title: Evidence for balancing selection from nucleotide sequence analyses of human G6PD.
abstract: Glucose-6-phosphate dehydrogenase (G6PD) mutations that result in reduced enzyme activity have been implicated in malarial resistance and constitute one of the best examples of selection in the human genome. In the present study, we characterize the nucleotide diversity across a 5.2-kb region of G6PD in a sample of 160 Africans and 56 non-Africans, to determine how selection has shaped patterns of DNA variation at this gene. Our global sample of enzymatically normal B alleles and A, A-, and Med alleles with reduced enzyme activities reveals many previously uncharacterized silent-site polymorphisms. In comparison with the absence of amino acid divergence between human and chimpanzee G6PD sequences, we find that the number of G6PD amino acid polymorphisms in human populations is significantly high. Unlike many other G6PD-activity alleles with reduced activity, we find that the age of the A variant, which is common in Africa, may not be consistent with the recent emergence of severe malaria and therefore may have originally had a historically different adaptive function. Overall, our observations strongly support previous genotype-phenotype association studies that proposed that balancing selection maintains G6PD deficiencies within human populations. The present study demonstrates that nucleotide sequence analyses can reveal signatures of both historical and recent selection in the genome and may elucidate the impact that infectious disease has had during human evolution.
authors.affiliation: Department of Biology, University of Maryland, College Park, MD 20742, USA. verrelli@wam.umd.edu
authors.forename: Brian C
authors.initials: BC
authors.lastname: Verrelli
authors.forename: John H
authors.initials: JH
authors.lastname: McDonald
authors.forename: George
authors.initials: G
authors.lastname: Argyropoulos
authors.forename: Giovanni
authors.initials: G
authors.lastname: Destro-Bisol
authors.forename: Alain
authors.initials: A
authors.lastname: Froment
authors.forename: Anthi
authors.initials: A
authors.lastname: Drousiotou
authors.forename: Gerard
authors.initials: G
authors.lastname: Lefranc
authors.forename: Ahmed N
authors.initials: AN
authors.lastname: Helal
authors.forename: Jacques
authors.initials: J
authors.lastname: Loiselet
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Tishkoff
mesh_terms: D017954:Africa South of the Sahara; D044383:Black People / Q000235:genetics; D019143:Evolution, Molecular; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D015810:Linkage Disequilibrium; D008288:Malaria / Q000235:genetics; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010802:Phylogeny; D011110:Polymorphism, Genetic; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA
chemical_list: D005954:Glucosephosphate Dehydrogenase