title: CYBB, an NADPH-oxidase gene: restricted diversity in humans and evidence for differential long-term purifying selection on transmembrane and cytosolic domains.
abstract: CYBB encodes the gp91-phox protein of the phagocytic NADPH oxidase; the innate immunity-related enzymatic complex responsible for the respiratory burst. Mutations in CYBB can cause chronic granulomatous disease (CGD), a primary immunodeficiency characterized by ineffective microbicidal activity, for which over 150 family-specific mutations have been described. It is also plausible that common SNPs in CYBB alter the expression or function of gp91-phox, determining differences in susceptibility to complex disorders such as autoimmune or infectious diseases. We have resequenced the exons, UTRs, and intronic regions of CYBB in 102 ethnically diverse individuals and genotyped nine tag-SNPs in 942 individuals from 52 worldwide populations. The 28 observed SNPs (none of which nonsynonymous) reside on 28 haplotypes that can be collapsed into five clades. CYBB shows lower diversity than other X-chromosome genes and most of the between-population genetic variance was observed among Africans and non-Africans. The African population shows the highest diversity and the lowest linkage disequilibrium (LD). Because there is extensive shared LD among non-Africans, tag-SNPs can be effectively employed in gene-centric association studies and are portable across Eurasian and Native American populations. Comparison of CYBB coding sequences among mammals evidences the action of long-term purifying selection, which is stronger on the C-terminal cytosolic domain than on the N-terminal transmembrane domain of gp91-phox.
authors.affiliation: Section of Genomic Variation, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Gaithersburg, Maryland, USA.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Tarazona-Santos
authors.forename: Toralf
authors.initials: T
authors.lastname: Bernig
authors.forename: Laurie
authors.initials: L
authors.lastname: Burdett
authors.forename: Wagner C S
authors.initials: WC
authors.lastname: Magalhaes
authors.forename: Cristina
authors.initials: C
authors.lastname: Fabbri
authors.forename: Jason
authors.initials: J
authors.lastname: Liao
authors.forename: Rodrigo A F
authors.initials: RA
authors.lastname: Redondo
authors.forename: Robert
authors.initials: R
authors.lastname: Welch
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000201:enzymology; D041321:Chromosomes, Human, X; D003600:Cytosol / Q000201:enzymology; D006239:Haplotypes; D006801:Humans; D007113:Immunity, Innate; D015810:Linkage Disequilibrium; D008562:Membrane Glycoproteins / Q000235:genetics*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D013045:Species Specificity
chemical_list: D008562:Membrane Glycoproteins; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases