Electronic Thesis/Dissertation


Genetic Variation at ICAM-1 and CD36: A Study of Malaria Resistance Candidate Loci in Diverse Global Human Populations Open Access

Infectious disease has played an important role in driving human evolution and human population genetic variation. Malaria, caused by Plasmodium falciparum, is a particularly important infectious disease and is arguably one of the strongest selective forces in recent human evolution. Signatures of natural selection within the human genome can be important indicators of functional and/or adaptive variation. Many genes that contain variants that provide protection from malaria show signatures of selection. The identification of signatures of selection can help to locate genetic variants that influence disease susceptibility that may be missed by conventional genotype/phenotype association studies, or modern genome-wide association studies. ICAM-1 and CD36 are two loci that code for receptors on the surface of endothelial cells. During a P.falciparum infection parasite proteins that are exported to the red blood cell surface adhere to ICAM-1 and CD36. This process of cytoadherence is the primary occurrence that leads to the development of fatal syndromes called severe and cerebral malarial. Because ICAM-1 and CD36 are integrally involved in the pathogenesis of these syndromes I hypothesized that variants at ICAM-1 and CD36 that are functionally adaptive in malaria endemic environments will be targets of natural selection. In the current study I have re-sequenced ICAM-1 and CD36 in several diverse African and non-African populations. Using these data I have identified single nucleotide polymorphisms and have described nucleotide diversity at each locus. I have inferred haplotype phase, characterized patterns of haplotype diversity at each locus, and examined patterns of linkage disequilibrium. I have also performed several tests of selective neutrality and have tested whether the alleles at each locus are correlated with malaria endemicity. The results of my analyses show that variants at these loci are indeed correlated with malaria endemicity and there are some suggestive signatures natural selection at both ICAM-1 and CD36. The work accomplished here contributes to our knowledge of the scope of genetic diversity at ICAM-1 and CD36 and helps to elucidate whether there are variants at these loci that are functionally adaptive in malaria endemic environments.

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