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The missense of smell: functional variability in the human odorant receptor repertoire

Nature Neuroscience volume 17, pages 114120 (2014) | Download Citation

Abstract

Humans have 400 intact odorant receptors, but each individual has a unique set of genetic variations that lead to variation in olfactory perception. We used a heterologous assay to determine how often genetic polymorphisms in odorant receptors alter receptor function. We identified agonists for 18 odorant receptors and found that 63% of the odorant receptors we examined had polymorphisms that altered in vitro function. On average, two individuals have functional differences at over 30% of their odorant receptor alleles. To show that these in vitro results are relevant to olfactory perception, we verified that variations in OR10G4 genotype explain over 15% of the observed variation in perceived intensity and over 10% of the observed variation in perceived valence for the high-affinity in vitro agonist guaiacol but do not explain phenotype variation for the lower-affinity agonists vanillin and ethyl vanillin.

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Acknowledgements

This work was supported by R01 DC005782, R01 DC012095, R03 DC011373, R01 DC013339, T32 DC000014 and a National Research Service Award postdoctoral fellowship F32 DC008932 to J.D.M. A portion of the work was performed using the Monell Chemosensory Receptor Signaling Core and Genotyping and DNA/RNA Analysis Core, which are supported, in part, by funding from the US National Institutes of Health NIDCD Core Grant P30 DC011735. A portion of the work was supported by the Defense Advanced Research Project Agency RealNose Project. Collection of psychophysical data was supported by grant # UL1 TR000043 from the Clinical and Translational Science Award program at the National Center for Advancing Translational Sciences. The FACS analysis was performed using the Duke Cancer Institute Flow Cytometry Core. We thank D. Marchuk for sharing equipment, L.B. Vosshall for supervising the collection of psychophysical data and DNA samples by A.K. in her laboratory, and R. Molday (University of British Columbia Centre for Macular Research) for 4D2 anti-rhodopsin antibody.

Author information

Author notes

    • Yun R Li
    • , Hanyi Zhuang
    •  & Somin S Lee

    Present addresses: School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA (Y.R.L.), Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China (H.Z.) and Department of Ecology and Evolutionary Biology, Osborn Memorial Labs, Yale University, New Haven, Connecticut, USA (S.S.L.).

Affiliations

  1. Monell Chemical Senses Center, Philadelphia, Pennsylvania, USA.

    • Joel D Mainland
    • , Casey Trimmer
    • , Lindsey L Snyder
    •  & Andrew H Moberly
  2. Department of Molecular Genetics and Microbiology, Duke University Medical Center, Research Drive, Durham North Carolina, USA.

    • Joel D Mainland
    • , Yun R Li
    • , Ting Zhou
    • , Kaylin A Adipietro
    • , Wen Ling L Liu
    • , Hanyi Zhuang
    • , Senmiao Zhan
    • , Somin S Lee
    • , Abigail Lin
    •  & Hiroaki Matsunami
  3. Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

    • Joel D Mainland
    •  & Andrew H Moberly
  4. Laboratory of Neurogenetics and Behavior, The Rockefeller University, New York, New York, USA.

    • Andreas Keller
  5. Department of Neurobiology and Duke Institute for Brain Sciences, Duke University Medical Center, Research Drive, Durham North Carolina, USA.

    • Hiroaki Matsunami

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Contributions

J.D.M. and H.M. conceived and designed the project. J.D.M., C.T., A.H.M., L.L.S., S.Z., W.L.L.L., T.Z., Y.R.L., H.Z., S.S.L., A.L. and K.A.A. performed research. A.K. collected the psychophysical data and provided DNA samples. J.D.M. carried out the analysis and wrote the paper with help from all authors. H.M. supervised the project.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Joel D Mainland.

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DOI

https://doi.org/10.1038/nn.3598

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