Dissertation Research: Nucleotide Variability at G6pd and the Signature of Malarial Selection in Humans

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Malaria is a major cause of illness and mortality in humans. Every year nearly 500 million people suffer from malaria and upward of 2 million people die from this tropical parasitic disease. Some human populations that have historically lived in regions with high levels of malaria infections carry genetic resistance factors to the disease. Among these genetic resistance factors are some variants (alleles) of the gene coding for glucose-6-phosphate dehydrogenase (G6PD). Thus G6pd is subject to positive natural selection in some human populations in malarious areas. Few examples of positive natural selection are recognized at the molecular level in humans and the effect of selection on the genome is not yet well understood. To understand the effect of selection on DNA nucleotide variability and to identify a signature of positive natural selection at the molecular level, this research will describe patterns of nucleotide variability within and around the gene coding for G6PD in humans. Specifically, this research will describe patterns of nucleotide variability within G6pd, and at ten other neighboring genes spanning over 2 Mb around G6pd in two distinct human populations from Africa and Iraq that bear independently arisen polymorphisms at G6pd that confer resistance to malaria. A random sample of 50 individuals from the Luo of Kenya, and 50 Iraqi Jews will be used in the study to (i) characterize the signature of selection on G6pd, (ii) characterize variation at loci linked to G6pd, (iii) estimate the age of the selected alleles based on patterns of nucleotide variability, and (iv) compare G6pd systems in Africa and Iraq to distinguish between deterministic factors (e.g. natural selection) and stochastic factors (e.g. genetic drift) that are responsible for shaping the observed nucleotide patterns.Patterns of nucleotide variability found in this study at G6pd that are due to selection by malaria will shed light on the evolutionary history of the association between Plasmodium falciparum (the primary human malaria parasite) and humans, a topic that is still not clearly understood. Furthermore, the ability to recognize the signature of positive natural selection in general at the molecular level in humans will be useful to possibly identify additional human genes that are subject to selection by various infectious diseases and ecological factors.