The mammalian odorant receptor (OR) repertoire is an attractive model to study evolution, because ORs have been subjected to rapid evolution between species, presumably caused by changes of the ...olfactory system to adapt to the environment. However, functional assessment of ORs in related species remains largely untested. Here we investigated the functional properties of primate and rodent ORs to determine how well evolutionary distance predicts functional characteristics. Using human and mouse ORs with previously identified ligands, we cloned 18 OR orthologs from chimpanzee and rhesus macaque and 17 mouse-rat orthologous pairs that are broadly representative of the OR repertoire. We functionally characterized the in vitro responses of ORs to a wide panel of odors and found similar ligand selectivity but dramatic differences in response magnitude. 87% of human-primate orthologs and 94% of mouse-rat orthologs showed differences in receptor potency (EC50) and/or efficacy (dynamic range) to an individual ligand. Notably dN/dS ratio, an indication of selective pressure during evolution, does not predict functional similarities between orthologs. Additionally, we found that orthologs responded to a common ligand 82% of the time, while human OR paralogs of the same subfamily responded to the common ligand only 33% of the time. Our results suggest that, while OR orthologs tend to show conserved ligand selectivity, their potency and/or efficacy dynamically change during evolution, even in closely related species. These functional changes in orthologs provide a platform for examining how the evolution of ORs can meet species-specific demands.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In color vision, the quantitative rules for mixing lights to make a target color are well understood. By contrast, the rules for mixing odorants to make a target odor remain elusive. A solution to ...this problem in vision relied on characterizing receptor responses to different wavelengths of light and subsequently relating these responses to perception. In olfaction, experimentally measuring receptor responses to a representative set of complex mixtures is intractable due to the vast number of possibilities. To meet this challenge, we develop a biophysical model that predicts mammalian receptor responses to complex mixtures using responses to single odorants. The dominant nonlinearity in our model is competitive binding (CB): Only one odorant molecule can attach to a receptor binding site at a time. This simple framework predicts receptor responses to mixtures of up to 12 monomolecular odorants to within 15% of experimental observations and provides a powerful method for leveraging limited experimental data. Simple extensions of our model describe phenomena such as synergy, overshadowing, and inhibition. We demonstrate that the presence of such interactions can be identified via systematic deviations from the competitive-binding model.
The olfactory system combines input from multiple receptor types to represent odor information, but there are few explicit examples relating olfactory receptor (OR) activity patterns to odor ...perception. To uncover these relationships, we performed genome-wide scans on odor-perception phenotypes for ten odors in 1000 Han Chinese and validated results for six of these odors in an ethnically diverse population (n = 364). In both populations, consistent with previous studies, we replicated three previously reported associations (β-ionone/OR5A1, androstenone/OR7D4, cis-3-hexen-1-ol/OR2J3 LD-band), but not for odors containing aldehydes, suggesting that olfactory phenotype/genotype studies are robust across populations. Two novel associations between an OR and odor perception contribute to our understanding of olfactory coding. First, we found a SNP in OR51B2 that associated with trans-3-methyl-2-hexenoic acid, a key component of human underarm odor. Second, we found two linked SNPs associated with the musk Galaxolide in a novel musk receptor, OR4D6, which is also the first human OR shown to drive specific anosmia to a musk compound. We noticed that SNPs detected for odor intensity were enriched with amino acid substitutions, implying functional changes of odor receptors. Furthermore, we also found that the derived alleles of the SNPs tend to be associated with reduced odor intensity, supporting the hypothesis that the primate olfactory gene repertoire has degenerated over time. This study provides information about coding for human body odor, and gives us insight into broader mechanisms of olfactory coding, such as how differential OR activation can converge on a similar percept.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Deciphering olfactory encoding requires a thorough description of the ligands that activate each odorant receptor (OR). In mammalian systems, however, ligands are known for fewer than 50 of more than ...1400 human and mouse ORs, greatly limiting our understanding of olfactory coding. We performed high-throughput screening of 93 odorants against 464 ORs expressed in heterologous cells and identified agonists for 52 mouse and 10 human ORs. We used the resulting interaction profiles to develop a predictive model relating physicochemical odorant properties, OR sequences, and their interactions. Our results provide a basis for translating odorants into receptor neuron responses and for unraveling mammalian odor coding.
Abstract
Among those many individuals who experience a reduced odor sensitivity (hyposmia/anosmia), some individuals also have disorders that lead to odor distortion, such as parosmia (i.e. distorted ...odor with a known source), or odor phantoms (i.e. odor sensation without an odor source). We surveyed a large population with at least one olfactory disorder (N = 2031) and found that odor distortions were common (46%), with respondents reporting either parosmia (19%), phantosmia (11%), or both (16%). In comparison to respondents with hyposmia or anosmia, respondents with parosmia were more likely to be female, young, and suffering from post-viral olfactory loss (P < 0.001), while respondents with phantosmia were more likely to be middle-aged (P < 0.01) and experiencing symptoms caused by head trauma (P < 0.01). In addition, parosmia, compared to phantosmia or anosmia/hyposmia, was most prevalent 3 months to a year after olfactory symptom onset (P < 0.001), which coincides with the timeline of physiological recovery. Finally, we observed that the frequency and duration of distortions negatively affects the quality of life, with parosmia showing a higher range of severity than phantosmia (P < 0.001). Previous research often grouped these distortions together, but our results show that they have distinct patterns of demographics, medical history, and loss in quality of life.
It is still not possible to predict whether a given molecule will have a perceived odor or what olfactory percept it will produce. We therefore organized the crowd-sourced DREAM Olfaction Prediction ...Challenge. Using a large olfactory psychophysical data set, teams developed machine-learning algorithms to predict sensory attributes of molecules based on their chemoinformatic features. The resulting models accurately predicted odor intensity and pleasantness and also successfully predicted 8 among 19 rated semantic descriptors (“garlic,” “fish,” “sweet,” “fruit,” “burnt,” “spices,” “flower,” and “sour”). Regularized linear models performed nearly as well as random forest–based ones, with a predictive accuracy that closely approaches a key theoretical limit. These models help to predict the perceptual qualities of virtually any molecule with high accuracy and also reverse-engineer the smell of a molecule.
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.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Anosmia-A Clinical Review Boesveldt, Sanne; Postma, Elbrich M; Boak, Duncan ...
Chemical senses,
09/2017, Letnik:
42, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Anosmia and hyposmia, the inability or decreased ability to smell, is estimated to afflict 3-20% of the population. Risk of olfactory dysfunction increases with old age and may also result from ...chronic sinonasal diseases, severe head trauma, and upper respiratory infections, or neurodegenerative diseases. These disorders impair the ability to sense warning odors in foods and the environment, as well as hinder the quality of life related to social interactions, eating, and feelings of well-being. This article reports and extends on a clinical update commencing at the 2016 Association for Chemoreception Sciences annual meeting. Included were reports from: a patient perspective on losing the sense of smell with information on Fifth Sense, a nonprofit advocacy organization for patients with olfactory disorders; an otolaryngologist's review of clinical evaluation, diagnosis, and management/treatment of anosmia; and researchers' review of recent advances in potential anosmia treatments from fundamental science, in animal, cellular, or genetic models. As limited evidence-based treatments exist for anosmia, dissemination of information on anosmia-related health risks is needed. This could include feasible and useful screening measures for olfactory dysfunction, appropriate clinical evaluation, and patient counseling to avoid harm as well as manage health and quality of life with anosmia.
Olfactory systems have evolved the extraordinary capability to detect and discriminate volatile odorous molecules (odorants) in the environment. Fundamentally, this process relies on the interaction ...of odorants and their cognate olfactory receptors (ORs) encoded in the genome. Here, we conducted a cell-based screen using over 800 mouse ORs against seven odorants, resulting in the identification of a set of high-affinity and/or broadly-tuned ORs. We then test whether heterologously expressed ORs respond to odors presented in vapor phase by individually expressing 31 ORs to measure cAMP responses against vapor phase odor stimulation. Comparison of response profiles demonstrates this platform is capable of discriminating between structural analogs. Lastly, co-expression of carboxyl esterase Ces1d expressed in olfactory mucosa resulted in marked changes in activation of specific odorant-OR combinations. Altogether, these results establish a cell-based volatile odor detection and discrimination platform and form the basis for an OR-based volatile odor sensor.
Highlights • Olfaction lacks a working model of odor-intensity coding. • Neural correlates of varying odor concentration lead to simplistic models. • New models are needed that predict intensity ...across odors, in mixtures, and after adaptation.
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