My recent post Africans reached America ca. 1310 C.E.? led to a comment by Ron Quiroriano, in which he wrote "Sickle cell anemia, is not an African only disease, its a natural defense against malaria, and is found through out tropical populations, it just reaches its peak distributions in Africans.", and this made me think about Malaria and the peopling of America. The outcome is today's post.
I had always believed that Malaria originated in Africa and that the only defense against it was the mutation that caused sickle cell anemia among Africans. But I was mistaken. Actually there are several strains of Plasmodium that cause malaria in humans and, there are several mutations among humans to fend off the disease.
Malaria a brief overview
Malaria is caused by microorganisms (actually protozooans) of the genus Plasmodium they are transmitted by mosquito bites. The infected person will suffer from fever, vomiting, fatigue and may even become severely ill and die.
There are different strains of Malaria, the worst is P. falciparum, which causes most deaths. The others: P. vivax, P. ovale, and P. malariae are more benign and lead to a more mild illness. This, in my opinion indicates a more recent origin for P. falciparum, as it is too virulent. The other strains have surely lived with us for a long time and evolved not to kill us (which is the best gambit for a parasite, why kill your host?).
The evolutionary pressure has selected positively some genetic traits among humans which give the carrier a better chance to reach maturity, mate and pass on those genes to their offspring. These mutations are found among people living in areas where Malaria is endemic.
There are different mutations that give different resistence against the illness: sickle cell trait, thalassaemia traits, glucose-6-phosphate dehydrogenase deficiency, the lack of Duffy antigens on red blood cells and Ovalocytosis.
This wide range of mutations indicates that they have arisen in different groups of humans in different areas as a response to the pressure of this terrible disease.
So Sickle Cell is prevalent in Africa and some variants of Haemoglobin diseases (HbC, HbD and HbE) are found in Africa and Asia. The alpha and beta Thalassaemia are found in a wide swath from Western Europe to Melanesia. All of them overlap the area where Malaria is predominant in the Old World.
But what about America? We will get there later. Now lets look at South East Asia.
Egg shaped red blood cells
Amato and Booth, (2) found that the hereditary Ovalocytosis is found among 5 to 20% of Melanesians in the coastal (malaria prone) areas of Papua New Guinea. This is comparable to the frequency among Malaysian and Indonesians. The trait is also found in the Philippines.
It causes oval shaped blood cells, hence its name.
It is several hundred times more common than the sporadic type of oval shaped red blood cells (elliptocytosis) found in other populations (at a 0.02 - 0.05% frequency), a clear indication that it is being selected for positively.
And as Rosanas-Urgell at al (2012) have proven by three independent studies (3): "strong associations between Southeast Asian ovalocytosis (SAO) and protection against P. vivax malaria by a mechanism that is independent of the Duffy antigen. P. vivax malaria may have contributed to shaping the unique host genetic adaptations to malaria in Asian and Oceanic populations."
The mention of Duffy antigen is because it was believed that this trait common in Africa indicated that P. vivax resistence evolved there, in the cradle of mankind when our distant human ancestors encountered P. Vivax, but it seems that this was not an Out Of Africa case. Actually it is quite the opposite.
And this is what Oleksyk, Smith and O'Brien (4) have asserted: "Plasmodium vivax is closely related to Asian primate malaria vectors, and Mu et al. (2005) have speculated that the pathogen may have emerged from Macaca to humans 53,000–265,000 years ago, and entered Africa afterwards."
But, as we will see below, the date may actually be much older. Anyway, 54 - 265 kya in South East Asia is very old, and takes us beyond the accepted date of an Out Of Africa event (ca. 60-100 kya). This means that P. vivax infected Homo erectus, which had been living in Asia for at least 1.5 million years.
From monkeys to Homo erectus
The ancient origin for Malaria infection among Hominids mentioned above is in line with Neafsey et al. (5) who compared P. Falciparum with P. vivax noticed some interesting differences between them:
"Other departures in the global population history of these two species are indicated by the topology and branch lengths of their respective phylograms... The relatively large degree of divergence between the IQ07 Peruvian isolate and the Brazil I and Salvador I strains of P. vivax suggests a distinct history in the New World relative to P. falciparum, which exhibits low diversity in the New World and is thought to have been introduced within the last 500 years via the African slave trade." (5).
In other words, P. vivax has had more time to diversify and evolve in America than the more recently introduced P. Falciparum. And this is what they say (Bold is mine):
"The high New World diversity of P. vivax, combined with the closer phylogenetic affinity of the three New World P. vivax isolates with the east Asian (North Korean) rather than the African (Mauritania I) or south Asian (India VII) strains, could suggest the precolonial arrival of P. vivax in the New World accompanying human dispersal from Asia by sea or, less likely, by the Bering land bridge during the last glacial maximum." (5).
Or, may I add, perhaps an even older arrival (they are constrained by orthodoxy and a late peopling of America, I am not). Incidentally, they calculate for P. vivax, "we can estimate the TMRCA as 768,000 years" (5), much older than the appearance of the first H. sapiens, and in line with H. erectus living in Asia.
This same theory, that Macaca passed it on to Hominids in South East Asia is also supported by other scholars like Escalante et al., who point out that the range of both species "overlapped, especially, during the late Pliocene and middle Pleistocene (0.7–2.5 Myr), making possible the exchange of parasites in any direction" (6). This period, once again, predates the appearance of Homo sapiens.
They are cautious however and state that "this investigation points to P. vivax being derived from ancestral macaque parasites when hominoids colonized Southeast Asia." (6) and calculate a TMRCA "between 45,680 and 81,607 years ago, and possibly as old as "132,445" years, and they write "this time frame includes the accepted estimates for the introduction of H. sapiens in Southeast Asia; however, other hominoids were present such as H. erectus" (6).
Jongwutiwes et al., (2005) (7) take it up and give an even older age: "We estimated the age of the most recent common ancestor (MRCA) of the mitochondrial genomes of both P. vivax and P. falciparum at around 200,000–300,000 years ago. This is close to previous estimates of the time of the human mitochondrial MRCA and the origin of modern Homo sapiens, consistent with the hypothesis that both of these Plasmodium species were parasites of the hominid lineage before the origin of modern Homo sapiens and that their population expansion coincided with the population expansion of their host." (6).
They re-estimate Escalante's data and obtain "the age of the MRCA were 206,000–314,000 years (A.L. Hughes, unpublished), in good agreement with the present study" (7).
Which they conclude "P. vivax became a parasite of hominids – presumably in Asia – long before the origin of modern Homo sapiens. By about 1 Mya, Homo erectus is known to have inhabited both Africa and a wide geographic area of southern Asia (Anton 2003). We hypothesize that P. vivax transferred from a monkey host to H. erectus in Southeast Asia sometime before 1 Mya and subsequently spread across southern Asia into Africa through the H. erectus population. This model assumes that P. vivax reached Africa by dispersal through a H. erectus population that was distributed nearly continuously across Africa and southern Asia." (7)
So we have an ancient origin for P.vivax in South Asia, and evidence that it infected H. erectus over 300,000 years ago. Now lets look at its current endemicity:
It is evident that the areas where P. vivax are endemic are Papua New Guinea, South East Asia and India. Which was the homeland of H. erectus. In Africa it is present but at low rates, and... surprisingly, it is very prevalent in America, in eastern Central America and in the Amazon basin. So How did it reach America?
P. vivax in America
A very interesting thesis by Petr Triska (9) looks into the Plasmodiums in America and concludes that "P. falciparum has been endemic to Americas for more than 600 years." (9), it is a Precolombine infection with later events of colonization due to African slave trade.
Regarding P. vivax Triska writes: "that Plasmodium vivax was
present in Americas prior European colonization and prior documented contacts with Polynesia.
Colonization of Americas from Africa is not supported in our network. Ancestral haplotype of Americas is not shared with Africa. Furthermore, majority of slaves dragged to Americas were embarked in West Africa, however, West Africans are highly resistant to P.vivax and P. vivax is not prevalent there." (9)
He finds no support for a recent (last 600 years) migration from Polynesia. Neither did he find any "suggestion that present day American population of malaria parasites emerged from African strains" (9). He finds "Population ages were in magnitude of tens of thousands years", a clear indication that it is very old.
The Homo erectus link
Another protection from Malaria is given by O blood group. Apparently (Cserti-Gazdewich et al. 2011) Heterozygotes 00 grants resistance against malaria while A0, B0 and AB probably have no resistance. Since Amerindians are almost exclusively O group ( 80-100%), we can suppose it is due to positive selection against Malaria. Curiously, another hot spot for high O blood group is in Northern Australia and Melanesia.
So, we have evidence that P. vivax infected Homo erectus in South East Asia. That it reached America long ago, that it did not come via Polynesia or Africa. So it reached the New World from Asia. That it is prevalent in the deep Amazon, meaning it got there long ago, when it was first inhabited. That South East Asians and Melanesians have a mutation (oval shaped red blood cells) that protects them against P. vivax Malaria.
And, incredibly, this strange "ovalocytosis" mutation found in South East Asia, has been detected in Mexico, in two patients with no ties with S.E. Asia! pure Native American Mexicans:
Lets quote Ramos-Kuri et al. (11): "We describe the finding of two Mexican patients with a specific 27-bp deletion in the solute carrier family 4 gene (SLC4A1Δ27) (also known as the band 3 gene found on chromosome 17q21–q22), characteristic of Southeast Asian ovalocytosis (SAO). The patients were asymptomatic, and the initial diagnosis was made by microscopic observation of the presence of typical stomatocytic ovalocytes. The gene deletion was confirmed by PCR and DNA sequencing. Both patients were heterozygous for the deletion. One patient is from Tabasco state, in southeastern Mexico, a malaria-endemic zone. The other patient is from Mexico City, which is not a malaria-endemic area. Their families have no non-Mexican ancestors and their previous generations were born in Mexico. Both patients carry the HLA-B*3501 subtype, characteristic of Amerindians and Asian populations. Familial and HLA data led us to conclude that these two patients are the first report of SLC4A1Δ27 in Amerindians. The nucleotide analysis showing a perfect match sequence between Southeast Asian and Mexican patients suggests, but does not prove, that the Mexican gene is not a de novo mutation. Instead, this gene might be the result of migration of individuals with Asian ancestry into the Mexican gene pool. We are looking for other families with the mutation to detect, by HLA analysis, the ancient ethnic origin of these patients." (11).
Does this imply that the mutation was carried to America by a common ancestor of both South East Asians and Amerindians? Or is it the outcome of an even older carrier that admixed with Native Americans in America? I am suggesting that Homo erectus reached America with this mutation and passed it on to Amerindians later, when modern H. sapiens reached the New World.
(1)Sickle Cell Anemia St George's University, 2007
(2) D. Amato and P.B. Booth, (2005), Hereditary Ovalocytosis in Melanesians PNG Med J 2005 Mar-Jun;48(1-2): 102-108.
(3) Rosanas-Urgell A, Lin E, Manning L, Rarau P, Laman M, Senn N, et al. (2012) Reduced Risk of Plasmodium vivax Malaria in Papua New Guinean Children with Southeast Asian Ovalocytosis in Two Cohorts and a Case-Control Study. PLoS Med 9(9): e1001305. doi:10.1371/journal.pmed.1001305
(4) Taras K. Oleksyk, Michael W. Smith, Stephen J. O'Brien, (2009) Genome-wide scans for footprints of natural selection 24 November 2009.DOI: 10.1098/rstb.2009.0219
(5) Daniel E Neafsey et al., (2012) The malaria parasite Plasmodium vivax exhibits greater genetic diversity than Plasmodium falciparum. Nature Genetics 44, 1046–1050 (2012) doi:10.1038/ng.2373
(6) Ananias A. Escalante, Omar E. Cornejo, Denise E. Freeland, Amanda C. Poe, Ester Durrego, William E. Collins, and Altaf A. Lal (2004). A monkey's tale: The origin of Plasmodium vivax as a human malaria parasite vol. 102 no. 6 doi: 10.1073/pnas.0409652102
(7) Somchai Jongwutiwes et al., (2005) Mitochondrial Genome Sequences Support Ancient Population Expansion in Plasmodium vivax Mol Biol Evol. 2005 Aug; 22(8): 1733–1739. Published online 2005 May 18. doi: 10.1093/molbev/msi168
(8) Plasmodiium Vivax global Endemicity map, 2010
(9) Petr Triska, (2011), Master's Thesis Masaryk University, Brno. Assessing human history by investigating phylogeography of Plasmodium parasites
(10) O blood group map
(11) Manuel Ramos-Kuri, Joaquin Carrillo Farga, Joaquin Zuniga, Maria Teresa Amador Guerrero, Julio Granados, Francisco J. Estrada (2005). Molecular Demonstration of SLC4A1 Gene Deletion in Two Mexican Patients with Ovalocytosis Human Biology Volume 77, Number 3, June 2005 pp. 399-405 | 10.1353/hub.2005.0052
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