Content area
Full Text
A R T I C L E S
The missense of smell: functional variability in the human odorant receptor repertoire
Joel D Mainland13, Andreas Keller4, Yun R Li2,6, Ting Zhou2, Casey Trimmer1, Lindsey L Snyder1,
Andrew H Moberly1,3, Kaylin A Adipietro2, Wen Ling L Liu2, Hanyi Zhuang2,6, Senmiao Zhan2, Somin S Lee2,6, Abigail Lin2 & Hiroaki Matsunami2,5
Humans have ~400 intact odorant receptors, but each individual has a unique set of genetic variations that lead to variationin 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.
npg 201 4 Nature America, Inc. All rights reserved.
The human genome contains ~800 odorant receptor genes that have been shown to exhibit high genetic variability13. In addition, humans exhibit considerable variation in the perception of odorants4,5, and
variation in an odorant receptor predicts perception in four cases: loss of function in OR11H7P, OR2J3, OR5A1 and OR7D4 leads to elevated detection thresholds for the respective agonists isovaleric acid6, cis-3-hexen-1-ol7, -ionone8 and androstenone9. These results suggest that although the olfactory system uses a combinatorial code in which responses of multiple receptor types lead to recognition of a given odorant, the response of a single receptor can have a large influence on the perception of an odorant.
Understanding the role of a single receptor requires functional data for receptor-odorant pairs. Matching mammalian odorant receptors to ligands has seen limited success, and the picture is even worse when considering human odorant receptors; ligands have been published for only 22 of the ~400 intact human odorant receptors6,817. This
lack of data is a critical bottleneck in the field; matching ligands to odorant receptors is...