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Abstract

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. (doron.lancet@weizmann.ac.il).
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NATURE GENETICS VOLUME 34
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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
1–3
. In the mouse, olfactory receptor
pseudogenes comprise 20% of the gene range;
in humans, a fraction roughly three times
larger seems to be inactivated
1,3
. This extreme
diminution of the functional olfactory recep-
tor repertoire is a relatively recent genomic
process
4
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
5–7
. Yet, these
could underlie only a small part of the
reported widespread phenotype variation
8,9
.
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
1
. 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
10
.
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
NND DDDD D D D D DDDD D D DNSS S S S S SS SS S S S S SSNN NNN NNNNN NN NNN NN
ab
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 http://www.nature.com/naturegenetics
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JUNE 2003 NATURE GENETICS
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
trait
9,11
. 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
12
. 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
6,7
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
deficits
8
. 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
13
.
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
genes
4
. 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
genome
14
. 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.
ACKNOWLEDGMENTS
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.
COMPETING INTERESTS STATEMENT
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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0.35
0.25
0.15
0.05
0.3
0.2
0.1
0
16 17 18 19 20 21 22 23 24
Number of intact ORs
Frequency
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
for African American individuals and µ = 19.40 and σ = 1.61 for non-African
individuals. The statistical significance of the difference in the number of
intact olfactory receptors (ORs) between African American and non-African
individuals was assessed by a Mann–Whitney U test (P = 0.0022) or by a χ
2
test (P = 0.014). A comparable P value was obtained if we did not assume
dominance of the functional allele and used the three different genotypes at
each locus (Mann–Whitney U test, P = 0.0001; χ
2
test, P = 0.015).
© 2003 Nature Publishing Group http://www.nature.com/naturegenetics
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