title: Origin and differential selection of allelic variation at TAS2R16 associated with salicin bitter taste sensitivity in Africa.
abstract: Bitter taste perception influences human nutrition and health, and the genetic variation underlying this trait may play a role in disease susceptibility. To better understand the genetic architecture and patterns of phenotypic variability of bitter taste perception, we sequenced a 996 bp region, encompassing the coding exon of TAS2R16, a bitter taste receptor gene, in 595 individuals from 74 African populations and in 94 non-Africans from 11 populations. We also performed genotype-phenotype association analyses of threshold levels of sensitivity to salicin, a bitter anti-inflammatory compound, in 296 individuals from Central and East Africa. In addition, we characterized TAS2R16 mutants in vitro to investigate the effects of polymorphic loci identified at this locus on receptor function. Here, we report striking signatures of positive selection, including significant Fay and Wu's H statistics predominantly in East Africa, indicating strong local adaptation and greater genetic structure among African populations than expected under neutrality. Furthermore, we observed a "star-like" phylogeny for haplotypes with the derived allele at polymorphic site 516 associated with increased bitter taste perception that is consistent with a model of selection for "high-sensitivity" variation. In contrast, haplotypes carrying the "low-sensitivity" ancestral allele at site 516 showed evidence of strong purifying selection. We also demonstrated, for the first time, the functional effect of nonsynonymous variation at site 516 on salicin phenotypic variance in vivo in diverse Africans and showed that most other nonsynonymous substitutions have weak or no effect on cell surface expression in vitro, suggesting that one main polymorphism at TAS2R16 influences salicin recognition. Additionally, we detected geographic differences in levels of bitter taste perception in Africa not previously reported and infer an East African origin for high salicin sensitivity in human populations.
authors.affiliation: Department of Genetics, University of Pennsylvania.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Campbell
authors.forename: Alessia
authors.initials: A
authors.lastname: Ranciaro
authors.forename: Daniel
authors.initials: D
authors.lastname: Zinshteyn
authors.forename: Renata
authors.initials: R
authors.lastname: Rawlings-Goss
authors.forename: Jibril
authors.initials: J
authors.lastname: Hirbo
authors.forename: Simon
authors.initials: S
authors.lastname: Thompson
authors.forename: Dawit
authors.initials: D
authors.lastname: Woldemeskel
authors.forename: Alain
authors.initials: A
authors.lastname: Froment
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Rucker
authors.forename: Sabah A
authors.initials: SA
authors.lastname: Omar
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Bodo
authors.forename: Thomas
authors.initials: T
authors.lastname: Nyambo
authors.forename: Gurja
authors.initials: G
authors.lastname: Belay
authors.forename: Dennis
authors.initials: D
authors.lastname: Drayna
authors.forename: Paul A S
authors.initials: PA
authors.lastname: Breslin
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Tishkoff
mesh_terms: D000483:Alleles; D001592:Benzyl Alcohols / Q000737:chemistry*; D044383:Black People / Q000235:genetics*; D019143:Evolution, Molecular; D005091:Exons; D056726:Genetic Association Studies; D014644:Genetic Variation; D005960:Glucosides / Q000737:chemistry*; D006239:Haplotypes; D006801:Humans; D008288:Malaria / Q000453:epidemiology / Q000235:genetics; D008957:Models, Genetic; D010802:Phylogeny; D058974:Phylogeography; D020641:Polymorphism, Single Nucleotide; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D012641:Selection, Genetic; D013649:Taste / Q000235:genetics*; D000098706:Taste Receptors, Type 2
chemical_list: D001592:Benzyl Alcohols; D005960:Glucosides; D043562:Receptors, G-Protein-Coupled; D000098706:Taste Receptors, Type 2; C005696:salicin
keywords: African genetic diversity; genotype–phenotype association; salicin taste perception; selection on standing variation