Allele Frequency-Based Analyses Robustly Map Sequence Sites Under Balancing Selection in a Malaria Vaccine Candidate Antigen

Corresponding author: Spencer D. Polley, London School of Hygiene and Tropical Medicine, Keppel St., London WC1E 7HT, United Kingdom., spencer.polley{at}lshtm.ac.uk (E-mail)

Communicating editor: D. CHARLESWORTH

The Plasmodium falciparum apical membrane antigen 1 (AMA1) is a leading candidate for a malaria vaccine. Here, within-population analyses of alleles from 50 Thai P. falciparum isolates yield significant evidence for balancing selection on polymorphisms within the disulfide-bonded domains I and III of the surface accessible ectodomain of AMA1, a result very similar to that seen previously in a Nigerian population. Studying the frequency of nucleotide polymorphisms in both populations shows that the between-population component of variance (F_ST) is significantly lower in domains I and III compared to the intervening domain II and compared to 11 unlinked microsatellite loci. A nucleotide site-by-site analysis shows that sites with exceptionally high or low F_ST values cluster significantly into serial runs, with four runs of low values in domain I and one in domain III. These runs may map the sequences that are consistently under the strongest balancing selection from naturally acquired immune responses.

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