Molecular population genetics of human CYP3A locus: signatures of positive selection and implications for evolutionary environmental medicine.
BACKGROUND
The human CYP3A gene cluster codes for cytochrome P450 (CYP) subfamily enzymes that catalyze the metabolism of various exogenous and endogenous chemicals and is an obvious candidate for evolutionary and environmental genomic study. Functional variants in the CYP3A locus may have undergone a selective sweep in response to various environmental conditions.


OBJECTIVE
The goal of this study was to profile the allelic structure across the human CYP3A locus and investigate natural selection on that locus.


METHODS
From the CYP3A locus spanning 231 kb, we resequenced 54 genomic DNA fragments (a total of 43,675 bases) spanning four genes (CYP3A4, CYP3A5, CYP3A7, and CYP3A43) and two pseudogenes (CYP3AP1 and CYP3AP2), and randomly selected intergenic regions at the CYP3A locus in Africans (24 individuals), Caucasians (24 individuals), and Chinese (29 individuals). We comprehensively investigated the nucleotide diversity and haplotype structure and examined the possible role of natural selection in shaping the sequence variation throughout the gene cluster.


RESULTS
Neutrality tests with Tajima's D, Fu and Li's D* and F*, and Fay and Wu's H indicated possible roles of positive selection on the entire CYP3A locus in non-Africans. Sliding-window analyses of nucleotide diversity and frequency spectrum, as well as haplotype diversity and phylogenetically inferred haplotype structure, revealed that CYP3A4 and CYP3A7 had recently undergone or were undergoing a selective sweep in all three populations, whereas CYP3A43 and CYP3A5 were undergoing a selective sweep in non-Africans and Caucasians, respectively.


CONCLUSIONS
The refined allelic architecture and selection spectrum for the human CYP3A locus highlight that evolutionary dynamics of molecular adaptation may underlie the phenotypic variation of the xenobiotic disposition system and varied predisposition to complex disorders in which xenobiotics play a role.
Chen
Xiaoping
X
State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Chinese National Human Genome Center at Beijing, Beijing, China.
Wang
Haijian
H
Zhou
Gangqiao
G
Zhang
Xiumei
X
Dong
Xiaojia
X
Zhi
Lianteng
L
Jin
Li
L
He
Fuchu
F
D000293:Adolescent; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D044466:Asian People; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005828:Genetics, Population; D006239:Haplotypes; D006801:Humans; D008297:Male; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics; D012641:Selection, Genetic / Q000235:genetics; D055815:Young Adult
D001189:Aryl Hydrocarbon Hydroxylases; C422408:CYP3A43 protein, human; C510164:CYP3A5 protein, human; C103123:CYP3A7 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human