AJHG - Effects of Natural Selection and Gene Conversion on the Evolution of Human Glycophorins Coding for MNS Blood Polymorphisms in Malaria-Endemic African Populations

Effects of Natural Selection and Gene Conversion on the Evolution of Human Glycophorins Coding for MNS Blood Polymorphisms in Malaria-Endemic African PopulationsWen-Ya Ko1, Kristin A. Kaercher1, Emanuela Giombini2, Paolo Marcatili2, Alain Froment3, Muntaser Ibrahim4, Godfrey Lema5, Thomas B. Nyambo5, Sabah A. Omar6, Charles Wambebe7, Alessia Ranciaro1, Jibril B. Hirbo1 and Sarah A. Tishkoff1, ,

1 Department of Genetics and Biology, School of Medicine and School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA
2 Department of Biochemical Sciences Rossi Fanelli University of Rome La Sapienza P.ale Aldo Moro, 5 - 00185 Rome, Italy
3 UMR 208, Institut de Recherche pour le Développement, Muséum National d'Histoire Naturelle, Musée de l'Homme, 75116 Paris, France
4 Department of Molecular Biology, Institute of Endemic Diseases, University of Khartoum, 15-Khartoum, Sudan
5 Department of Biochemistry, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania
6 Kenya Medical Research Institute, Center for Biotechnology Research and Development, 54840-00200 Nairobi, Kenya
7 International Biomedical Research in Africa, Abuja, Nigeria


Abstract

Malaria has been a very strong selection pressure in recent human evolution, particularly in Africa. Of the one million deaths per year due to malaria, more than 90% are in sub-Saharan Africa, a region with high levels of genetic variation and population substructure. However, there have been few studies of nucleotide variation at genetic loci that are relevant to malaria susceptibility across geographically and genetically diverse ethnic groups in Africa. Invasion of erythrocytes by Plasmodium falciparum parasites is central to the pathology of malaria. Glycophorin A (GYPA) and B (GYPB), which determine MN and Ss blood types, are two major receptors that are expressed on erythrocyte surfaces and interact with parasite ligands. We analyzed nucleotide diversity of the glycophorin gene family in 15 African populations with different levels of malaria exposure. High levels of nucleotide diversity and gene conversion were found at these genes. We observed divergent patterns of genetic variation between these duplicated genes and between different extracellular domains of GYPA. Specifically, we identified fixed adaptive changes at exons 34 of GYPA. By contrast, we observed an allele frequency spectrum skewed toward a significant excess of intermediate-frequency alleles at GYPA exon 2 in many populations; the degree of spectrum distortion is correlated with malaria exposure, possibly because of the joint effects of gene conversion and balancing selection. We also identified a haplotype causing three amino acid changes in the extracellular domain of glycophorin B. This haplotype might have evolved adaptively in five populations with high exposure to malaria.
AJHG - Effects of Natural Selection and Gene Conversion on the Evolution of Human Glycophorins Coding for MNS Blood Polymorphisms in Malaria-Endemic African Populations