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

Mol Biol Evol. 2013 Sep;30(9):2157-67. doi: 10.1093/molbev/mst119. Epub 2013 Jul 2.


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.

Keywords: chronic granulomatous disease; immunogenetics; innate immunity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Asian People
  • Bacteria / enzymology
  • Bacterial Infections / complications
  • Bacterial Infections / enzymology
  • Bacterial Infections / ethnology
  • Bacterial Infections / genetics*
  • Bacterial Proteins / metabolism
  • Black People
  • Catalase / metabolism
  • Evolution, Molecular
  • Genetic Variation
  • Granulomatous Disease, Chronic / complications
  • Granulomatous Disease, Chronic / enzymology
  • Granulomatous Disease, Chronic / ethnology
  • Granulomatous Disease, Chronic / genetics*
  • Haplotypes
  • Host-Pathogen Interactions
  • Humans
  • Membrane Glycoproteins / classification
  • Membrane Glycoproteins / genetics*
  • Molecular Sequence Data
  • Mutation
  • NADPH Oxidase 2
  • NADPH Oxidases / classification
  • NADPH Oxidases / genetics*
  • Phylogeny
  • Selection, Genetic
  • White People


  • Bacterial Proteins
  • Membrane Glycoproteins
  • Catalase
  • CYBB protein, human
  • NADPH Oxidase 2
  • NADPH Oxidases
  • CYBA protein, human
  • NCF2 protein, human
  • NCF4 protein, human