Evolutionary Dynamics of the Human NADPH Oxidase Genes CYBB, CYBA, NCF2, and NCF4: Functional Implications

• DOI: 10.1093/molbev/mst119
• Publication Date: 2013-07-03T04:41:09Z
• Authors: Eduardo Tarazona-...; Moara Machado; Wagner C.S. Magal...; Renee Chen; Fernanda Lyon; Laurie Burdett; Andrew Crenshaw; Cristina Fabbri; Latife Pereira; Laelia Pinto; Rodrigo A.F. Redondo; Ben Sestanovich; Meredith Yeager; Stephen J. Chanock
• Keywords: 0303 health sciences; Membrane Glycoproteins; Bacteria; innate immunity; immunogenetics; chronic granulomatous disease; Molecular Sequence Data; Black People; Genetic Variation; NADPH Oxidases; Bacterial Infections; Catalase; Granulomatous Disease, Chronic; Evolution, Molecular; 03 medical and health sciences; Asian People; Bacterial Proteins; Haplotypes; Host-Pathogen Interactions; Mutation; NADPH Oxidase 2; Animals; Humans; Amino Acid Sequence; Phylogeny

The phagocyte NADPH oxidase catalyzes the reduction of O2 to reactive oxygen species with microbicidal activity. It is composed of two membrane-spanning subunits, gp91-phox and p22-phox (encoded by CYBB and CYBA, respectively), and three cytoplasmic subunits, p40-phox, p47-phox, and p67-phox (encoded by NCF4, NCF1, and NCF2, respectively). Mutations in any of these genes can result in chronic granulomatous disease, a primary immunodeficiency characterized by recurrent infections. Using evolutionary mapping, we determined that episodes of adaptive natural selection have shaped the extracellular portion of gp91-phox during the evolution of mammals, which suggests that this region may have a function in host-pathogen interactions. On the basis of a resequencing analysis of approximately 35 kb of CYBB, CYBA, NCF2, and NCF4 in 102 ethnically diverse individuals (24 of African ancestry, 31 of European ancestry, 24 of Asian/Oceanians, and 23 US Hispanics), we show that the pattern of CYBA diversity is compatible with balancing natural selection, perhaps mediated by catalase-positive pathogens. NCF2 in Asian populations shows a pattern of diversity characterized by a differentiated haplotype structure. Our study provides insight into the role of pathogen-driven natural selection in an innate immune pathway and sheds light on the role of CYBA in endothelial, nonphagocytic NADPH oxidases, which are relevant in the pathogenesis of cardiovascular and other complex diseases.