Evolutionary dynamics of the human NADPH oxidase genes CYBB, CYBA, NCF2, and NCF4: Functional implications

E. Tarazona Santos, M. Machado, W. Magalhães, R. Chen, F. Lyon, L. Burdett, A. Crenshaw, C. Fabbri, L. Pereira, L. Pinto, R.A. Fernandes Redondo, B. Sestanovich, M. Yeager, S. Chanock, Molecular Biology and Evolution 30 (2013) 2157–2167.


Journal Article | Published | English
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Abstract
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.
Publishing Year
Date Published
2013-09-01
Journal Title
Molecular Biology and Evolution
Volume
30
Issue
9
Page
2157 - 2167
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Cite this

Tarazona Santos E, Machado M, Magalhães W, et al. Evolutionary dynamics of the human NADPH oxidase genes CYBB, CYBA, NCF2, and NCF4: Functional implications. Molecular Biology and Evolution. 2013;30(9):2157-2167. doi:10.1093/molbev/mst119
Tarazona Santos, E., Machado, M., Magalhães, W., Chen, R., Lyon, F., Burdett, L., … Chanock, S. (2013). Evolutionary dynamics of the human NADPH oxidase genes CYBB, CYBA, NCF2, and NCF4: Functional implications. Molecular Biology and Evolution, 30(9), 2157–2167. https://doi.org/10.1093/molbev/mst119
Tarazona Santos, Eduardo, Moara Machado, Wagner Magalhães, Renee Chen, Fernanda Lyon, Laurie Burdett, Andrew Crenshaw, et al. “Evolutionary Dynamics of the Human NADPH Oxidase Genes CYBB, CYBA, NCF2, and NCF4: Functional Implications.” Molecular Biology and Evolution 30, no. 9 (2013): 2157–67. https://doi.org/10.1093/molbev/mst119.
E. Tarazona Santos et al., “Evolutionary dynamics of the human NADPH oxidase genes CYBB, CYBA, NCF2, and NCF4: Functional implications,” Molecular Biology and Evolution, vol. 30, no. 9, pp. 2157–2167, 2013.
Tarazona Santos E, Machado M, Magalhães W, Chen R, Lyon F, Burdett L, Crenshaw A, Fabbri C, Pereira L, Pinto L, Fernandes Redondo RA, Sestanovich B, Yeager M, Chanock S. 2013. Evolutionary dynamics of the human NADPH oxidase genes CYBB, CYBA, NCF2, and NCF4: Functional implications. Molecular Biology and Evolution. 30(9), 2157–2167.
Tarazona Santos, Eduardo, et al. “Evolutionary Dynamics of the Human NADPH Oxidase Genes CYBB, CYBA, NCF2, and NCF4: Functional Implications.” Molecular Biology and Evolution, vol. 30, no. 9, Oxford University Press, 2013, pp. 2157–67, doi:10.1093/molbev/mst119.

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