Genetic variation in a human odorant receptor alters odour perception

• Published in: Nature Vol. 449; no. 7161; pp. 468 - 472
• Main Authors: Keller, Andreas, Zhuang, Hanyi, Chi, Qiuyi, Vosshall, Leslie B., Matsunami, Hiroaki
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.09.2007; Nature Publishing; Nature Publishing Group
• Subjects: Amino acids; Androstadienes - analysis; Androstadienes - pharmacology; Androstenes - analysis; Androstenes - pharmacology; Animals; Biochemistry; Biological and medical sciences; Cell Line; Chemical properties; Fundamental and applied biological sciences. Psychology; Genetic aspects; Genetic diversity; Genetic variation; Genetic Variation - genetics; Genotype; Genotypes; Human subjects; Humanities and Social Sciences; Humans; letter; Molecular Sequence Data; multidisciplinary; Odorants; Odors; Olfactory receptors; Olfactory system and olfaction. Gustatory system and gustation; Pan troglodytes; Perception; Perception - drug effects; Perception - physiology; Polymorphism, Single Nucleotide - genetics; Receptors, Odorant - genetics; Receptors, Odorant - metabolism; Science; Science (multidisciplinary); Smell; Smell - drug effects; Smell - genetics; Smell - physiology; Solvents; Steroids; Vertebrates: nervous system and sense organs; United States; Human; Steroid; Testosterone; Androgen; Aminoacid; Perception; Testicular hormone; Sex steroid hormone; In vitro; Variance; Polymorphism; Biological receptor
• ISSN: 0028-0836; 1476-4687; 1476-4687; 1476-4679
• DOI: 10.1038/nature06162

The scent of androstenone In humans, there is considerable variation between individuals in both their sensitivity to certain smells and their subjective experience of them. A new study is the first to show that genetic variation in a single human odorant receptor correlates with perceptual variation. OR7D4, an odorant receptor, is selectively activated in vitro by androstenone, a testosterone metabolite thought by some to be a candidate human pheromone. Variations in the gene encoding OR7D4 affected how the subjects thought the androstenone smelt — some found it pleasant, others offensive, to others it was odourless — and also how intense that smell was. In humans, there is considerable variation between individuals in their sensitivity to certain smells and their subjective experience of them. This paper identifies a potential genetic source of variability in perception of odorous steroids. OR7D4, an odorant receptor, is selectively activated in vitro by androstenone and variants of the gene are associated with differences in psychophysical performance in human subjects Human olfactory perception differs enormously between individuals, with large reported perceptual variations in the intensity and pleasantness of a given odour. For instance, androstenone (5α-androst-16-en-3-one), an odorous steroid derived from testosterone, is variously perceived by different individuals as offensive (“sweaty, urinous”), pleasant (“sweet, floral”) or odourless 1 , 2 , 3 . Similar variation in odour perception has been observed for several other odours 4 , 5 , 6 . The mechanistic basis of variation in odour perception between individuals is unknown. We investigated whether genetic variation in human odorant receptor genes accounts in part for variation in odour perception between individuals 7 , 8 . Here we show that a human odorant receptor, OR7D4, is selectively activated in vitro by androstenone and the related odorous steroid androstadienone (androsta-4,16-dien-3-one) and does not respond to a panel of 64 other odours and two solvents. A common variant of this receptor (OR7D4 WM) contains two non-synonymous single nucleotide polymorphisms (SNPs), resulting in two amino acid substitutions (R88W, T133M; hence ‘RT’) that severely impair function in vitro . Human subjects with RT / WM or WM / WM genotypes as a group were less sensitive to androstenone and androstadienone and found both odours less unpleasant than the RT / RT group. Genotypic variation in OR7D4 accounts for a significant proportion of the valence (pleasantness or unpleasantness) and intensity variance in perception of these steroidal odours. Our results demonstrate the first link between the function of a human odorant receptor in vitro and odour perception.