The Missense of Smell : Functional Variability in the Human Odorant 1 Receptor Repertoire

26 2 Humans have approximately 400 intact odorant receptors, but each individual 27 has a unique set of genetic variations that lead to variation in olfactory perception. 28 We used a heterologous assay to determine how often genetic polymorphisms in 29 odorant receptors alter receptor function. We identified agonists for 18 odorant 30 receptors and found that 63% of the odorant receptors we examined had 31 polymorphisms that altered in vitro function. On average, two individuals differ 32 functionally at over 30% of their odorant receptor alleles. To show that these in 33 vitro results are relevant to olfactory perception, we verified that variations in 34 OR10G4 genotype explain over 15% of the observed variation in perceived 35 intensity and over 10% of the observed variation in perceived valence for the high 36 affinity in vitro agonist guaiacol, but do not explain phenotypic variation for the 37 lower affinity agonists vanillin and ethyl vanillin. 38 3 The human genome contains approximately 800 odorant receptor genes that have been 39 shown to exhibit high genetic variability 1-3. In addition, humans exhibit considerable 40 variation in the perception of odorants 4, 5 and variation in an odorant receptor predicts 41 perception in four cases: loss of function in OR11H7P, OR2J3, OR5A1, and OR7D4 42 leads to elevated detection thresholds for the respective agonists isovaleric acid 6 , cis-3-43 hexen-1-ol 7 , -ionone 8 , and androstenone 9. These results suggest that although the 44 olfactory system uses a combinatorial code where multiple receptors encode a given 45 odorant, a single receptor can have a large influence on the perception of an odorant. 46 Understanding the role of a single receptor requires functional data for 47 receptor/odorant pairs. Matching mammalian odorant receptors to ligands has seen 48 limited success, and the picture is even worse when considering human odorant 49 receptors; ligands have been published for only 22 of the approximately 400 intact 50 human odorant receptors 6, 8-17. This lack of data is a critical bottleneck in the field; 51 matching ligands to odorant receptors is essential for understanding the olfactory system 52 at all levels and is building viable models of olfaction. 53 Using a high-throughput system for functional testing of odorant receptors 18 , we can 54 now elucidate the role of missense single nucleotide polymorphisms in odorant receptor 55 function. Here we identify ligands for several orphan odorant receptors, …