Genetic variation in a human odorant receptor alters odour perception (original) (raw)
- Letter
- Published: 16 September 2007
Nature volume 449, pages 468–472 (2007)Cite this article
- 9880 Accesses
- 467 Citations
- 144 Altmetric
- Metrics details
Abstract
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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Additional access options:
Similar content being viewed by others
References
- Wysocki, C. J. & Beauchamp, G. K. Ability to smell androstenone is genetically determined. Proc. Natl Acad. Sci. USA 81, 4899–4902 (1984)
Article ADS CAS Google Scholar - Gower, D. B., Nixon, A. & Mallet, A. I. in Perfumery (eds Van Toller, S. & Dodd, G. H.) 47–75 (Chapman & Hall, London, 1998)
Google Scholar - Bremner, E. A., Mainland, J. D., Khan, R. M. & Sobel, N. The prevalence of androstenone anosmia. Chem. Senses 28, 423–432 (2003)
Article CAS Google Scholar - Guillot, M. Physiologie des sensations—anosmies partielles et odeurs fondamentales. C.R. Hebd. Acad. Sci. 226, 1307–1309 (1948)
Google Scholar - Gilbert, A. N. & Kemp, S. E. Odor perception phenotypes: multiple, specific hyperosmias to musks. Chem. Senses 21, 411–416 (1996)
Article CAS Google Scholar - Whissell-Buechy, D. & Amoore, J. E. Odour-blindness to musk: simple recessive inheritance. Nature 242, 271–273 (1973)
Article ADS CAS Google Scholar - Menashe, I., Man, O., Lancet, D. & Gilad, Y. Different noses for different people. Nature Genet. 34, 143–144 (2003)
Article CAS Google Scholar - Gilad, Y. & Lancet, D. Population differences in the human functional olfactory repertoire. Mol. Biol. Evol. 20, 307–314 (2003)
Article CAS Google Scholar - Saito, H., Kubota, M., Roberts, R. W., Chi, Q. & Matsunami, H. RTP family members induce functional expression of mammalian odorant receptors. Cell 119, 679–691 (2004)
Article CAS Google Scholar - Keller, A. & Vosshall, L. B. Human olfactory psychophysics. Curr. Biol. 14, R875–R878 (2004)
Article CAS Google Scholar - Stevens, D. A. & O’Connell, R. J. Enhanced sensitivity to androstenone following regular exposure to pemenone. Chem. Senses 20, 413–419 (1995)
Article CAS Google Scholar - Zhuang, H. & Matsunami, H. Synergism of accessory factors in functional expression of mammalian odorant receptors. J. Biol. Chem. 282, 15284–15293 (2007)
Article CAS Google Scholar - Zhang, X. et al. Characterizing the expression of the human olfactory receptor gene family using a novel DNA microarray. Genome Biol. 8, R86 (2007)
Article Google Scholar - Doty, R. L., McKeown, D. A., Lee, W. W. & Shaman, P. A study of the test–retest reliability of ten olfactory tests. Chem. Senses 20, 645–656 (1995)
Article CAS Google Scholar - Doty, R. L. & Laing, D. G. in Handbook of Olfaction and Gustation (ed. Doty, R. L.) 203–228 (Marcel Dekker, New York, 2003)
Book Google Scholar - Dravnieks, A. Odor quality: semantically generated multidimensional profiles are stable. Science 218, 799–801 (1982)
Article ADS CAS Google Scholar - Cleveland, W. S. Robust locally weighted regression and smoothing scatterplots. J. Am. Stat. Assoc. 74, 829–836 (1979)
Article MathSciNet Google Scholar - Malnic, B., Hirono, J., Sato, T. & Buck, L. B. Combinatorial receptor codes for odors. Cell 96, 713–723 (1999)
Article CAS Google Scholar - Wysocki, C. J., Dorries, K. M. & Beauchamp, G. K. Ability to perceive androstenone can be acquired by ostensibly anosmic people. Proc. Natl Acad. Sci. USA 86, 7976–7978 (1989)
Article ADS CAS Google Scholar - Dorries, K. M., Schmidt, H. J., Beauchamp, G. K. & Wysocki, C. J. Changes in sensitivity to the odor of androstenone during adolescence. Dev. Psychobiol. 22, 423–435 (1989)
Article CAS Google Scholar - Dalton, P., Doolittle, N. & Breslin, P. A. Gender-specific induction of enhanced sensitivity to odors. Nature Neurosci. 5, 199–200 (2002)
Article CAS Google Scholar - Mainland, J. D. et al. One nostril knows what the other learns. Nature 419, 802 (2002)
Article ADS CAS Google Scholar - Wang, L., Chen, L. & Jacob, T. Evidence for peripheral plasticity in human odour response. J. Physiol. (Lond.) 554, 236–244 (2004)
Article CAS Google Scholar - Jacob, S., Kinnunen, L. H., Metz, J., Cooper, M. & McClintock, M. K. Sustained human chemosignal unconsciously alters brain function. Neuroreport 12, 2391–2394 (2001)
Article CAS Google Scholar - Wyart, C. et al. Smelling a single component of male sweat alters levels of cortisol in women. J. Neurosci. 27, 1261–1265 (2007)
Article CAS Google Scholar - Krautwurst, D., Yau, K. W. & Reed, R. R. Identification of ligands for olfactory receptors by functional expression of a receptor library. Cell 95, 917–926 (1998)
Article CAS Google Scholar - Laird, D. W. & Molday, R. S. Evidence against the role of rhodopsin in rod outer segment binding to RPE cells. Invest. Ophthalmol. Vis. Sci. 29, 419–428 (1988)
CAS PubMed Google Scholar - Keller, A. & Vosshall, L. B. A psychophysical test of the vibration theory of olfaction. Nature Neurosci. 7, 337–338 (2004)
Article CAS Google Scholar
Acknowledgements
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.
Author information
Author notes
- Andreas Keller and Hanyi Zhuang: These authors contributed equally to this work.
Authors and Affiliations
- Laboratory of Neurogenetics and Behaviour, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA,
Andreas Keller & Leslie B. Vosshall - Department of Molecular Genetics and Microbiology, and,
Hanyi Zhuang, Qiuyi Chi & Hiroaki Matsunami - Department of Neurobiology, Duke University Medical Centre, Research Drive, Durham, North Carolina 27710, USA,
Hiroaki Matsunami
Authors
- Andreas Keller
You can also search for this author inPubMed Google Scholar - Hanyi Zhuang
You can also search for this author inPubMed Google Scholar - Qiuyi Chi
You can also search for this author inPubMed Google Scholar - Leslie B. Vosshall
You can also search for this author inPubMed Google Scholar - Hiroaki Matsunami
You can also search for this author inPubMed Google Scholar
Corresponding authors
Correspondence toLeslie B. Vosshall or Hiroaki Matsunami.
Ethics declarations
Competing interests
A.K., H.Z., Q.C., L.B.V. and H.M. filed a patent application relevant to this work on 8 May 2007.
Supplementary information
Supplementary Information
The file contains Supplementary Methods with additional references, Supplementary Figures S1-S10 with Legends and Supplementary Tables S1-S6. (PDF 9302 kb)
Rights and permissions
About this article
Cite this article
Keller, A., Zhuang, H., Chi, Q. et al. Genetic variation in a human odorant receptor alters odour perception.Nature 449, 468–472 (2007). https://doi.org/10.1038/nature06162
- Received: 20 June 2007
- Accepted: 08 August 2007
- Published: 16 September 2007
- Issue Date: 27 September 2007
- DOI: https://doi.org/10.1038/nature06162
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.
Editorial Summary
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.