Role of parasitic selection in the evolution of human hemoglobin mutations

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Malaria is a major force in human evolution. Pressure from this disease has driven the evolution of several antimalarial traits in people, the best known of which is sickle hemoglobin. Although hemoglobin polymorphisms have been linked to antimalarial properties for decades, how these mutations protect against infections remains a mystery. An exciting new line of research emerging from my laboratory points to a novel mechanism involving the molecular details of how malaria parasites digest hemoglobin. Recently, we showed that mutations conferring drug resistance to parasites significantly reduce parasite fitness because they interfere with hemoglobin digestion. Intriguingly, these fitness-linked metabolic changes have a pronounced effect on the processing of peptides originating from the amino terminus of hemoglobinthe same locus as the human sickle trait. Subsequently, we have found that parasites preferentially digest wildtype over sickle hemoglobin, which suggests that the protective properties of this molecule may relate to its intrinsic digestibility. The goal of this research is to systematically evaluate the relationship between hemoglobin mutations, protein digestion, and parasite fitness using a new generation of high-resolution mass spectrometry methods. Our approach is to construct a detailed digestion map of the parasite's hemoglobin metabolism and identify the contributions of individual enzymes to this pathway using genetically engineered parasites. This enzyme/peptide association map will allow us to unravel this complex semi-ordered pathway and associate metabolic perturbations with specific enzymes. Once these maps have been constructed, we will systematically evaluate the impact sickle hemoglobin, and other human mutations, have on the parasite's nutrition. We will also use an exciting new isotope-based approach for measuring the fitness cost of hemoglobin mutations. If successful, this project will 1) establish a new generation of analytical tools that will allow researchers to investigate protein metabolism in intact cells, 2) elucidate an essential metabolic pathway in the world's most deadly parasitic disease, and 3) shed light on one of the most significant forces that have shaped the evolution of our species. I am requesting funds to support three graduate students and two undergraduate students to join me in this exciting new line of research.