The mammalian olfactory system displays species-specific adaptations to different ecological niches. To investigate the evolutionary dynamics of olfactory sensory neuron (OSN) subtypes across mammalian evolution, we applied RNA sequencing of whole olfactory mucosa samples from mouse, rat, dog, marmoset, macaque, and human. We find that OSN subtypes, representative of all known mouse chemosensory receptor gene families, are present in all analyzed species. Further, we show that OSN subtypes expressing canonical olfactory receptors are distributed across a large dynamic range and that homologous subtypes can be either highly abundant across all species or species/order specific. Highly abundant mouse and human OSN subtypes detect odorants with similar sensory profiles and sense ecologically relevant odorants, such as mouse semiochemicals or human key food odorants. Together, our results allow for a better understanding of the evolution of mammalian olfaction in mammals and provide insights into the possible functions of highly abundant OSN subtypes.

25The mammalian olfactory system displays species-specific adaptations to different ecological 26 niches. To investigate the evolutionary dynamics of olfactory sensory neuron (OSN) sub-types 27 across 95 million years of mammalian evolution, we applied RNA-sequencing of whole olfactory 28 mucosa samples from mouse, rat, dog, marmoset, macaque and human. We find that OSN 29 subtypes representative of all known mouse chemosensory receptor gene families are present 30 in all analyzed species. Further, we show that OSN subtypes expressing canonical olfactory 31 receptors (ORs) are distributed across a large dynamic range and that homologous subtypes 32 can be either highly abundant across all species or species/order-specific. Interestingly, highly 33 abundant mouse and human OSN subtypes detect odorants with similar sensory profiles, and 34 sense ecologically relevant odorants, such as mouse semiochemicals or human key food 35 odorants. Taken together, our results allow for a better understanding of the evolution of 36 mammalian olfaction in mammals and provide insights into the possible functions of highly 37 abundant OSN subtypes in mouse and human. 38 39 3 MAIN TEXT 40

Significance What makes a molecule have a smell? This simple question represents a significant gap in our understanding of olfaction. To answer it, we trained models to predict whether molecules were odorous based on molecular characteristics and noted which characteristics were needed to make correct predictions. We found that molecules with sufficient volatility and hydrophobicity are generally odorous, which suggests that reaching olfactory receptors is the dominant barrier for prospective olfactory stimuli. Based on these criteria, there are billions of molecules that are likely odorous but have never been smelled. We can now recognize an odorous molecule from its structure, and this guides us to discover new classes of odorants and include all types of odorants in our study of smell.

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Highlights d We produced a novel atlas of mouse odor-guided behavior for 73 molecules d Odorant structure and mouse behavior are mutually predictive in novel mice d Odor valence explains most behavioral variance and covariance with human perception d Concentration qualitatively and quantitatively impacts mouse olfactory behavior