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Of more than 1,000 human olfactory receptor genes, more than half seem to be pseudogenes. We investigated whether the most recent of these disruptions might still segregate with the intact form by genotyping 51 candidate genes in 189 ethnically diverse humans. The results show an unprecedented prevalence of segregating pseudogenes, identifying one of the most pronounced cases of functional population diversity in the human genome.
Department of Molecular Genetics and the Crown Human Genome Center, The Weizmann Institute of Science, Rehovot 76100, Israel. Correspondence should be
addressed to D.L. (
JUNE 2003 143
Different noses for different people
Idan Menashe, Orna Man, Doron Lancet & Yoav Gilad
Of more than 1,000 human olfactory receptor genes, more than
half seem to be pseudogenes. We investigated whether the most
recent of these disruptions might still segregate with the intact
form by genotyping 51 candidate genes in 189 ethnically diverse
humans. The results show an unprecedented prevalence of
segregating pseudogenes, identifying one of the most pronounced
cases of functional population diversity in the human genome.
The olfactory receptor repertoire is the largest gene superfamily in
mammals, including 1,000–1,400 coding regions distributed in clus-
ters over most chromosomes
. In the mouse, olfactory receptor
pseudogenes comprise 20% of the gene range;
in humans, a fraction roughly three times
larger seems to be inactivated
. This extreme
diminution of the functional olfactory recep-
tor repertoire is a relatively recent genomic
and is probably ongoing. Accordingly,
we conjectured that a substantial fraction of
the human olfactory receptors might segregate
between an intact and pseudogene form.
Indeed, isolated cases of olfactory segregating
pseudogenes have been reported
. Yet, these
could underlie only a small part of the
reported widespread phenotype variation
We therefore launched a whole-genome search
for single-nucleotide polymorphisms (SNPs)
that exchange between the intact and pseudo-
genic forms in olfactory receptor loci.
We used two strategies to screen for such polymorphisms. First,
we focused on olfactory receptor pseudogenes that have only one
open reading frame disruption
. We sequenced 50 of these in a
chimpanzee, owing to the notion that if the pseudogene state is not
shared between the two higher apes, it may be recent and thus have
a better chance of generating a human polymorphism. This identi-
fied 33 olfactory receptor loci for further scrutiny. Second, we
searched the Celera human SNP database for variations with poten-
tial to affect protein integrity. In this realm, we included 9 cases of
in-frame stop codons and 9 cases in which a SNP represented a mis-
sense change in a highly conserved amino acid and, hence, was
probably functionally important
We genotyped the total of 51 olfactory receptor loci in 189 indi-
viduals from several ethnic origins. We confirmed that 26 of these
loci segregate in our sample, either between the disrupted and intact
Figure 1 The observed individual olfactory receptor
genotypes in African American (a) and non-African
(b) individuals. Red indicates homozygous
olfactory receptor disruption; dark green denotes
homozygously intact olfactory receptor; light green
represents heterozygotes. Individuals (rows) and
olfactory receptor loci (columns) are ordered
according to their disruption level. Disruption type
is indicated above: N, nonsense mutation; D,
deletion or insertion; S, missense substitution
at a highly conserved site. The 178 putative
phenotypes seen in the 189 individuals based
on recessive inheritance are in accordance with
a computed expectation value assuming
Hardy–Weinberg equilibrium and based on
the allele frequencies present.
© 2003 Nature Publishing Group
144 VOLUME 34
alleles (18 loci) or between the conserved and modified forms (8 loci;
Fig. 1). Consequently, each of the individuals examined had a unique
genotypic pattern. The resulting phenotypic effect may be evaluated
on the basis of the suggestion that olfactory dysfunction is a recessive
. We observed great diversity: 178 different functional
genomes among the 189 individuals studied. Such a high level of
documented interindividual variability in a gene family is unprece-
dented, except in the case of the major histocompatibility complex.
The latter includes the most polymorphic loci in humans; two of the
primary genes, HLA-B and HLA-DRB1, have 200 allelic variants
each, and every individual carries a unique haplotype signature
. In
the case of olfactory receptor genes, each locus is only biallelic, but
the number of functionally variable loci is much larger.
Notably, non-African individuals had significantly fewer functional
olfactory receptors than did African American individuals (Fig. 2).
This result substantiates our previous reports
suggesting that dif-
ferent evolutionary pressures may have shaped the chemosensory
repertoire in different human populations.
We extrapolated the number of segregating olfactory receptor
pseudogenes in the entire human genome to be at least 60, of which
48 are expected to have a minor allele frequency above 1%
(Supplementary Note and Supplementary Table 1 online). These
numbers are in rough agreement with the reported count of different
modes of specific anosmias, human odorant-specific sensory
. Thus, the genotypic disparity that we observed might
underlie at least some of the reported human phenotypic variation.
Future association studies will help substantiate the detailed relation-
ships between individual olfactory receptor disruptions and defined
cases of odorant-specific olfactory threshold variability.
Most genotype–phenotype association studies are based either on
rare gene disruptions (that is, mutations underlying monogenic
traits) or on combinations of frequent variants involving missense
rather than nonsense DNA alterations. The widespread occurrence of
segregating olfactory pseudogenes that we report is rather unusual,
and only a few analogous cases have been described
It is interesting to ask whether this functional polymorphism is
unique to olfactory receptors, stemming from their gene superfam-
ily undergoing a recent rapid decline in the number of functional
. An intriguing alternative is that this phenomenon is more
widespread and affects other gene families with high expansion rate
and low selective pressure due to partial functional redundancy. A
potential target for a relevant genome-wide search could be the
20,000 pseudogenes estimated to be present in the human
. Although many of these are processed pseudogenes or
may never have been functional, it is possible that an appreciable
number of pseudogenes, which have arisen by recent mutations,
will eventually be shown to constitute segregating null alleles.
These would comprise a hitherto unexplored domain of human
genotypic heterogeneity.
Note: Supplementary information is available on the Nature Genetics website.
We thank M. Przeworski for helpful discussions. D.L. holds the Ralph and Lois
Silver Chair in Human Genomics. This work was supported by the Crown Human
Genome Center at the Weizmann Institute of Science and by an Israel Ministry of
Science grant to the National Laboratory for Genome Infrastructure.
The authors declare that they have no competing financial interests.
Received 15 January; accepted 28 March 2003
Published online 5 May 2003; doi:10.1038/ng1160
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16 17 18 19 20 21 22 23 24
Number of intact ORs
Figure 2 Phenotype distribution for different ethnic groups. The population
frequency of the counts of deduced functional loci in African American (light
bars) and non-African (dark bars) individuals. Olfactory receptor loci were
considered intact if the individual carried at least one copy of the intact
allele. The broken line curves are Gaussian fits with µ = 20.06 and σ = 1.73
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© 2003 Nature Publishing Group
... Of course, in order for phenotypic differences to be explained by genetics, there has to be sufficient genetic variation in the system. The olfactory receptors in the olfactory system display an unusually high level of genetic diversity (Menashe, Man, Lancet, & Gilad, 2003;Olender et al., 2012), with an estimated 2.5 times higher rate of variants per base pair than any average coding exon (Olender et al., 2012). Further, this genetic variability may be responsible for significant phenotypic differences between people, as about 1/3 of OR alleles are predicted to be functionally different between any two people (Mainland et al., 2013). ...
... Perception of specific odors also varies by individual, classified by three main categories: 1) anosmia -the inability to smell an odor, 2) hyposmia -decreased sensitivity to an odor, 3) hyperosmia -increased sensitivity to an odor. A large body of literature confirms abundant variation in single odorant perception resulting in changes in many phenotypes, such as odor detection threshold, pleasantness or intensity rating, and odor character (John E. Amoore, 1977; John E. Amoore & Forrester, 1976;Blakeslee, 1918;Bremner et al., 2003;Gilbert & Kemp, 1996;Hasin-Brumshtein et al., 2009;Keller & Vosshall, 2004, 2016Keller, Zhuang, Chi, Vosshall, & Matsunami, 2007;Menashe et al., 2003;Whissell-Buechy & Amoore, 1973;Charles J. Wysocki & Gilbert, 1989). ...
... In the search for genetic explanations of phenotypic diversity, association studies require sufficient genetic variability. Olfactory receptors (ORs) comprise one of the largest mammalian gene superfamilies (Glusman et al., 2001;Menashe et al., 2003;Olender et al., 2012). While there are estimated to be ~400 functioning ORs in humans, the whole gene family comprises around 851 genes, where approximately 50% are pseudogenes, or genes annotated as nonfunctional (Olender et al., 2012). ...
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... Másfelől ma már több közlemény adatai mentén is kirajzolódik, hogy nemcsak a fajok között van nagy különbség az ún. OR-gének számában (illatérzékelésért felelős gének), de a receptorok orrüregbeni mintázata értelmében fajokon belül is meghatározó különbségek lehetnek (Olender et al. 2004) (Menashe et al. 2003). Ez azt jelenti, hogy a földrajzi és népcsoportok közötti genetikai távolságok arányában valószínűsíthető egy alapvető íz-és illatérzékelésbeni különbség. ...
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The COVID-19 pandemic caused by SARS-CoV-2 virus quickly spread globally, infecting over half a billion individuals, and killing over 6 million*. One of the more unusual symptoms was patients' complaints of sudden loss of smell and/or taste, a symptom that has become more apparent as the virus mutated into different variants. Anosmia and ageusia, the loss of smell and taste, respectively, seem to be transient for some individuals, but for others persists even after recovery from the infection. Causes for COVID-19-associated chemosensory loss have undergone several hypotheses. These include non-functional or destroyed olfactory neurons and gustatory receptors or of their supporting cells, disruption of the signaling protein Neuropilin-1, and disruption in the interaction with semaphorins, key molecules in the gustatory and olfactory axon guidance. The current paper will review these hypotheses and chart out potential therapeutic avenues.
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Qualitative assessment refers to conditions where wines are assessed primarily on the characteristics typically associated with a wine’s provenance, or stylistic or varietal attributes. Although wine competitions imply objectivity, the results suggest otherwise. In addition, one of the principal goals of commercial tasting is to promote sales and media exposure. Thus, the semblance of objectivity is adequate. Although seeming a damning indictment, human perception is so idiosyncratic, almost no two consumer preferences will be identical. Ranking and wine descriptions tell more about the preferences of the provider(s) than the wine. Acknowledging this situation should free consumers to select wines on personal criteria, unfettered by the opinions of others. What wine courses and societies have the potential to do is permit members to gain experience with a wide range of wines, finding their own preferences and confidence to assess on their own. Where desired, the experience gained could be used to develop memory models for the characteristics of the varieties, styles of wine preferred. For those who love wine, focused attention on a wine’s sensory pleasures can enhance one’s quality of life.
Recent studies of olfaction have highlighted the gap that separates physicochemical sensation and perception. Perception is a combination of models of reality, based on long experience, and sensory input. Such models typically incorporate visual, gustatory, and somatosensory (trigeminal) inputs. Once these patterns has been established, they can skew sensory input to conform to expectations. Thus, although it is desirable for consumers, and necessary for wine assessors, to develop prototypic sensory memories of particular wine types and age effects, it is critical that tasters guard against these constructs from warping what is actually being detected. One of the most intriguing aspects of olfaction is both its malleability (being strongly influence by extrinsic factors, notably the context under which the wine is sampled), but also the strong influence of experience-based percepts. Olfactory attributes are alternatively described in “concrete” terms (descriptors such as fruity or floral) or assessed using holistic (artistic) terms. Attempting to correlate these expressions with the chemical nature of a wine is fraught with multiple difficulties, both technical and perceptive, and may never be resolved. Nonetheless, one of the principal goals of sensory analysis is to make such correlations. Without it, aiding grape growers and winemakers to understand the basis of consumer likes, and how to adjust vineyard and winery procedures to produce wines that will be appreciated will remain severely restricted.
Background Our previous bivariate genome-wide association study in dizygotic twins suggested that the olfactory transduction pathway genes were associated with obesity in Northern Han Chinese adults. In this study, we attempted to verify the associations of the olfactory transduction pathway genes score with obesity in population with the same genetic background, and to estimate the interaction between gene variants and potential environment factors. Methods A case-control study was conducted in Qingdao, China in 2019-2021, which enrolled 301 obesity cases and 307 controls. Based on the candidate gene selection method, 29 single nucleotide polymorphisms (SNPs) in 7 olfactory pathway genes were selected. Genomic deoxyribonucleic acid (DNA) was isolated and purified from the peripheral blood leukocytes by using DNA extraction kits and was genotyped by the MassArray system. The weighted genetic score of each gene was calculated to analyze the effect of whole gene. The effect of gene scores on obesity and the gene-environment interaction were estimated by logistic regression. Results After adjusting for age, sex, smoking, alcohol drinking, physical activity, we observed positive associations of OR4D1 (OR = 1.531, 95% CI = 1.083-2.164, P = 0.016) and OR52K1 (OR = 1.437, 95% CI = 1.055-1.957, P = 0.022) gene scores with obesity, as well as negative associations of OR2L8 (OR = 0.708, 95% CI = 0.504-0.995, P = 0.046) and CALML3 (OR = 0.601, 95% CI = 0.410-0.881, P = 0.009) gene scores with obesity. Significant multiplicative model interaction between OR4D1 and smoking (Pinteraction = 0.041) as well as CALML3 and smoking (Pinteraction = 0.026) on obesity were identified. Stratified analysis showed that in smokers, OR4D1 gene score was positively associated with obesity (OR = 2.673, 95% CI = 1.348-5.299, P = 0.005) and CALML3 gene score was negatively correlated with obesity (OR = 0.252, 95% CI = 0.103-0.618, P = 0.003). The relationships were not statistically significant in non-smokers (OR4D1: OR= 1.216, 95% CI = 0.806-1.836, P = 0.351; CALML3: OR = 0.764, 95% CI = 0.492-1.188, P = 0.232). Conclusions Genetic variations in the olfactory pathway were associated with obesity in Northern Han Chinese adults. Smoking modified the effect of OR4D1 and CALML3 gene variants on obesity.
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Some adult humans cannot detect the odor of androstenone (5 alpha-androst-16-en-3-one), a volatile steroid. To test for the presence of genetic variance associated with this trait, adult twins were tested for their ability to smell androstenone and another odorant, pyridine, that is readily perceived by most adults. Ascending concentration, two-sample (odor versus blank) forced choice tests were used to assess sensitivity to these odorants. Intraclass correlations for identical and fraternal twin detection thresholds to pyridine were small and not significantly different. However, intraclass correlations for thresholds to androstenone were significantly different, with the correlation for identical twins being greater than that for the fraternal twins. These data indicate a genetic component of variation in sensitivity to this odor. Investigations that use genetic variation could offer a new tool for studies of olfactory transduction mechanisms.
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The recognition of odorants by olfactory receptors represents the first stage in odor discrimination. Here, we report the generation of an expression library containing a large and diverse repertoire of mouse olfactory receptor sequences in the transmembrane II-VII region. From this library, 80 chimeric receptors were tested against 26 odorants after transfection into HEK-293 cells. Three receptors were identified to respond to micromolecular concentrations of carvone, (-) citronellal, and limonene, respectively. We also found that the mouse I7 receptor, unlike the rat I7 receptor, prefers heptanal instead of octanal, as a result of a single valine-to-isoleucine substitution. This finding represents the beginning of a molecular understanding of odorant recognition. The identification, on a large scale, of cognate receptor-odorant interactions should provide insight into olfactory coding mechanisms.
The mammalian olfactory system can recognize and discriminate a large number of different odorant molecules. The detection of chemically distinct odorants presumably results from the association of odorous ligands with specific receptors on olfactory sensory neurons. To address the problem of olfactory perception at a molecular level, we have cloned and characterized 18 different members of an extremely large multigene family that encodes seven transmembrane domain proteins whose expression is restricted to the olfactory epithelium. The members of this novel gene family are likely to encode a diverse family of odorant receptors.
Three types of odour blindness or specific anosmia have been studied, but genetical evidence so far obtained is tentative. Specific anosmia to the musk pentadecalactone (Thibetolide) is found in about 7% of tested subjects. Results on 109 Caucasian families are presented in whom all known inherent and environmental interferences with olfactory sensitivity have been excluded. Insensitivity to musk occurred in thirty six families; males and females were equally affected. The offspring from twenty marriages between smellers were analyzed by the a priori method and there was almost exact correspondence between the expected and observed results. Among the fifteen marriages between smeller and nonsmeller, thirteen produced only smeller children, probably because of small family size. Two marriages produced a total of three children, one smeller and two nonsmellers. A marriage between nonsmellers produced two children, both non smellers. The data acquired with this test protocol, though not conclusively ruling out polygenic inheritance, strongly suggest that the inability to smell pentadecalactone is inherited as a simple recessive autosomal character. The high incidence of the anosmia suggests a genetic polymorphism, but might result from relaxation of natural selection on nonsmellers. human olfactory sense.
The extent of polymorphism in TCRBV6S1 was examined by screening 203 individuals of diverse ethnic backgrounds by using SSCP. Three alleles were detected, including two that were described previously (TCRBV6S1*1 and *2P). The third allele (TCRBV6S1*3P), identified in these studies, is a pseudogene because, similar to allele *2P, it contains a substitution of a highly conserved cysteine residue near CDR3. Among a panel of 126 Caucasian donors, alleles *1, *2P, and *3P were observed to have frequencies of 0.72, 0.12, and 0.16, respectively. The extent of this survey suggests that it is unlikely for there to be additional common variants of TCRBV6S1. The approach used here enables rapid typing for polymorphism in a TCRBV gene that results in an allelically determined hole in the TCR repertoire.
The initial step in olfactory discrimination involves the interaction of odorous ligands with specific receptors on the surface of olfactory sensory neurons. The foundation for a molecular understanding of odor recognition in vertebrates was provided by the identification of a family of genes encoding putative odorant receptors, by Buck & Axel in 1991. Odorant receptor (OR) genes from the largest gene family in the vertebrate genome. This review summarizes progress over the past seven years. Major new insights are: Olfaction is accomplished in vertebrates by a very large number of receptors; olfactory sensory neurons express a small subset of the OR repertoire; in rat and mouse, axons of neurons expressing the same OR converge onto defined glomeruli in the olfactory bulb.
The genes that encode molecules involved in antigen presentation within the class I and class II regions of the mammalian major histocompatibility complex (MHC) include several that are highly polymorphic. There is evidence that this polymorphism is maintained by positive selection, most likely overdominant selection, relating to their role in presenting foreign peptides to T cells. This selection can maintain allelic lineages for much longer periods of time than neutral polymorphisms are expected to last, but sharing of polymorphic amino acid motifs among species of different mammalian orders is due to independent (or convergent) evolution rather than common ancestry. It has been suggested that interallelic recombination (gene conversion) plays a role in enhancing polymorphism, but there is evidence of striking differences among loci with respect to the rate at which such recombination has contributed to current polymorphism. Recent attempts to interpret linkage relationships in the MHC region as evidence of ancient genomic duplications are not supported by phylogenetic analysis. Rather, natural selection may have played a role in the linkage of other genes to those of the MHC.