Chem. Senses 26: 1167-1174,
2001
© Oxford University Press 2001
Identification of Non-functional Human VNO Receptor Genes Provides Evidence for Vestigiality of the Human VNO
Beckman Institute, Division of Biology, 139-74, California Institute of Technology, Pasadena, CA 91125, USA 1 Department of Molecular Biotechnology, University of Washington, Seattle, WA 98195, USA * These authors have contributed equally
Correspondence to be sent to: Hiroaki Shizuya, Beckman Institute, Division of Biology, 139-74, California Institute of Technology, Pasadena, CA 91125. e-mail: shizuya{at}its.caltech.edu
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Abstract |
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In mammals, the vomeronasal organ (VNO) contains chemosensory receptor cells that bind to pheromones and induce a variety of social and reproductive behaviors. It has been traditionally assumed that the human VNO (Jacobson's organ) is a vestigial structure, although recent studies have shown minor evidence for a structurally intact and possibly functional VNO. The presence and function of the human VNO remains controversial, however, as pheromones and VNO receptors have not been well characterized. In this study we screened a human Bacterial Artificial Chromosome (BAC) library with multiple primer sets designed from human cDNA sequences homologous to mouse VNO receptor genes. Utilizing these BAC sequences in addition to mouse VNO receptor sequences, we screened the High Throughput Genome Sequence (HTGS) database to find additional human putative VNO receptor genes. We report the identification of 56 BACs carrying 34 distinct putative VNO receptor gene sequences, all of which appear to be pseudogenes. Sequence analysis indicates substantial homology to mouse V1R and V2R VNO receptor families. Furthermore, chromosomal localization via FISH analysis and RH mapping reveal that the majority of the BACs are localized to telomeric and centromeric chromosomal localizations and may have arisen through duplication events. These data yield insight into the present state of pheromonal olfaction in humans and into the evolutionary history of human VNO receptors. (Sequence data from this article have been deposited with the DDBJ/EMBL/Genbank Data Libraries under accession nos. AF305393-305416.)
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Introduction |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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The vomeronasal organ (VNO) is an olfactory sensory structure that responds to soluble compounds such as pheromones and induces characteristic social and reproductive behaviors (Halpern, 1987
; Buck, 2000).
The VNO is located anterior to the primary olfactory system, residing within a
tissue pouch in the septum of the nose. Neurons from the VNO project to the
accessory olfactory bulb (AOB), which in turn sends neurons to the amygdala
and hypothalamus. Since this neural pathway bypasses higher cognitive centers,
it is believed that the pathway mediates innate behavioral and neuroendocrine
responses. VNO sensory neurons have dendrites that terminate in specialized
odorant-binding microvilli or cilia, within which VNO receptors are expressed
(Dulac and Axel, 1998).
VNO receptors are seven-transmembrane-domain receptors distinct from the
well-characterized multigene family of odorant receptors (OR) consisting of
1000 genes (Strader et al.,
1995). It is believed that both ORs and VNO receptors induce a
G-protein-coupled signal transduction pathway after binding ligand, although
ligands have not been identified for VNO receptors. Studies in mice have
uncovered two evolutionarily independent families of VNO receptors that
utilize different G-proteins and are expressed in two distinct subsets of VNO
sensory neurons (Dudley and Moss,
1999; Kumar et al.,
1999). The VIR VNO receptor family, which comprises an
estimated 35 genes, lacks introns and has short N-terminal extracellular
domains that act in combination with transmembrane domains to form a
ligand-specific binding pocket (Dulac and
Axel, 1995). The V2R VNO receptor family, which comprises
an estimated 150 genes, contains introns and has very large N-terminal
extracellular domains that may bind ligand
(Herrada and Dulac, 1997;
Matsunami and Buck, 1997;
Ryba and Tirindelli, 1997).
Recent studies have uncovered a third family of highly conserved VNO receptors
(V3R) that appear distantly related to V1Rs. Like V1Rs, V3Rs appear to contain
short N-terminal extracellular domains and are expressed in the apical half of
the VNO neuroepithelium (Pantages and
Dulac, 2000).
To date, pheromonal olfaction has not been well characterized in humans. It
has been traditionally assumed that the human VNO is a vestigial structure
that had degenerated during the development of higher cortical centers
responsible for sexual behavior and function. For instance, studies attempting
to characterize sensory cells or nerve fibers in the adult VNO epithelium
either failed or were inconclusive (Doving
and Trotier, 1998). Moreover, an anatomical study of 562 adults
failed to locate the vomeronasal vestibule in 70% of subjects, and other
studies have failed to locate the AOB in humans
(Keverne, 1999). Despite these
results, recent studies have raised the possibility that the human VNO may be
structurally intact and possibly functional. Volumetric measurements of the
human fetal VNO suggest that it contains sensory receptor-like cells and does
not atrophy during development (Boehm and
Gasser, 1993; Smith et
al., 1997). Also, whole-cell recordings of isolated
microvillar human VNO cells suggest that voltage-dependent inward currents
take place in response to androstadienone, estratetraenol and
pregnadienendione. Functional magnetic resonance imaging studies indicate that
VNO exposure to these compounds induces activation of the hypothalamus,
amygdala and other centers responsible for emotion and innate behavior
(Monti-Bloch et al.,
1998). The contradictory results of these studies imply that
further work is necessary to characterize the human VNO.
The identification of human VNO receptors may aid in resolving the
controversial existence of the human VNO. Recently, a single human putative
VNO receptor gene known as V1RL1 was identified and reported to be
expressed in the olfactory mucosa
(Rodriguez et al.,
2000). Given the gene's low homology to mouse VNO receptors (28%
identical and 47% similar to the mouse V1ra2 product at the amino acid level)
as well as its tissue specificity, it remains to be shown whether V1RL1 is a
VNO receptor or simply an odorant receptor with pheromone-like ligand
properties. To identify additional human VNO receptor genes, we scanned a
human Bacterial Artificial Chromosome (BAC) library and the GenBank
High-Throughput Genome Sequencing (HTGS) database with human
pheromone-receptor-like cDNA sequences and with mouse V1R and
V2R genes. We report the identification of 56 BACs carrying 34
distinct putative VNO receptor gene sequences, all of which appear to be
pseudogenes.
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Materials and methods |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Identification of putative human VNO receptor sequences
All GenBank entries were searched for the keywords `human VNO receptor' and `human pheromone receptor'; the search yielded five different human cDNA sequences homologous to mouse VNO receptor gene sequences. The five cDNAs include two that had been isolated from Schwannoma tumor cells (AA553508, AA551068), one from a testis cDNA library (AA442630) and two (AA969989, AA806860) from a combination of three cDNA libraries (testis, fetal lung and B-cell).
Screening of human BAC library
The five cDNA sequences were aligned using the program Pileup (University of Wisconsin, GCG 8.1 software package). Using Primer3, primers were designed to amplify short fragments corresponding to transmembrane domains. The primers include
- 442630, spanning transmembrane region 3 (Forward
5'-TCACAGCCAACACCTTCCTCC-3' Reverse
5'-GTGGACAAGGGCCAGGTGAC-3');
- 551068, spanning transmembrane region 5 (Forward
5'-ACCAGCCTCTCCCCAAGACC-3' Reverse
5'-TGCCCATAGCGAGGTTGAGG-3');
- 989AD, spanning transmembrane region 7 (Forward
5'-GCCTGACACCTTCAATAAGTCAAGTTC-3', Reverse
5'-GGGCAAAGATGCAGCCAAG-3'); and
- 969989, spanning transmembrane region 7 (Forward 5'-CCTT
CCCCTTGATGCTGTGG-3', Reverse
5'-GGATACCGGGGCTCCTTGAC-3').
The primers were used to screen a 4x human genomic BAC library
(CIT-A) by polymerase chain reaction (PCR)
(Kim et al., 1996).
After identifying BACs, we confirmed that the BACs carried putative VNO
receptor genes by cloning the PCR fragment (Promega-T Easy Vector System) and
sequencing it via T7/SP6 sequencing primers. BACs were presumed to contain
putative VNO receptor sequences if BlastX and BlastN suggested homology to
mouse VNO receptor sequences. These confirmed BACs were further sequenced by
primer walking. (These sequences have been deposited with GenBank under
accession numbers AF305393-AF305416.) Additionally, all BACs were
fingerprinted via restriction mapping (HindIII and EcoRI,
separately) to determine overlap.
Sequence analysis
The BlastX program was used to determine sequence characteristics of the putative VNO receptor genes, including the presence of nonsense and frameshift mutations. Any resulting frameshift mutations were verified through DNA sequence alignments with mouse and rat VNO receptor genes. All putative human VNO receptor gene sequences (both DNA and amino acid) were aligned with mouse VNO receptor sequences using ClustalX, the Windows interface for the ClustalW multiple sequence alignment program. This program was also used to generate phylogenetic trees from the alignments. In the case of V2R-like human pseudogenes, intron/exon structure prediction was not performed because the various tools used did not yield reproducible data. The mouse VNO receptor genes (and their corresponding GenBank entries) used in the alignment were V1R1 (Y12725), V1R2 (Y12724), V1R5 (M21, Y17566), V1R6 (M24, Y17567), V2R1 (AF011411), V2R2 (NM_009492), V2R3 (AF011413), V2R4 (NM_009493), V2R5 (AF011415), V2R6 (AF011416), V2R7 (AF011417), V2R8 (NM_009494), V2R9 (NM_009495), V2R10 (NM_009486), V2R11 (NM_009487), V2R12 (NM_009488), V2R13 (AF011423), V2R14 (NM_009489), V2R15 (NM_009490) AND V2R16 (NM_009491).
Chromosomal mapping
Chromosomal localization of CIT-A BACs was determined by radiation hybrid
(RH) mapping and by fluorescence in situ hybridization
(Cox et al., 1990;
Trask, 1999). For RH mapping,
BAC ends were sequenced with either the primers 5'-pBAC108L and
3'-pBAC108L, or 5'-pBeloBAC and 3'-pBeloBAC, depending on
the BAC vector used. These BAC-end sequences were then used to design primers
for PCR amplification of DNA from the Stanford G3 and Genebridge 4 panels.
With the exception of 679A7, at least two of these approaches were used to
establish a BAC's chromosomal location.
HTGS screening
Once all BACs carrying putative VNO receptors had been mapped and characterized, the sequences were used to search the HTGS database to identify additional sequences. Mouse VNO receptor genes (see above) were also used to scan the database. Sequence analysis of the positive HTGS clones was performed as described above. Additionally, BlastX was performed using 1-2 kb sequence upstream and downstream of the putative genes in order to identify additional exons and other entities such as Alus. The chromosomal locations of these BACs was based on their GenBank database entries.
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Results |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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A PCR screen of human BAC library CIT-A was carried out using four primer sets designed from human cDNA sequences homologous to mouse VNO receptors. The screen yielded a total of 22 BACs, and restriction mapping indicated that 11 of these represented distinct putative VNO receptor gene sequences. Utilizing these 11 BAC sequences, as well as mouse VNO receptor gene sequences, we scanned the human HTGS database and identified 38 additional putative VNO receptor sequences carried on 34 BACs. Sequence alignment analysis indicated that 23 of these represented distinct sequences, yielding a total of 34 distinct gene sequences carried on CIT-A and HTGS BACs (Table 1).
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Analysis of the 34 distinct HTGS and CIT-A sequences revealed that 27 carried frameshift mutations, 24 carried nonsense mutations, and 19 carried both nonsense and frameshift mutations. Thus, 32 of the 34 distinct putative VNO receptor sequences were pseudogenes. The two sequences that were not pseudogenes included AC024199.1 and AC023191.1, which contained only 260 and 144 bp of coding sequence respectively. Further sequence analysis suggested that of the 34 distinct sequences, 22 were homologous to mouse V1R genes whereas 12 were homologous to mouse V2R genes (Figure 1a, 1a(cont), 1b).
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Radiation hybrid and fluorescence in situ hybridization mapping revealed that the CIT-A BACs mapped predominantly to pericentromeric and subterminal locations on chromosomes 7, 16, 19 and 21. Although the cytogenetic locations of the HTGS BACs were not known at the time of the search, the BACs are annotated to indicate that they are widely distributed over chromosomes 1, 2, 3, 4, 7, 9, 10, 11, 13, 15, 16, 17 and 19 (Table 1). In some cases, BACs carrying distinct putative VNO receptor sequences mapped to the same cytogenetic positions. These include three sets of BACs that mapped near the centromere of chromosome 7 (7p11.1 and 7q11.1), three sets that mapped around the centromere of chromosome 16 (16p11.2 and 16q11.1), and two sets of BACs that mapped near the telomere of chromosome 19 (19q13.4—the V1RL1 gene also mapped to this location). Interestingly, four BACs each carried two putative VNO receptor gene sequences separated by 21-124 kb.
BlastX analysis indicated that a number of putative VNO receptor sequences had been inactivated via Alu insertion. Two BACs (AL161418.3 and AC010422.4) contained Alu sequences within coding regions, while four others (AC025953.2, 378E6, 34G7, and AC011457.1) contained Alu sequences immediately adjacent to coding regions. An additional eight BACs (AC012018.6, AC022202.4, AC025699.3, AL157387.1, AC022860.3, AC009139.4, AC011457.1 and AC016588.4) contained Alu sequences further upstream or downstream of the putative VNO receptor gene (Table 1).
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Our data suggest that human VNO receptors throughout the genome have undergone significant degeneration as a result of missense mutations, frameshift mutations and Alu insertions. These results are consistent with an independent, small-scale search for human VNO receptor genes in which seven psuedogenes were identified (Giorgi et al., 2000
). The work here extends the implications of the
study by providing greater evidence that human VNO receptor genes throughout
the genome have undergone significant degeneration. It should be noted that a
more recent HTGS screening for putative VNO receptors was performed, yielding
an additional set of 16 sequences that were all identified as pseudogenes
(data not included). Although nearly all putative VNO receptors in this study appear to be pseudogenes with deleterious mutations, it is nonetheless possible that some of these pseudogenes are expressed in the VNO or olfactory epithelium as truncated proteins. This possibility seems unlikely given the high degree of sequence degeneration and the extremely short coding regions of the pseudogenes. One may make the argument that the pseudogenes are expressed since we screened a BAC library with primers designed from human cDNA sequences. Because the cDNA sequences were from testis as well as from several tumor cell lines, it is indeed possible that the original cDNA sequences were in fact misexpressed pseudogenes. It remains to be shown, however, that these pseudogenes are expressed in the VNO and that they play functional roles in human pheromonal olfaction. In addition to being misexpressed pseudogenes, it is also possible (but less likely) that the cDNAs were simply not VNO receptor genes or that they arose from genomic contamination of the cDNA library.
Chromosomal mapping of the sequences in this study revealed clusters of
putative VNO receptors in subterminal and pericentromeric localizations. This
pattern, plus the observation that four BACs carried two VNO receptor genes
separated by 21-124 kb, suggests that VNO receptors may be genomically
clustered like odorant receptors (Sullivan
et al., 1996; Trask
et al., 1998). Thus, like odorant receptors, VNO
receptors may have arisen through duplication events. Such a claim may be
challenging to verify due to the sequence divergence that has resulted from
the degeneration of these genes over time. On the other hand, analysis of the
level of degeneration between duplicated pairs of genes could yield insight
into the evolutionarily decline of human VNO receptors.
Our data support the theory that most human VNO receptors have degenerated
over time, which further suggests that the human VNO is a vestigial structure.
Since our data do not prove that all human VNO receptors are pseudogenes, it
is possible that humans have retained a few VNO receptors that have
irreplaceable functions. Thus, the recently identified V1RL1 gene may
have played a significant role in pheromone olfaction and was thus under
selective pressure not to degenerate. The role may not be that of the
conventional mammalian VNO receptor, however, since V1RL1 exhibits
only 28% identity to the closest mouse V1R gene and is expressed in
the olfactory mucosa. It is possible that V1RL1 was once a VNO
receptor which evolved into an odorant receptor with pheromone-like ligand
properties, but further work will be necessary to prove this point. The
pseudogenes in our study, which exhibit greater homology to mouse VNO
receptors, may not have been under such selective pressure in humans. They may
have served as conventional pheromone receptors in the VNO, an organ that is
believed to have degenerated in humans once higher cortical centers began to
replace its functions (Keverne,
1999). It should be noted that there exists a lack of direct
evidence that V1R and V2R receptors act as chemosensory pheromone receptors,
though the complete absence of human counterparts to rodent VnRs seems to add
support to such a role.
This experiment offers data that can be used in future experiments to characterize human VNO receptor genes and the human VNO. Conserved regions within these human putative VNO receptor gene sequences can be used to generate additional primers for DNA library screening. Degenerate primers designed from conserved regions in mouse VNO receptors can also be used for such screening. As additional mouse VNO receptor genes are identified and characterized (e.g. the recently identified V3R family), more accurate alignment analyses and synteny comparisons can be performed, which may aid in locating additional human VNO receptor genes. Also, evolutionary studies may be performed by searching for the homologs of these putative human VNO receptor genes in other primates. By comparing the structural properties of these pseudogenes and the presence of Alu sequences across species, it may be possible to elucidate the evolutionary degeneration of human VNO receptors. The latter may yield insight into the evolutionary history of the human VNO, the functional existence of which remains unclear. Additional work to characterize the human VNO may include in situ hybridization experiments with primer sequences from this study as well as neural tracing experiments to characterize VNO sensory neurons.
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Acknowledgments |
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This work is supported by grants from DOE (HS2.00002-1-DOE.000005) and from NIH (R01 DC04209).
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Accepted July 31, 2001
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