The Pith: the genetic relationships between bacteria in our stomach can tell us a lot about the relationships between various groups of people. Additionally, the distribution of different strains of bacteria may have significant public health implications.

The above image is from a paper which was pushed online yesterday in PLoS ONE: Evolutionary History of Helicobacter pylori Sequences Reflect Past Human Migrations in Southeast Asia. It’s a paper which caught my attention for several reasons. First, I’ve exhibited some curiosity about the history and prehistory of Southeast Asia of late. Elucidating this region’s historical dynamics may bear upon more general questions of human evolutionary and cultural process. Second, H. pylori is a fascinating organism whose connection to specific human populations is tight enough that it can shed light on past interactions of different groups. In short, just like humans H. pylori exhibits regional specificity and local history. But additionally, H. pylori is also subject to natural selection after introduction into a new population, and so can serve as a window upon cultural contacts which might otherwise leave a light demographic footprint. In other words, the spread of H. pylori across human populations may be compared to the spread of Buddhism. This religion came to China and Japan with some Buddhists of South and Central Asian origin, but by and large its spread was memetic rather than through natural increase of a Buddhist population.

First, let’s hit the abstract:

The human population history in Southeast Asia was shaped by numerous migrations and population expansions. Their reconstruction based on archaeological, linguistic or human genetic data is often hampered by the limited number of informative polymorphisms in classical human genetic markers, such as the hypervariable regions of the mitochondrial DNA. Here, we analyse housekeeping gene sequences of the human stomach bacterium Helicobacter pylori from various countries in Southeast Asia and we provide evidence that H. pylori accompanied at least three ancient human migrations into this area: i) a migration from India introducing hpEurope bacteria into Thailand, Cambodia and Malaysia; ii) a migration of the ancestors of Austro-Asiatic speaking people into Vietnam and Cambodia carrying hspEAsia bacteria; and iii) a migration of the ancestors of the Thai people from Southern China into Thailand carrying H. pylori of population hpAsia2. Moreover, the H. pylori sequences reflect iv) the migrations of Chinese to Thailand and Malaysia within the last 200 years spreading hspEasia strains, and v) migrations of Indians to Malaysia within the last 200 years distributing both hpAsia2 and hpEurope bacteria. The distribution of the bacterial populations seems to strongly influence the incidence of gastric cancer as countries with predominantly hspEAsia isolates exhibit a high incidence of gastric cancer while the incidence is low in countries with a high proportion of hpAsia2 or hpEurope strains. In the future, the host range expansion of hpEurope strains among Asian populations, combined with human motility, may have a significant impact on gastric cancer incidence in Asia.

H. pylori can be separated into very distinctive lineages of geographically limited scope, despite some horizontal gene flow. One clade seems generally restricted to western Eurasia, another to eastern Eurasia, and there are some Africa specific lineages as well. But within these particular clades one can drill-down to a finer-grain. For example, there are Indian lineages within the broader west Eurasian family of strains. As mutation over time results in the build up of distinctive variants in localized populations, a simple assessment of mutational steps between lineages can allow one to infer a tree of descent from a common ancestor.

Let’s tack for a moment to some history without microbial goodness. To some extent Southeast Asia can be considered part of “Greater India,” more or less. This is most evident in Thailand and Cambodia, two nations which are cultural heirs to the Khmer civilization which produced Angor Wat. The religious and artistic sensibilities of both these modern societies are deeply imprinted by South Asian norms through that precursor polity. The Theravada Buddhism of these societies still has a vital connection to South Asia (especially Sri Lanka) and is more obviously Indian in its sensibility than for example the Zen sect of Japan (which derives from Chinese Chan). In Vietnam there remains a small group of Malay Cham Saivite Hindus, the remnants of the Champa Empire.

The affinities in maritime Southeast Asia are a bit clouded because of the interposition of Islam between moderns and the Dharmic past. Only the Balinese remain as a vital living heir to the Indian-influenced polities of early Indonesia, Srivijaya and Majapahit. Despite this notional reality the Indian influence remains discernible even among Muslim Indonesians, in particular in East Java, where shadow puppet shows of the Ramayana remain popular. Like Angor Wat, Borobudur in Java is a testament to the monumental Indian past. But even the avowed Islamic flavor of modern maritime Southeast Asia may have some Indian connection, insofar as there is the possibility that South Asian Muslims were critical players in the eastern Indian ocean trade network which slowly Islamicized over the course of the second millennium.

We are then presented with the question: if the Indian influence in Southeast Asia was so strong in the past, where are the genes of Indians? The authors note that mitochondrial DNA analyses, the maternal lineage, show no South Asian specific lineages in appreciable frequencies among native populations. A fixation on mtDNA seemed rather strange to me for two reasons. First, with the PanAsian SNP data set there’s some autosomal data. Second, there are strong reasons to suppose that Indian migrants would be male. The myths and sketchy historical references of this period don’t seem to envisage mass folk migrations, where Indian men bring their women and children and recreate their homelands. Rather, often these men are portrayed as religious specialists or military leaders of genius. The authors note that there is evidence of Indian artisans in Thailand ~2,000 years ago. This is eminently plausible, there are references to towns of Indian merchants in Sumeria ~4,000 years ago! But again, there is no reason that these artisans necessarily brought their wives. Rather, if they were purchased for their skills they may simply have been the human property which was the object of capitalist transactions between two autocrats.

The nature of cultural transfer, and the relatively high fidelity of that transfer, implies to me that some Indians did migrate to Southeast Asia. But they were few, and their genetic impact was minimal. Rather, what we see is the power of memes to operate very differently from genes. The Indian memes rapidly swallowed up the cultural commanding heights, and became normative from Java to northern Thailand (northern Vietnam is the exception to this rule, as it was influenced by China).

H. pylori shares many of the same tendencies as memes, despite its more concrete biological character. As bacteria it can spread rapidly within a population, and decouple itself from the endogenous natural increase of its original hosts. That spread can be driven by natural selection which means that it isn’t a good representation of the ancestry of its hosts. But even natural selection can’t erase the inferences one can make about original contacts between distinct groups.

In this paper the authors present evidence from the nature of H. pylori in Southeast Asia that there was tangible physical contact between Indians and Southeast Asians in the antique past. More precisely, below is a figure which shows the nature of relationships of west Eurasian H. pylori lineages in India and Southeast Asia, with European and other west Eurasian samples as a control.

What you see here is that Indian H. pylori is basal to the Southeast Asian branches, though within the same clade against the European lineages. This tells you that there’s an affinity between Indian and Southeast Asian lineages under consideration here, but that that affinity is diminished by a period of separation. This matters because some regions of Southeast Asia, such as Malaysia, have a large Indian population which arrived in the past few centuries. The fact that there is a distinct Southeast Asia specific lineage suggests that there has been a long period of separation between the two populations, and one can’t attribute the frequency of the west Eurasian Indian H. pylori simply to recent contacts. At least in most of Southeast Asia. It turns out that in the Philippines the west Eurasian H. pylori cluster with Spanish populations. This has to be the outcome of hundreds of years of colonialism.

There’s also this fascinating historical and geographical tidbit:

A study on the distribution of H. pylori virulence factor cagA among Vietnamese identified 84% of the strains harbouring the type II of the cag-right motif…which is characteristic for East Asian strains (hpEastAsia), ranging from 76% in Ho Chi Minh city in South Vietnam to 93% in Hanoi in North Vietnam. However, there was a remarkable difference in the frequency of cag-right motif of type I which is predominant in European (hpEurope) strains. While the type I motif was absent from North Vietnam, it was found in 8/49 (16%) of the samples from Ho Chi Minh city near the Mekong delta. Interestingly, prior to annexation by the Vietnamese in the 17^th century, this city was an important Khmer sea port known as Prey Nokor…Thus, hpEurope strains also seem to be frequent among Vietnamese in the Mekong delta, and thus the Annamite mountain range that originates in the Tibetan and Yunnan regions of southwest China and forms Vietnam’s border with Laos and Cambodia seem to have shaped an effective natural barrier for the containment of Indian influence in the Mekong basin, explaining the low prevalence of hpEurope strains elsewhere in Vietnam.

The geographic contours of the nation-state of Vietnam as we understand it today are a relatively new phenomenon. The Vietnamese people, the Kinh, are an ancient nation. But for most of the past ~2,000 years what we know as Vietnam was divided between the Kinh in the north, and the Khmers and later Austronesian Chams in the center and south. Unlike the other peoples of Southeast Asia the Kinh looked to the north, to China, as their cultural model. While India’s influence in Southeast Asia (excepting the Chola adventures) has been through “soft power,” the Chinese have periodically ruled Vietnam directly, and otherwise placed it into the category of tributary state.

There needn’t be any geographical determinism here. Projection of cultural or military power declines in proportion to distance. In relation to culture that projection does not decline linearly, but often exhibits a sharp break. The Vietnamese did not move the Annamite range south when they defeated Champa and began to swallow the eastern flank of the Khmer kingdom. Rather, they shifted populations and cultural identities of populations, and therefore the civilizational boundaries. The line which separated Indic and Sinic moved south with the spread of the Kinh and the retreat of the Khmer. This did not eliminate in totality the Indic influence. Hindu Cham remain in Vietnam, while forms of Therevada Buddhism have some purchase in the Mekong delta, unlike in the rest of country where Chinese derived Mahayana reigns supreme. And so it is that Indic H. pylori also remains as a residual in the southern regions of Vietnam, evidence of the trade and cultural networks which bound it to Greater India as some point in the past.

Next let’s look at the distribution of East Asia specific H. pylori:

The figure is hard to read, but here’s the short of it: there are Amerindian, Taiwan-Oceanian, Chinese, and Southeast Asia specific lineages. More specifically the authors attempt to infer the origin of one particular Southeast Asia specific lineage which exhibits some overlap in southern China. This is because they believe that it can trace the migration of the Austro-Asiatics, likely the first agriculturalists in Southeast Asia. The H. pylori strain in question spans southern China to Malaysia. The geographic zone encompasses regions now inhabited by Thai or Malay speakers, but it seems likely that at one point the whole zone was dominated by Austro-Asiatics. The clincher would be to see if Munda from northeast India carry this same H. pylori strain. In fact an analysis of the phylogenetic tree of strains of H. pylori found in Austro-Asiatic populations or their descendants might be able to move the needle on whether they’re exogenous to India or not (the “older” lineages should be basal).

So far I’ve been focused on issues of phylogeny. How populations of humans and bacteria relate to each other. But there are functional and adaptive implications and dynamics at work. In terms of adaptation it seems that some strains of H. pylori are simply more fit than others in some environments. The Spanish presence in the Philippines was very light demographically over the centuries of their colonial rule. There was considerable residential segregation of the Spanish away from the natives, and the Chinese, who outnumbered the Spaniards often by two orders of magnitude. And yet you have a situation where H. pylori of Spanish provenance seems to be dominant. Why? The authors report that there’s a fair amount of evidence that European H. pylori strains are generalists who outcompete the specialist East Asian and Amerindian lineages. I think one can’t ignore the reality that the “European” strains are endemic to a huge swath of western Eurasia, from Europe to India. Because of their large population sizes these lineages probably have more diversity than the other populations, and so can adapt to a wide range of conditions.

A functional and public health concern is that East Asia H. pylori may be the cause of the much higher stomach cancer rates in that region of the world. You probably know that H. pylori is a critical player in ulcers, so its impact in this region shouldn’t be a surprise. Prior to reading this paper I’ve heard that East Asian stomach cancer rates were due to condiments used. This goes to show the difficulty of much of medical science which relies on correlations and rough guesses about causality.

Obviously I’m interested in what markers such as the distribution of pathogens which are reliant on humans can tell us about history. But over the long term the complex interplay between these pathogens, disease risk, and other phenotypic characteristics, is where the real action is going to be.

Citation: Breurec S, Guillard B, Hem S, Brisse S, Dieye FB, & et al. (2011). Evolutionary History of Helicobacter pylori Sequences Reflect Past Human Migrations in Southeast Asia PLoS ONE : 10.1371/journal.pone.0022058

Image credit: Mark Alexander

July 20th, 2011 Tags: Austro-Asiatic, H. pylori, Southeast Asia
by Razib Khan in Anthroplogy, Genetics, Medicine | 14 comments | RSS feed | Trackback >