The evolutionary origins of Southeast Asian Ovalocytosis

Abstract

Southeast Asian Ovalocytosis (SAO) is a common red blood cell disorder that is maintained as a balanced polymorphism in human populations. In individuals heterozygous for the SAO-causing mutation there are minimal detrimental effects and well-documented protection from severe malaria caused by Plasmodium vivax and Plasmodium falciparum; however, the SAO-causing mutation is fully lethal in utero when homozygous. The present-day high frequency of SAO in Island Southeast Asia indicates the trait is maintained by strong heterozygote advantage. Our study elucidates the evolutionary origin of SAO by characterizing DNA sequence variation in a 9.5 kilobase region surrounding the causal mutation in the SLC4A1 gene. We find substantial haplotype diversity among SAO chromosomes and estimate the age of the trait to be approximately 10,005 years (95% CI: 4930-23,200 years). This date is far older than any other human malaria-resistance trait examined previously in Southeast Asia, and considerably pre-dates the widespread adoption of agriculture associated with the spread of speakers of Austronesian languages some 4000 years ago. Using a genealogy-based method we find no evidence of historical positive selection acting on SAO (s=0.0, 95% CI: 0.0-0.03), in sharp contrast to the strong present-day selection coefficient (e.g., 0.09) estimated from the frequency of this recessively lethal trait. This discrepancy may be due to a recent increase in malaria-driven selection pressure following the spread of agriculture, with SAO targeted as a standing variant by positive selection in malarial populations.

The radial expansion of the Diego blood group system polymorphisms in Asia: mark of co-migration with the Mongol conquests

“…Positive and significant Spearman’s rank correlation coefficients were found between the distribution of rs2285644 (derived nucleotide: A) and that of SNP mutations previously known to be responsible for preeclampsia, renal tubular acidosis, and mostly SAO [25]; the two latter being usually associated [42]. To go further, among the 12 mutations known to be responsible for the SAO [43], we have identified 4 SNPs: rs5036 (hg19 chr17:g.42338945T>C, ancestral nucleotide: C, responsible for band 3-Memphis non-synonymous polymorphism [44]), rs16940582 (hg19 chr17:g.42339745C>T, derived nucleotide: T), rs16940585 (hg19 chr17:g.42339762G>A, derived nucleotide: A) and rs2521602 (hg19 chr17:g.42336424G>A, derived nucleotide: A), whose distribution was always, worldly and only at Asiatic scale too, correlated with rs2285644 (A). These different results could be considered as a track of association between Diego polymorphism and SAO.…”

Genetic Predisposition to Infectious Disease

“…Due to a combination of these forces, the entry of P. falciparum malaria into the RBC is impaired. SAO is maintained as a balanced polymorphism among human populations [ 14 ], and to highlight the genetic selective pressure for this condition, there is a 35% incidence of SAO in the north coast of Madang Province in Papua New Guinea, a geographic location where malaria is endemic [ 15 ].…”

Accurate light microscopic diagnosis of South‐East Asian ovalocytosis

“…Most of the common Mendelian diseases of humankind (eg, sickle‐cell disease, the thalassemias, and glucose‐6‐phosphate dehydrogenase deficiency [G6PD])—are considered to offer a survival advantage against malaria, the strongest known selective pressure impacting the human genome . The inherited red blood cell (RBC) polymorphism South‐East Asian ovalocytosis (SAO) arose in humans approximately 10 000 years ago likely as a consequence of malaria selection pressure . Despite homozygous lethality in utero, the balanced polymorphism affords heterozygotes survival advantage against both falciparum and vivax malarias and occurs on the Malay Peninsula, the Indonesian, and Philippine archipelagos, and through much of Melanesia at prevalence rates as high as 30% .…”

“…1 The inherited red blood cell (RBC) polymorphism South-East Asian ovalocytosis (SAO) arose in humans approximately 10 000 years ago likely as a consequence of malaria selection pressure. 2 Despite homozygous lethality in utero, the balanced polymorphism affords heterozygotes survival advantage against both falciparum 3,4 and vivax malarias 5 and occurs on the Malay Peninsula, the Indonesian, and Philippine archipelagos, and through much of Melanesia at prevalence rates as high as 30%. [6][7][8][9] The impact of this polymorphism on the clinical course of Plasmodium falciparum and Plasmodium vivax infection and transmission dynamics, including possible interaction with other co-inherited RBC variants (eg, α-thalassemia, G6PD, and Gerbich blood group) has been scarcely explored.…”