The other red cell disease that protects against the other malaria

Oval red cells (CC The New Messiah)

It is generally well known that the sickle-cell disease, relatively common in parts of Africa, or rather its associated allele when heterozygous, has a protective effect against malaria, specifically to the variant caused by Plasmodium falciparium.

But there is at least another adaption to another kind of malaria: the one caused by P. vivax. This one, the SE Asian ovalocytosis (SAO), has only been discovered and studied in the last years and seems to exist only in some populations of Malaysia and Papua. This study confirms that the SAO defect effectively protects against P. vivax.

Ana Rosanas Urgell et al., Reduced Risk of Plasmodium vivax Malaria in Papua New Guinean Children with Southeast Asian Ovalocytosis in Two Cohorts and a Case-Control Study. PLoS Medicine 2012. Open access ··> LINK [doi:10.1371/journal.pmed.1001305] 

Abstract

Background

The erythrocyte polymorphism, Southeast Asian ovalocytosis (SAO) (which results from a 27-base pair deletion in the erythrocyte band 3 gene, SLC4A1Δ27) protects against cerebral malaria caused by Plasmodium falciparum; however, it is unknown whether this polymorphism also protects against P. vivax infection and disease.

Methods and Findings

The association between SAO and P. vivax infection was examined through genotyping of 1,975 children enrolled in three independent epidemiological studies conducted in the Madang area of Papua New Guinea. SAO was associated with a statistically significant 46% reduction in the incidence of clinical P. vivax episodes (adjusted incidence rate ratio [IRR] = 0.54, 95% CI 0.40–0.72, p<0.0001) in a cohort of infants aged 3–21 months and a significant 52% reduction in P. vivax (blood-stage) reinfection diagnosed by PCR (95% CI 22–71, p = 0.003) and 55% by light microscopy (95% CI 13–77, p = 0.014), respectively, in a cohort of children aged 5–14 years. SAO was also associated with a reduction in risk of P. vivax parasitaemia in children 3–21 months (1,111/µl versus 636/µl, p = 0.011) and prevalence of P. vivax infections in children 15–21 months (odds ratio [OR] = 0.39, 95% CI 0.23–0.67, p = 0.001). In a case-control study of children aged 0.5–10 years, no child with SAO was found among 27 cases with severe P. vivax or mixed P. falciparum/P. vivax malaria (OR = 0, 95% CI 0–1.56, p = 0.11). SAO was associated with protection against severe P. falciparum malaria (OR = 0.38, 95% CI 0.15–0.87, p = 0.014) but no effect was seen on either the risk of acquiring blood-stage infections or uncomplicated episodes with P. falciparum. Although Duffy antigen receptor expression and function were not affected on SAO erythrocytes compared to non-SAO children, high level (>90% binding inhibition) P. vivax Duffy binding protein–specific binding inhibitory antibodies were observed significantly more often in sera from SAO than non-SAO children (SAO, 22.2%; non-SAO, 6.7%; p = 0.008).

Conclusions

In three independent studies, we observed strong associations between 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.

 

Extremely ancient introgression in Papuans

Melanesians

Neanderfollia mentions today[cat] new genetic research that has found unusual diversity in gene OAS1 among Papuans. They contend that this is caused by extremely old introgression that they estimate in more than three million years (more than the age of the genus Homo).

Fernando L. Méndez et al., Global genetic variation at OAS1 provides evidence of archaic admixture in Melanesian populations. Molecular Biology and Evolution 2012. Pay per view.

Abstract

Recent analysis of DNA extracted from two Eurasian forms of archaic human show that more genetic variants are shared with humans currently living in Eurasia than with anatomically modern humans in sub-Saharan Africa. While these genome-wide average measures of genetic similarity are consistent with the hypothesis of archaic admixture in Eurasia, analyses of individual loci exhibiting the signal of archaic introgression are needed to test alternative hypotheses and investigate the admixture process. Here, we provide a detailed sequence analysis of the innate immune gene, OAS1, a locus with a divergent Melanesian haplotype that is very similar to the Denisova sequence from the Altai region of Siberia. We re-sequenced a 7 kb region encompassing the OAS1 gene in 88 individuals from 6 Old World populations (San, Biaka, Mandenka, French Basque, Han Chinese, and Papua New Guineans) and discovered previously unknown and ancient genetic variation. The 5′ region of this gene has unusual patterns of diversity, including 1) higher levels of nucleotide diversity in Papuans than in sub-Saharan Africans, 2) very deep ancestry with an estimated time to the most recent common ancestor of >3 million years, and 3) a basal branching pattern with Papuan individuals on either side of the rooted network. A global geographic survey of >1500 individuals showed that the divergent Papuan haplotype is nearly restricted to populations from eastern Indonesia and Melanesia. Polymorphic sites within this haplotype are shared with the draft Denisova genome over a span of ∼90 kb and are associated with an extended block of linkage disequilibrium, supporting the hypothesis that this haplotype introgressed from an archaic source that likely lived in Eurasia.

This is what I have been arguing since December 2010: “denisovan” admixture in Australasian and SE Asian aborigines stems from Homo erectus (diverged from our line at least 1.8 Ma ago) or even maybe a most distant cousin (maybe H. floresiensis, argued by some to be more archaic than H. erectus in key elements like the wrist or toes). 

Yet I am a bit skeptic of the age estimate, because, unless the H. floresiensis australopithecine hypothesis could be confirmed, the date is out of bounds for Humankind proper and creates many conceptual challenges, which are admittedly hard to swallow. While the “australopithecine hobbit” hypothesis would fit this scenario, it remains hard to swallow that the two genus would still be inter-fertile just a few dozen millennia ago and then again, why would archaic admixture come from this remote relative and not the much closer H. erectus, which we know lived in East Asia until rather recently. 

Finally I am in general very skeptic of age estimates as such and their ability to be able to inform more than they confuse. Normally I find them too recent but the opposite (too ancient) can also happen, I imagine. They are in any case just estimates: educated guesses and nothing else.

Update:

Got a copy of the paper (thanks again) and I would say that these two figures are of special interest:

Fig. 2 – Median joining network of OAS 1 haplotypes

Fig. 3 Geographic distribution of the deep lineage in A) Old World populations and B) South East Asians and Oceanians.

I find particularly notable that the haplotype has been found at very low frequencies in South Asia and nowhere else West of Wallace Line. It can be backflow but may also be indicator about the possible location of the admixture event.

Certainly nothing seems to suggests in these or other maps (1, 2) of “Denisovan” admixture that the episode could have happened in Altai or nearby areas as some readers, stubborn proponents of obsolete migration models, have insisted on. Instead all the evidence suggests that the admixture episode happened in SE or otherwise Tropical Asia, whether deep in Indonesia or more towards the mainland is debatable indeed.

See also:

• Neanderthal gene flow found in modern humans (on Green 2010)
• Exploring the Neanderthal admixture episode (version 1)
• Denisova hominins, Neanderthals, Melanesians and so on… (on Reich 2010)
• Explaining ‘Denisovan’ and also ‘Neanderthal’ admixture: the simplest scenario (where I first hypothesize that H. erectus and also maybe a relative of Neanderthals like the Hathnora hominin, could be the actual culprits).
• Is X-DNA lineage Neanderthal?
• Denisovan admixture widespread beyond Wallace Line, non-existent elsewhere – but then:
• Minimal Denisovan admixture in SE Asians.
• ‘Denisovan’ admixture may actually be from H. erectus.