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

Eduardo Tarazona-Santos, Moara MacHado, Wagner C.S. Magalhães, 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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2157-2167
Number of pages11
JournalMolecular biology and evolution
Volume30
Issue number9
DOIs
StatePublished - Sep 1 2013

Keywords

  • chronic granulomatous disease
  • immunogenetics
  • innate immunity

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics

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    Tarazona-Santos, E., MacHado, M., Magalhães, W. C. S., Chen, R., Lyon, F., Burdett, L., Crenshaw, A., Fabbri, C., Pereira, L., Pinto, L., Redondo, R. A. F., Sestanovich, B., Yeager, M., & Chanock, S. J. (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