The nearly complete sequence of the human genome has greatly enhanced our understanding of human genetics. This single reference sequence, however, is not able to capture the extent and nature of human genetic variation. Efforts are now are shifting to describing patterns of variation across populations and regions of the genome particularly as it relates to human genetic diseases. Disease association studies are proving useful in identifying individuals at risk for certain diseases; however, much of human genomic variation is not related to disease. Patterns of variation can be shaped by natural selection (e.g. on variants in disease-related genes) and historical processes (e.g., migration and genetic drift). Natural selection affects variation associated with a specific gene or set of genes. Additionally, regions associated with a given disease comprise a relatively small portion of the entire genome. Historical processes, on the other hand, affect the entire genome. While a clearer picture of human evolutionary history is emerging, it is not known to what extent historical processes have shaped patterns of variation at disease genes. This study will assess the role of historical processes in shaping variation at genes conferring resistance to the infectious disease, malaria. Each year malaria affects ~500 million people and kills ~2 million with the vast majority of these deaths occurring in Africa. Alternate forms (alleles) of the beta-globin and G6PD genes are known to confer resistance to malaria and these alleles are found at high frequencies in populations residing in malarial environments. Interestingly the same alleles that confer resistance to malaria can also cause inherited diseases (i.e., sickle cell anemia, G6PD deficiency). The question is what is the relative role of natural selection and historical processes in shaping patterns of variation in and around these genes? To address this the reseachers will perform a two-way controlled comparison of patterns of DNA sequence variation in these two genes in four African populations with different susceptibility to malaria as a selective agent. Two of the four populations (the Luo and Dogon) occupy regions of sub-Saharan Africa that are strongly impacted by malaria, and two populations (the San and Southeastern Bantus) live outside malaria areas. Additionally, to dissect the role of historical processes in shaping variation in these populations, DNA sequences of two other gene regions that are not affected by malaria will be determined. One of these regions is on the tip of chromosome 16 (16p13.3) and the other is within an intron of Duchenne Muscular Dystrophy gene (Dmd intron 44) on the X chromosome. This experimental design should provide a sound hypothesis-testing framework for distinguishing those forces that act a single gene from those that affect the whole genome. Furthermore, collaborations with researchers at the Center for Disease Control in Atlanta and at the Kenya Medical Research Institute in Nairobi, Kenya, as well as the involvement of students from the University of Arizona and Pima Community College, will enhance the intellectual and training environment of this research.
