. No cases have been reported to the World Health Organization from the former endemic countries Mexico or Colombia since 1979." [5].

The issue of mutation rates is controversial: allow me to quote "Our data suggest that the T. pallidum genome is evolving in a largely clonal manner amenable to phylogenetic analysis" [5]. This is interesting because clonal evolution stabilizes favorable multilocus associations, "restrained recombination on an evolutionary scale, with genetic exchange scarce enough to not break the prevalent pattern of clonal population structure" [2]

Actually scholars recognize that "A limitation on comparative studies has been the small amount of variation present in the T. pallidum genome [...] the level of polymorphism found between T. pallidum strains is quite low [...] for this reason, the level of resolution in the phylogenetic tree is relatively poor."[5]

The authors of one paper conclude that "it is unlikely that these SNPs have accumulated in a clockwork manner." [5].

I have expressed my reservations regarding "clocks", and in the case of T. pallidum, with a small genome, clonal evolution and limited variation between the different subspecies, it is in my opinion difficult to consider if a mutation rate is slow, fast or correct (as Melo et al. do). Perhaps it is a slow evolving bacteria, 10 or even 100 times slower than other bacteria. The dates calculated on bacterial mutation rates may be well off mark.

Sources

[1] de Melo FL, de Mello JCM, Fraga AM, Nunes K, Eggers S, (2010). Syphilis at the Crossroad of Phylogenetics and Paleopathology. PLoS Negl Trop Dis 4(1): e575. doi:10.1371/journal.pntd.0000575
[2] Michel Tibayrenc and Francisco J. Ayala, (2012 Reproductive clonality of pathogens: A perspective on pathogenic viruses, bacteria, fungi, and parasitic protozoa. PNAS (2012) www.pnas.org/cgi/doi/10.1073/pnas.1212452109
[3] Arturo Centurion-Lara et al., (2013). Fine Analysis of Genetic Diversity of the tpr Gene Family among Treponemal Species, Subspecies and Strains. PLoS Negl Trop Dis. May 2013; 7(5): e2222. Published online May 16, 2013. doi: 10.1371/journal.pntd.0002222
[4] RR Gray et al., (2006). Molecular Evolution of the tprC, D, I, K, G, and J Genes in the Pathogenic Genus Treponema. Mol Biol Evol (2006) 23 (11): 2220-2233. doi: 10.1093/molbev/msl092. First published online: August 22, 2006
[5] Harper KN, Ocampo PS, Steiner BM, George RW, Silverman MS, et al., (2008). On the Origin of the Treponematoses: A Phylogenetic Approach. PLoS Negl Trop Dis 2(1): e148. doi:10.1371/journal.pntd.0000148

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