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Genetic variation in a human odorant receptor alters odour perception


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 odourless1,2,3. Similar variation in odour perception has been observed for several other odours4,5,6. 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 individuals7,8. 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.

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Figure 1: OR7D4 is selectively activated by androstenone and androstadienone.
Figure 2: Functional characterization of OR7D4 polymorphisms.
Figure 3: OR7D4 variation affects androstenone and androstadienone intensity perception.
Figure 4: OR7D4 variation affects androstenone and androstadienone quality perception.

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L.B.V. and A.K. thank E. Gotschlich, B. Coller, A. N. Gilbert, I. Gomez, P. Hempstead and C. Vancil; H.M. and H.Z. thank H. Amrein, M. Cook, M. Kubota, D. Marchuk, R. Molday, D. Tracey and R. Valdivia. This research was supported in part by an NIH Clinical and Translational Science Award to Rockefeller University and by grants to L.B.V. from the Irma T. Hirschl Trust, to H.M. from the NIH, to H.Z. from an NIH National Research Service Award, and to A.K. from a Marco S. Stoffel Fellowship.

Author Contributions H.Z. and H.M. screened for androstenone receptors, identified polymorphisms, performed functional expression of receptor variants, and genotyped the human subjects with assistance from Q.C. A.K. and L.B.V. devised the human olfactory psychophysics study, for which A.K. supervised data collection and analysis.

The sequences of the human OR7D4 variants are deposited in Genbank under accession numbers EU049291–EU049294.

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Correspondence to Leslie B. Vosshall or Hiroaki Matsunami.

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A.K., H.Z., Q.C., L.B.V. and H.M. filed a patent application relevant to this work on 8 May 2007.

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The file contains Supplementary Methods with additional references, Supplementary Figures S1-S10 with Legends and Supplementary Tables S1-S6. (PDF 9302 kb)

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Keller, A., Zhuang, H., Chi, Q. et al. Genetic variation in a human odorant receptor alters odour perception. Nature 449, 468–472 (2007).

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