Dissertation/Thesis Abstract

Variation in the human genome and protection against Malaria
by Woods, Caira Michelle, Ph.D., New York University, 2010, 165; 3396718
Abstract (Summary)

Malaria is one of the most prevalent communicable diseases, resulting in 500 million clinical cases and at least 1 million deaths per year. The greatest burden of mortality due to malaria is found in sub-Saharan Africa and Southeast Asia. Malaria is known to be a major selective force in the evolution of humans; however, the extent of its selection on the human genome is unknown. Traits like the complement receptor 1 (CR1) L allele, α +-thalassemia homozygosity, blood group O, haptoglobin 2-2 genotype and apolipoprotein E (apoE) genotypes have been associated with differential susceptibility to severe malaria in case-control studies. By genotyping and analyzing frequencies of the aforementioned polymorphisms in a malaria-endemic region of Papua New Guinea (PNG), I have been able to identify a non-random association between the protective traits CR1 LL and α+-thalassemia homozygosity. These protective traits were co-inherited leading me to propose that there has been selection for a "superchild" highly resistant to malaria on the north coast of PNG. This non-random association also suggests that positive epistasis is occurring between these genetic traits.

Apolipoproteins, which function in lipid transport, are essential for development and replication of Plasmodium spp., the protozoan parasites responsible for malaria. The Plasmodium parasite must scavenge lipids from the liver and bloodstream in order to develop and replicate in hepatocytes and erythrocytes. This requirement may have influenced selection of protective host apolipoprotein polymorphisms. Therefore, I have determined the frequency of apolipoprotein alleles in West African and Pacific Asian populations in which malaria has historically been absent or present. I have also compared allele frequencies and malariometric indices in these populations. My data show that apolipoprotein L-I alleles are not under selection by malaria, whereas the apoE 4 allele increases risk of infection in two malaria-endemic populations. This finding along with global population structure data suggests that malaria and not diet alone have played a role in the global distribution of the apoE 4 allele.

Indexing (document details)
Advisor: Day, Karen P.
Commitee: Fairhurst, Rick, Fisher, Edward, Perez-Perez, Guillermo, Raper, Jayne
School: New York University
Department: Basic Medical Science
School Location: United States -- New York
Source: DAI-B 71/03, Dissertation Abstracts International
Subjects: Genetics, Parasitology, Epidemiology
Keywords: Apolipoprotein E, Apolipoprotein L-I, Human genome, Malaria susceptibility, Population structure
Publication Number: 3396718
ISBN: 9781109653175