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April 15, 2010

When diversity is good for disease

ResearchBlogging.orgYesterday I pointed to a new paper, Plasmodium vivax clinical malaria is commonly observed in Duffy-negative Malagasy people. P. vivax is the least virulent of the malaria inducing pathogens, and it is presumably responsible for the fact that the Duffy antigen locus is one of the more ancestrally informative ones in the human genome. In most of Eurasia the the Duffy negative null allele* is present at very low frequencies, less than 5%, and often simply absent. In contrast, in Sub-Saharan Africa the Duffy negative variant reaches frequencies as high as 95% in West Africa, and and 90% in many other regions. In North Africa and the Middle East the frequencies are intermediate, likely due to the necessity for local adaptation to malaria in many regions, and the historical introduction of the Duffy negative allele via the slave trade.

_47495404__47060392_rajoelina_afp-1Before genomics, looking at the Duffy locus was one simple way that geneticists ascertained the proportion of white admixture in the African American population. The Duffy negative allele was nearly absent in Europeans, and present in frequencies of ~95% in West Africa. Therefore, the ~70% frequency in African Americans indicates what we know from other sources, a substantial minority European contribution to their ancestry. The people of Madagascar are similar insofar as they are a byproduct of admixture between African and non-African populations. The source of the non-African ancestry is rather easy to determine, unlike most African countries Madagascar has one language, Malagasy, and it is of the Barito family of languages. Aside from Malagasy the Barito languages are spoke only in a small region of southern Borneo in Indonesia. There are other aspects of the Malagasy culture which make their Southeast Asian provenance clear. The photo above is of Andry Rajoelina, the current President of Madagascar. Two aspects of his visage are salient, his youth (he used to be a disk jockey!), and the fact that his features do not seem typical Sub-Saharan African. Many of the leaders of Madagascar, including the former royal family, are from the highlands where Asiatic features and folkways are more prevalent.

But there is also a clear African component to the Malagasy, more obvious among coastal populations, but also possibly dominant in a genetic sense in terms of proportion to the Asian according to research using uniparental markers. An analysis of Y lineage Fst genetic distances suggests that the Malagasy are, on the whole, somewhat closer to East Africans than to people from Borneo. I stipulate on the whole because as implied above there seems to be regional variation, which Southeast Asian ancestry and culture least hybridized with a Sub-Saharan African in the central highlands, likely for ecological reasons.

malagas1If the Duffy negative allele was viewed purely as a neutral locus, and so ancestrally informative, one would assume that the Malagasy were mostly African. In the figure to the left the red tinted portions represent Duffy negative proportions, the green Duffy positive, and the darker shade P. vivax positivity. The green star indicates a site where P. vivax positivity was only found among the Duffy positive, while at the sites with red stars it was found among both antigen state groups. As you can see at none of the sites was the Duffy positive allele modal, and at Andapa the frequency of Duffy negative was typical of much of Sub-Saharan Africa. In the total data set 72% of the individuals were Duffy negative. Going by the previous cited work this would underestimate Asian ancestry, which seems likely to be near parity, if not quite.

Two points come to mind:

1) It seems clear that the Duffy locus is not neutral. It is subject to natural selection, as even though the malaria caused by P. vivax is relatively mild, it t does reduce fitness. Natural selection should result in an increase in frequency of the negative allele in regions where malaria caused by P. vivax is endemic. In the American South malaria was not as extreme of a problem, nor does Duffy negative status have a strong side effect (e.g., sickle cell), so it was a neutral locus and appropriate to inform ancestry.

2) Modern African populations may not be an accurate representation of the allele frequencies of Duffy in the ancestral groups which contributed to the ancestry of the Malagasy. More plainly, the Africans who intermarried with the Barito speakers may have had much higher frequencies of Duffy positive alleles because natural selection had not proceeded so that the null allele was driven to near fixation.

To assess the plausibility of #2, one needs to know how the Malagasy, or more accurately, the speakers of the Barito language which became Malagasy, got where they are. Unfortunately, no one really knows, and the hypotheses are controversial because of their speculative nature. It seems likely that the Southeast Asian mariners initially arrived in the western Indian ocean region ~2,000 years ago, but widespread settlement of Madagascar’s interior may not have been occurring until ~1,000 years ago. By the 13th century there was a large Muslim city in the north of Madagascar integrated into the Indian ocean trade network, so Madagascar is on the fringes of written history at that point. The anthropological evidence seems to point to a sojourn on the coast of East Africa by Southeast Asians, as there are aspects of Malagasy culture which seem related to Bantu groups in that area. Additionally, there some genetic data which point to an African contribution on the mtDNA from populations further north on the coast, toward Kenya, and Y DNA which suggests a connection with the adjacent region of the continent in Mozambique. A model of how this could occur is that the initial colonists in East Africa picked up local wives along the northern coast, and eventually resettled in Madagascar. After this settlement there were periodic migration of Africans from nearby regions, either voluntary or forced through slavery, which added the later diversity. The fact that this component is male-biased would point to slavery of the sort practiced in the New World, whereby Africans were forced to work in agriculture and male robustness was prized (this is in contrast with much of the Middle East, where female African domestic servants were the primary driver of slavery).

mapmapOne of the mysterious aspects of the arrival of the Malagasy is that there aren’t records by the literate polities which fringed the Indian ocean of their movements. But why should there be? Open ocean traders were generally marginal to these states, who simply extracted rents from the activities of the merchants and migrants. It seems entirely plausible that many populations have been on the move throughout history, their impact in particular regions slowly being ablated by time. There is one aspect of Africa which makes it entirely plausible that the Barito presence would disappear or be marginal: the local populations seem biologically very well adapted to the pathogens on the continent. It is notable for example that the Arab and Persian cultural influence in East Africa never spread inland beyond the Indian ocean littoral. And yet these groups were present on the East African coast from the time of the Romans on. It seems likely to me that Africa is relatively resistant to “back-migration” from Eurasia on ecological grounds. North Africa is part of the Palearctic ecozone, while the highlands of Ethiopia are also ecologically distinct. Both these regions are strongly shaped genetically by populations with Eurasian connections, in the former case predominantly so, but both they are exceptions which prove the rule.

The maps to the left show topography and population density respectively. In Madagascar in the highlands Southeast Asians could transfer wet rice agriculture, and also escape the most baleful influences of African diseases (which would naturally be introduced with African populations). It is also where there is the greatest population density. In contrast the coastal regions are more lightly populated and have more African influence. Like South Africa or the Kenyan highlands I believe that Madagascar was one region of Sub-Saharan Africa which was open to the settlement of outsiders who lacked biological defenses because of its ecology. Granted, it seems to have been unsettled before the Malagasy arrived, but if its pathogen environment was equivalent to that of the mainland I suspect that African genes and culture would have replaced the Malagasy component rather rapidly. The Malagasy are just one of many populations which made some sort of great trek. Most of them disappear, get absorbed or become extinct. But in a few rare cases, such as in that of Iberians in the 16th century, or Polynesians 2,000 years ago, and the Malagasy, these travelers encountered territory which they were able to settle easily. And so we have concrete evidence of their past existence, their present existence. You couldn’t plausibly invent the cultural makeup of Madagascar, because our model of history and human population movement is simplified, and all the outliers and rough edges have been hidden or consciously removed.

Though the highlands of Madagascar allowed the Southeast Asian settlers a refuge for endogenous population growth, which allowed them to perpetuate their culture and leave a stamp on the island, Madagascar is African, and much of the island is clearly suited for malaria. The evolutionary dynamics may be contingent on the peculiarities of the island’s demographic history, but they will still proceed nonetheless. It is noted in these results that though varieties of P. vivax seem to have moved from the Duffy positive to the Duffy negative segment of the population, it is still much more virulent in those who are Duffy positive. There were 15 times as many full blown cases of P. vivax induced malaria (as opposed to positive infection status) among those who were Duffy positive than among those who were negative. Nevertheless, the emergence of strains able to infect Duffy negative blood cells opens up the possibility for more virulent strains in the future which could result in many more cases of full blown malaria within this population.

Let me jump to the conclusion:

Our observations in Madagascar showing conclusive evidence that P. vivax is capable of causing blood-stage infection and disease in Duffy-negative people illustrate that in some conditions P. vivax exhibits a capacity for infecting human erythrocytes without the Duffy antigen. The data assembled in this study suggest that conditions needed to clear the barrier of Duffy negativity may include an optimal human admixture. In Madagascar with significant numbers of Duffy-positive people and full susceptibility of hepatocytes in Duffy negatives, P. vivax may have sufficient exposure to Duffynegative erythrocytes, allowing more opportunities for de novo selection or optimization of an otherwise cryptic invasion pathway that nevertheless seems less efficient than the Duffy-dependent pathway.

There are several issues that I’ve glossed over in this paper, and one of them is that there are other populations which have a mix of negative and positive individuals. Implicitly the American South is one. But malaria is not endemic in most of the South. But in Brazil there is a similar racial mixture, and its climate is conducive to tropical diseases. It seems there are issues with detecting the P. vivax pathogen within blood cells, and so earlier studies as to the possibility of the infection of those who were Duffy negative were often muddled or inconclusive. In this study they established the existence of this group rather clearly, but is it due to the peculiarities of Madagascar’s population mixture and history? True, Brazil also has an admixed population whose Duffy allele frequencies are interchangeable with that of Madagascar, but Brazil has been settled for only the past ~300 years or so, with much of the population being of more recent origin (Brazil had the highest slave attrition rate on the American mainland, which explains the African nature of Afro-Brazilian culture. Many of the slaves were from Africa, or first generation, at emancipation). A lower bound for Madagascar is ~1,000 years, and the coexistence of Barito and African populations is likely closer to ~2,000 years. So the existence of P. vivax lines which can penetrate the negative allele population may be a function of the longer time given to the emergence of adaptive strategies.

I suspect the fact that there is a component of what ecologists term “patchiness” in the settlement patterns of various populations and ecology in Madagascar might have aided in the persistence of the Duffy positive allele. It seems that in much of the rest of Africa once agriculture became common and the conditions for the mosquito which carries P. vivax improved the Duffy negative allele swept to fixation. At this point the P. vivax infection rates were so low that natural selection became less of an issue (the extant variation was reduced, and only a small proportion of the population would have been subject to selection). It is on marginal areas where fixation did not occur that you’d have the diversity which might allow for the emergence of different P. vivax lineages. Another place to look besides Madagascar would be the margins of Ethiopia, as well as South Africa, where Bantu farmers came up against a very different ecologies and populations which they could not assimilate, or did so only partly.

* Duffy is really the the antigen itself, so “Duffy negative” means lacking the antigen. But I’m going to use the shorthand Duffy negative to point to the alleles which confer this state, which have names such as FY*A and FY*B. The gene itself is DARC.

Citation: Ménard D, Barnadas C, Bouchier C, Henry-Halldin C, Gray LR, Ratsimbasoa A, Thonier V, Carod JF, Domarle O, Colin Y, Bertrand O, Picot J, King CL, Grimberg BT, Mercereau-Puijalon O, & Zimmerman PA (2010). Plasmodium vivax clinical malaria is commonly observed in Duffy-negative Malagasy people. Proceedings of the National Academy of Sciences of the United States of America, 107 (13), 5967-71 PMID: 20231434

Image credit: BBC, Wikipedia

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