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.

Genome-Wide Scan for Signatures of Human Population Differentiation and Their Relationship with Natural Selection, Functional Pathways and Diseases

“…In our knowledge this represents the first attempt to connect human population genetic data and comparative data at a genome-wide level. Our finding does not conflict with previous studies performed on a restricted number of genes [30]. It is well established that comparative data provides the most unambiguous evidence for selection, but relatively vague assertion on the type of selection and if the selection is currently acting in a population [6].…”

Diversity in the Glucose Transporter-4 Gene (SLC2A4) in Humans Reflects the Action of Natural Selection along the Old-World Primates Evolution

“…This lack of common variation in the C-terminal part of the gene is even more surprising after verifying trough the UCSC Genome Browser that among mammals, the genomic region downstream of intron 6 is as much variable as the region upstream of exon 7 (data not shown). Second, the African set shows a larger Watterson's θ (which depends on the number of segregating sites), but unexpectedly, they show a lower nucleotide diversity (which mostly depends on common variants, π SLC2A4  = 0.00038) than non-Africans (Table 1, [39], [40], [41]. For most of the human genome, African populations show larger π values than non-Africans, which is likely due to the bottleneck occurred approximately 40–50 thousand years ago during the migration of humans “Out of Africa” [42].…”

Characterization of a candidate locus for malaria susceptibility in human populations: a (TA)n microsatellite in the promoter region of the CYBB gene, the gp91phox subunit of the NADPH oxidase

“…We selected 13 common CYBB SNPs and used them to determine haplotypes on the same 89 individuals for which the TA microsatellite in the promoter region was genotyped (Table 1). We used the same genotyping methods that Tarazona‐Santos et al . (in press).…”

“…We have recently performed an extensive population genetics analysis of coding and non‐coding regions of CYBB on a wide set of globally diverse human populations, by combining re‐sequencing analysis and single nucleotide polymorphism (SNP) genotyping (Tarazona‐Santos et al ., in press). Here, we further characterize the promoter TA microsatellite in the context of our findings.…”

“…(2004) in African, Europeans and Asians. Tarazona‐Santos et al . (in press) have determined the haplotype structure of CYBB at SNPs level in different human populations.…”