title: 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.
authors.affiliation: Department of Biological Sciences, Northern Arizona University, Flagstaff, AZ 86011, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Paquette
authors.affiliation: Eijkman Institute for Molecular Biology, Jakarta, Indonesia.
authors.forename: A
authors.initials: A
authors.lastname: Harahap
authors.affiliation: Division of Pediatric Hematology & Oncology, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkla 90110, Thailand.
authors.forename: V
authors.initials: V
authors.lastname: Laosombat
authors.affiliation: Department of Biological Sciences, Northern Arizona University, Flagstaff, AZ 86011, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Patnode
authors.affiliation: Eijkman Institute for Molecular Biology, Jakarta, Indonesia.
authors.forename: A
authors.initials: A
authors.lastname: Satyagraha
authors.affiliation: Eijkman Institute for Molecular Biology, Jakarta, Indonesia.
authors.forename: H
authors.initials: H
authors.lastname: Sudoyo
authors.affiliation: Department of Biological Sciences, Northern Arizona University, Flagstaff, AZ 86011, USA.
authors.forename: M K
authors.initials: MK
authors.lastname: Thompson
authors.affiliation: Advanced Medical and Dental Institute, Universiti Sains Malaysia, 13200 Kepala Batas, Pulau Pinang, Malaysia.
authors.forename: N M
authors.initials: NM
authors.lastname: Yusoff
authors.affiliation: Department of Biological Sciences, Northern Arizona University, Flagstaff, AZ 86011, USA. Electronic address: jason.wilder@nau.edu.
authors.forename: J A
authors.initials: JA
authors.lastname: Wilder
mesh_terms: D001457:Anion Exchange Protein 1, Erythrocyte / Q000235:genetics*; D001210:Asia, Southeastern; D004612:Elliptocytosis, Hereditary / Q000235:genetics*; D019143:Evolution, Molecular; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008288:Malaria / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA
chemical_list: D001457:Anion Exchange Protein 1, Erythrocyte; C454201:SLC4A1 protein, human
keywords: Malaria; Ovalocytosis; SLC4A1; Soft sweep