Humans use a family of more than 400 olfactory receptors (ORs) to detect odors, but there is currently no model that can predict olfactory perception from receptor activity patterns. Genetic variation in human ORs is abundant and alters receptor function, allowing us to examine the relationship between receptor function and perception. We sequenced the OR repertoire in 332 individuals and examined how genetic variation affected 276 olfactory phenotypes, including the perceived intensity and pleasantness of 68 odorants at two concentrations, detection thresholds of three odorants, and general olfactory acuity. Genetic variation in a single OR was frequently associated with changes in odorant perception, and we validated 10 cases in which in vitro OR function correlated with in vivo odorant perception using a functional assay. In 8 of these 10 cases, reduced receptor function was associated with reduced intensity perception. In addition, we used participant genotypes to quantify genetic ancestry and found that, in combination with single OR genotype, age, and gender, we can explain between 10% and 20% of the perceptual variation in 15 olfactory phenotypes, highlighting the importance of single OR genotype, ancestry, and demographic factors in the variation of olfactory perception. olfaction | genetic variation | human genome | odor intensity | ancestry U nderstanding how the olfactory system detects odorants and translates their features into perceptual information is one of the fundamental questions in olfaction. Although early color vision researchers were unable to directly observe receptor responses, perceptual deficits caused by genetic variation (i.e., color blindness) helped show that color vision is mediated by three receptors responding to different wavelengths of light (1, 2). Guillot (3), and then Amoore (4), extended this idea to olfaction and proposed that cataloging specific anosmias (the inability to perceive a particular odorant) may provide similar clues linking genes and perception. Early applications of this idea failed, presumably because olfaction relies on hundreds of receptors, and without direct observation of their responses, psychophysical tests could not untangle the fundamental rules of odor coding. However, with the advent of next-generation genome sequencing to profile olfactory receptor (OR) genes and cell-based assays to identify ligands for ORs, receptor variation can now be matched to individuals and receptor responses can be directly observed.Humans have approximately 400 OR genes that are intact in at least part of the population, but individuals have different repertoires of pseudogenes, copy number variations, and single nucleotide polymorphisms (SNPs) that can alter receptor responses (5-7). While nonfunctional genes are rare in the genome (on average approximately 100 heterozygous and 20 homozygous pseudogenes in an individual), they are significantly enriched in OR genes (8). This provides a useful set of "natural knockouts" to examine the role of a single OR in olfactory pe...

Mammalian odorant receptors are a diverse and rapidly evolving set of G protein-coupled receptors expressed in olfactory cilia membranes. Most odorant receptors show little to no cell surface expression in nonolfactory cells due to endoplasmic reticulum retention, which has slowed down biochemical studies. Here we provide evidence that structural instability and divergence from conserved residues of individual odorant receptors underlie intracellular retention using a combination of large-scale screening of odorant receptors cell surface expression in heterologous cells, point mutations, structural modeling, and machine learning techniques. We demonstrate the importance of conserved residues by synthesizing consensus odorant receptors that show high levels of cell surface expression similar to conventional G protein-coupled receptors. Furthermore, we associate in silico structural instability with poor cell surface expression using molecular dynamics simulations. We propose an enhanced evolutionary capacitance of olfactory sensory neurons that enable the functional expression of odorant receptors with cryptic mutations.