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

• Published in: American journal of human genetics Vol. 88; no. 6; pp. 741 - 754
• Main Authors: KO, Wen-Ya, KAERCHER, Kristin A, RANCIARO, Alessia, HIRBO, Jibril B, TISHKOFF, Sarah A, GIOMBINI, Emanuela, MARCATILI, Paolo, FROMENT, Alain, IBRAHIM, Muntaser, LEMA, Godfrey, NYAMBO, Thomas B, OMAR, Sabah A, WAMBEBE, Charles
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Cell Press 10.06.2011; Elsevier
• Subjects: Africa South of the Sahara; Amino Acid Substitution; Animals; Bacteria; Base Sequence; Biological and medical sciences; Biological variation; Endemic Diseases; Erythrocytes; Erythrocytes - metabolism; Erythrocytes - parasitology; Ethnic Groups - genetics; Exons; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genetic Loci; Genetic Predisposition to Disease; Genetics of eukaryotes. Biological and molecular evolution; Glycophorin - chemistry; Glycophorin - classification; Glycophorin - genetics; Human protozoal diseases; Humans; Infectious diseases; Malaria; Malaria, Falciparum - blood; Malaria, Falciparum - epidemiology; Malaria, Falciparum - genetics; Medical genetics; Medical sciences; MNSs Blood-Group System - genetics; Molecular and cellular biology; Molecular Sequence Data; Parasitic diseases; Phylogeny; Plasmodium falciparum; Polymorphism; Polymorphism, Single Nucleotide; Protein Structure, Tertiary; Protozoal diseases; Selection, Genetic; Africa South of the Sahara; Africa; Human; Protozoal disease; Malaria; Parasitosis; Blood; African; Natural selection; Infection; Molecular evolution; Coding; Genetics; Population; Gene conversion; Polymorphism
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2011.05.005

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 3-4 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.