This research provides novel insights into the history of malaria in Southeast Asia and the Western Pacific. Moreover, it will supply a detailed analysis of the geographic origins and spread of an allele that profoundly affects human health in both positive and negative ways (by mitigating the effects of malaria, while also being recessively lethal). As a result, this research enables insight into the historical evolutionary processes that shape current patterns of human health in the Southeast Asian region. In addition, it presents significant training opportunities for students at the high school, college, and graduate level in the field of molecular population genetics.
Malaria acts as a powerful agent of natural selection in many affected human populations. By studying the evolutionary origins of alleles that confer resistance to malarial disease we can gain insights into the co-evolutionary relationship between malaria-causing Plasmodium parasites and human hosts. This study examines the evolutionary history of Southeast Asian Ovalocytosis (SAO). This trait is associated with strong resistance to malaria-related mortality but is lethal in utero when an individual is homozygous for the causal allele. As a consequence, SAO is likely maintained as a balanced polymorphism in affected populations. The goal of this project is to estimate the time and place where SAO originated by re-sequencing SAO and wildtype alleles from a geographically diverse panel of affected individuals. At present, the vast majority of our understanding of the evolutionary origins of human malaria-resistance comes from studies of sub-Saharan African traits. SAO has a distribution that is largely restricted to Southeast Asia and the Western Pacific -- an area from which we know comparatively little regarding human adaptation to malaria. This project tests whether SAO origins are contemporaneous with other (primarily African) malaria resistance alleles studied to date, and also will determine the geographic setting in which this adaptive allele evolved.
(SAO), a trait that confers strong resistance to malarial disease. Our approach was to sequence DNA closely linked to the causal SAO mutation to examine patterns of molecular variability. We found that SAO chromosomes harbor substantial variation, consistent with an age in the range of 7,500 - 8,000 years, making SAO the oldest malaria-resistance allele known in Asia and among the oldest worldwide. These results are significant because they suggest a relatively early onset of malaria-driven natural selection in Island Southeast Asia, and indicate a much longer timeframe of human adaptation to malaria than is presently recognized. In addition to relatively old origins of SAO, our data allowed us to estimate the evolutionary advantage conferred by SAO in malarial environments. Based on the patterns we observe, we estimate that SAO-carriers have had an ~2% fitness advantage relative to wildtype individuals over the evolutionary history of the allele. Interestingly, techniques that allow for estimation of the present-day selection coefficient affecting SAO allow us to estimate a nearly 10% fitness advantage for SAO carriers in some populations, suggesting that natural selection favoring SAO carriers has become more intense in the recent past. This could be caused by a recent increase in the insensity of malaria-driven natural selection in Southeast Asia, consistent with a recent increase in virulence of malarial disease. This project offered outstanding research training opportunities for students at a variety of levels. Specifically, data collection was carried out by two high school students and five undergraduate students. Two graduate students carried out much of the data analysis and dissemination, resulting in Masters theses for each. Several of these students are members of populations that are under-represented in the sciences. In addition, this project cemented a productive international collaboration between researchers at Northern Arizona University and the Eijkman Institute for Molecular Biology (Jakarta, Indonesia).
