Monday, June 4, 2012

Age of the Association between Helicobacter pylori and Man


When modern humans left Africa ca. 60,000 years ago (60 kya), they were already infected with Helicobacter pylori, and these bacteria have subsequently diversified in parallel with their human hosts. But how long were humans infected by H. pylori prior to the out-of-Africa event? Did this co-evolution predate the emergence of modern humans, spanning the species divide?


At the global level, H. pylori has been subdivided by population genetic tools such as STRUCTURE [5] into multiple, relatively distinct populations that are specific for large geographical areas: hpEurope, hpSahul, hpEastAsia, hpAsia2, hpNEAfrica, hpAfrica1 and hpAfrica2 (Figure 1) [6][8]

Neighbor-joining population tree of extant populations of H. pylori.

Phylogeographic patterns in H. pylori have been shown to reflect significant demographic events in human prehistory [6], [11]. H. pylori has accompanied anatomically modern humans since their migrations out of Africa some 60,000 years ago (60 kya), and mirrors the human pattern of increased genetic distance and decreased diversity with distance from Africa [7]. However, the age of an association between humans and H. pylori has not been elucidated, other than that it predates 60 kya.

The distribution of H. pylori populations in Africa.


Bayesian cluster analysis was performed with the non-admixture model of STRUCTURE [5] for estimates of the total number of populations, K, between 2 and 5, which was the highest value of K that yielded consistent clustering and consistent probability estimates between individual runs. Almost half of the San haplotypes (26/56, 46%) belong to hpAfrica2 (Figure 3A, Figure 4A,B, Table 2). hpAfrica2 isolates were found in all three San communities, ranging in frequency from 28% of all haplotypes (!Xun) to 55% (Khwe, Khomani).We also identified 35 hpAfrica2 haplotypes among isolates from the Northern Sotho near Pretoria and from Xhosa and Europeans in Cape Town. 

Bayesian population assignments using STRUCTURE V2.0.

The consensus tree from this analysis shows that the southern (Khomani, Bantu) San haplotypes fell into a young clade which emerged from an more ancestral population of hpAfrica2 haplotypes, all of which were from San and most of which were from the northern Khwe and !Xun (Figure 3C). These observations suggest that hpAfrica2 evolved within the San and was subsequently transmitted to Bantus.
Almost all non-other haplotypes from San were assigned to hpAfrica1. In contrast, to the results described above, these were less diverse (π 95% CL [2.50, 2.82%]) than hpAfrica1 from Bantus ([3.10, 3.20%]), suggesting that the San had acquired hpAfrica1 from Bantu.

We therefore shotgun sequenced the genome of H. cetorum strain MIT 99-5665, which represents the closest known relative of H. pylori and Hac [15] (Figure 2), and used the orthologous nucleotide sequences from that genome as an outgroup for rooting the CLONALFRAME tree. Independent analyses yielded the same rooting branch point when the tree was rooted with and based on orthologs that were shared between H. pylori and enterohepatic Helicobacter genomes (data not shown). 

A comparison of global H. pylori and human mtDNA phylogenies.

The TMRCA of all H. pylori plus Hac lineages was 88–116 kya (CLONALFRAME: 88–92 kya; IMA: 92–116 kya; Table 4, Figure 6A). The date for the coalescence of non-recombining Y-chromosome lineages in modern humans is similar at 90 kya [39] to 141.5±15.6 kya [40] whereas the date of split between L0 and L1–6 mtDNA haplogroups in humans is older, 194.3±32.5 kya, (Figure 6B) [16], [17]. Despite the different age estimates, the topology and branching pattern of the genealogies are strikingly similar between H. pylori and human mtDNA (Figure 6).

The TMRCA for the split between hpAfrica2 and Hac is 43–56 kya (Table 4), and hpAfrica2 subsequently split (32–47 kya) into the northern and southern isolates. We note that a similar date (40 kya) was recently estimated for the TMRCA of Y-chromosome haplogroup A-M51 among the San by Henn et al. [20], which also subsequently split between northern and southern San populations. Within the other super-lineage, the estimated TMRCA was 36–52 kya for the African populations hpAfrica1 and hpNEAfrica (Table 4).

Finally, the genetic diversity is greater among hpAfrica2 from San than from Bantu, indicating that it was transmitted to Bantu in the last few hundred years since their arrival in southern Africa.

Our data shows that anatomically modern humans were infected by H. pylori long before their migrations out of Africa of ~60 kya [7], [42]. We estimate the minimum age of that association to be approximately 100 kyr (range 88–116). This is comparable to the age of the coalescence of the human Y-chromosome and about half of the coalescent for mtDNA. The age of a coalescent is a minimal date estimate because lineage sorting and bottlenecks lead to extinction of older lineages, resulting in a single genealogical source of all subsequent descendents.

We therefore propose that the association of H. pylori with humans also reflects a host jump to humans from an unknown species, which occurred approximately 100 kya or earlier. In principle, two later host jumps might explain the existence of two super-lineages of H. pylori, but this seems less likely because the similar phylogeographical patterns of H. pylori and mtDNA haplogroups indicate that they have undergone a parallel evolutionary history. 

Chronological reconstruction of the major population events occurring during the intimate human-H. pylori association.


The phylogeographic diversity within H. pylori is inconsistent with a single human expansion from Africa. H. pylori accompanied humans on the migration of ~60 kya [7], reaching Oceania not long thereafter [8]. However, European H. pylori possess distinct properties from most other global populations of these bacteria. H. pylori from Europe, the Middle East, western Asia and India belong to the hpEurope population [6], [7], [10], [58][60], which unlike Europeans is typified by great genetic diversity, greater than in Africa except for southern Africa where strong genetic diversity results from the presence of the second super-lineage (hpAfrica2). The great diversity of hpEurope was attributed to the fact that it is a hybrid population which arose from the admixture of AE1 (Ancestral Europe 1) and AE2 (Ancestral Europe 2) (Figure 4B) [6], [7]. AE1 arose in Central Asia after H. pylori was carried out of Africa during the Out of Africa migration of ~60 kya [7], and its descendants are found among extant hpAsia2. However, the data in Figure 6A indicate that AE2, whose extant descendents in hpNEAfrica are associated with northeast Africa, first split from its sister lineage hpAfrica1 36–52 kya, after the (first) Out of Africa migration. We therefore hypothesize that a second Out of Africa migration in the last 52 kya brought AE2 to the Levant, after which it came into secondary contact with AE1. Subsequent extensive admixture resulted in hpEurope, which subsequently spread to Europe and western Asia (Figure 8).

Thus, if initial Europeans were colonized with H. pylori, those bacteria were subsequently replaced by hpEurope, similar to the replacement of hspAmerind strains by hpEurope strains among Amerindians from South America [73]. To illustrate these interpretations, we show approximate routes and timings for a second colonization of Europe based on the properties of H. pylori populations (Figure 8), in which migration waves from North East Africa and Central Asia met and admixed in the Middle East and/or Western Asia sometimes 10–52 kya. The widespread presence of hpEurope in Mediterranean Africa is then attributed to later migrations to northern Africa, including migrations from Iberia (mtDNA haplogroup H1; 8–9 kya) [74], the Near East (mtDNA haplogroup M1; 35 kya) [75]; autosomal DNA; >12 kya [76]), or even as recently as the expansion of the Islamic caliphate in the last 1200 years. Our model also summarizes the dates of other human migrations that have distributed H. pylori from its southern African source (Figure 8).

9 comments:

  1. Interesting (notwithstanding the unbelievably short age estimates). Good catch.

    I made a quick reference at my blog. Something that intrigues me is that no Neanderthal/Erectus/Denisovan exogenous H. pylori clades have been detected.

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    1. The Age issue will be settled soon enough Maju, with whole genome sequences becoming more and more available due to a reduction in cost, the margin of error on mutation rate estimates will also decrease.
      With respect to Neandertal/Erectus/Denisovan H.pylori, wouldn't you need live specimens to perform gastric biopsies on? I don't think it is like ancient DNA or anything, although I may be wrong......

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    2. The study included a feline strain (Helicobacter acinonychis, or Hac) but no Amerindian ones. It's bizarre from a simple sampling point of view and again betrays the pro-African bias in genetics publications. Amerindian data is probably messy and doesn't easily fit the model. But, more importantly, I'm not aware of any other cases of a host jump from humans to other species. Even if it occurred, it's unclear why it happened only once, plus, oddly enough, precisely during the early stages of the evolution of the most divergent San strains. If the host jump happened from felines to humans (as it did in the case of HIV that jumped from chimps to humans), then it's clear where those divergent San strains come from. Definitely not because San are that ancient. Admixture with African hominins may then also explain the divergent mtDNA types found in Africa.

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    3. All divergent mtDNA in Africa still springs from the same root which is dated to no older than 200KYA, Hominini is the reputed common ancestor of chimps and humans that lived greater than 6 million years ago, neither is there any evidence for old homo species like antecessor, ergaster, erectus et. al having an mtMRCA with living humans before all living humans have one with each other.

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  2. We have genetic evidence for some kind of archaic admixture in Africa (http://www.pnas.org/content/early/2011/08/29/1109300108), but in the absence of fossil DNA we can't ascertain it. The presence of admixture shifts the root of a tree. But I wasn't trying to shift the discussion over to mtDNA. It's the feline strain of H.p that caught my eye.

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    1. "The presence of admixture shifts the root of a tree"
      Where is the evidence for this? Also if that were the case, non-Africans, who have been proven to have denisovan and/or neandertal admixture (3-8%) would have more genetic diversity due to this Admixture, but clearly this is not the case as a decline in genetic diversity is still observed further from Africa, even in the face of the fact that archaic admixture is present in these populations.

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  3. "Where is the evidence for this?"

    http://onlinelibrary.wiley.com/doi/10.1002/ajpa.21506/abstract

    "Also if that were the case, non-Africans, who have been proven to have denisovan and/or neandertal admixture (3-8%) would have more genetic diversity due to this Admixture, but clearly this is not the case as a decline in genetic diversity is still observed further from Africa, even in the face of the fact that archaic admixture is present in these populations."

    African populations may just be more admixed with archaics than non-African populations. The only reason we can so confidently talk about Denisovan and Neandertal contributions to the modern human gene pool is because we have ancient DNA from those two species of archaic hominins. In Africa we don't have and probably won't have this evidence. But judging from the fact that African linguistic diversity is low (and language is the chief indicator of behavioral modernity) Africa must have been peopled relatively late. It's consistent with the presence of an Upper Paleolithic Eurasian skull in South Africa (Hofmeyr) and with the reduced levels of megafauna extinction in Africa. (If humans became modern in Africa, giraffes wouldn't have survived.) Africa's high intragroup allele diversity then stems from 1) archaic admixture at greater amounts than outside of Africa; 2) higher mutation rate; 3) higher level of intraspecific admixture or any combination of the three.

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    1. German Sources: “http://onlinelibrary.wiley.com/doi/10.1002/ajpa.21506/abstract”

      On the contrary that source you provided that was focused only on the America's (speaking just from the abstract) does not contradict neither the serial founder model nor that the presence of archaic admixture 'shifts the root of the tree' as you put it, since this is what it says:

      “we find that genetic diversity is still largely hierarchically structured and that gene flow between neighboring groups has had surprisingly little impact on macrogeographic patterns of genetic diversity in the Americas.”

      German Says: “African populations may just be more admixed with archaics than non-African populations.”

      Yet, there has never been any Y or mtDNA found in Africa that is considered by any geneticist as 'archaic'.

      German Says: “In Africa we don't have and probably won't have this evidence.”

      Now that would be quite convenient for you would it not?, however you shouldn't expect me to take it serious with out any evidence.

      German Says: “But judging from the fact that African linguistic diversity is low”

      It is estimated that about one third of the World's languages are spoken in Africa, where as the contribution of Africa to the World's population is only about one seventh.

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  4. "On the contrary that source you provided that was focused only on the America's (speaking just from the abstract) does not contradict neither the serial founder model nor that the presence of archaic admixture 'shifts the root of the tree' as you put it, since this is what it says..."

    I gave you the reference in the hopes that you would educate yourself about the contents of the paper. It's useless to argue with me on the basis of misguided abstract reading. Here's a relevant quote: "The tree is rooted in northern North America because the gene identities between the three northern North America populations and the other Native American populations are particularly low. European admixture has contributed to this low identity, and, in principle, it could account for the position of the root." The situation with archaic admixture is no different from any other admixture.

    "Yet, there has never been any Y or mtDNA found in Africa that is considered by any geneticist as 'archaic'."

    First of all, haploid systems are too mutable. The very fact that "archaic admixture" was detected outside of mtDNA and Y-DNA speaks to the unreliable nature of both. Y-DNA is a good example: African SNPs aren't found on lineages outside of Africa (see the recent paper by Klyosov (http://www.scirp.org/journal/aa) clearly indicating that there was no out-of-Africa migration. Hg A seems to be old but it's SNPs aren't found on lineages outside of Africa. This may indicate that hg A is an archaic introgression into a founding modern human population in Africa that arrived there some 40,000 years ago. See also an exchange on my blog (http://anthropogenesis.kinshipstudies.org/2012/05/the-stereotype-of-a-beringian-refugium/#comment-169) regarding a reversed Y-DNA tree.

    "Now that would be quite convenient for you would it not?, however you shouldn't expect me to take it serious with out any evidence."

    This doesn't make sense. I was talking about the lack of fossil DNA from Africa and you're asking me to give evidence for the lack of fossil DNA in Africa????

    "It is estimated that about one third of the World's languages are spoken in Africa, where as the contribution of Africa to the World's population is only about one seventh."

    What matters is the number of unique linguistic stocks in Africa: there are no more than 20 of those, including isolates (Nilo-Saharan, Afroasiatic, Laal, etc.). Read Sands, Dimmendaal and other post-Greenbergian historical linguistics in Africa. In the New World, there are 140 stocks and isolates.

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