Doctoral Dissertation Improvement: Patterns of Genetic Diversity and Signatures of Natural Selection at the Intercellular Adhesion Molecule-1 (ICAM-1) and CD36 Loci

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

Understanding the scope of human genetic variation and how evolutionary forces like natural selection, genetic drift, and mutation have shaped the human genome is key to describing the genetic history that underlies all human populations. Identifying patterns of nucleotide variation that have resulted from natural selection may also help identify genetic variants that influence disease susceptibility and will further clarify the context of modern human evolution. Malaria, resulting from infection by Plasmodium falciparum, causes millions of deaths each year, and is one of the strongest selective forces in recent human evolution. Because genetic variants at malaria resistance candidate genes may be targets of natural selection, nucleotide diversity at these loci can be examined to identify variants that affect susceptibility to malarial disease. African populations are particularly informative for studying patterns of genetic variation at malaria susceptibility candidate genes because they contain a high level of genetic diversity and are likely to have previously unknown genetic variants. In addition, due to high malarial endemicity in certain regions of Africa, it is likely that evidence of local adaptation to malaria will be detected within diverse African populations. The aim of this project is to examine patterns of nucleotide variation, using DNA re-sequencing technology, at two malaria resistance candidate genes, intercellular adhesion molecule-1 (ICAM-1) and CD36, in a diverse group of African and non-African human populations (39 total populations). This project will: 1) identify and characterize patterns of nucleotide diversity at two loci that have been suggested to influence susceptibility to malarial disease, 2) conduct statistical analyses to identify signatures of natural selection and examine the effects of demography, and 3) test for correlations between genetic diversity and climate, subsistence strategy, ethnicity, and the prevalence of P. falciparum infection. These data will add to our limited knowledge of genetic diversity and the demographic history of African populations. These data will also add to our knowledge of how demography and natural selection have shaped patterns of variation within the human genome. Ultimately, this research will provide a clearer picture of human genetic adaptation and the co-evolution of human and P. falciparum genomes, and will contribute to the training of a doctoral student from an underrepresented group in anthropological genetics.