Olfactory Genomics

Olfaction - the sense of smell - is a molecularly complex sensory processing system, which is capable of producing accurate odor perception. It is based on input from hundreds of sensory neuronal types equipped with diverse molecular sensors – olfactory receptor (OR) proteins. Humans show high variability in their olfactory faculties, attributed in significant part to genetic variation, mainly single nucleotide polymorphism (SNP) or copy number variation (CNV). Our working hypothesis is that genetic variations in the ORs underlie odorant sensitivity differences, specific anosmia (diminished sensitivity) and specific hyperosmia (enhanced sensitivity). In contrast, genetic variations in auxiliary olfactory genes, mediating neuronal transduction, development and maintenance, constitute the basis for general olfactory sensitivity phenotypes. An example is our reported association between a frame-disrupting SNP in the receptor gene OR11H7P and a lower sensitivity for the odorant isovaleric acid. We used 1000 genome project data to bioinformatically infer all protein variants (haplotypes) in 413 OR genes, potentially related to differences in odorant binding. We found that every individual genome contains different OR combinations. Further, we show that about two thirds of the human OR loci segregate between an intact and inactivated alleles. The OR genes portray a case of unusually high genetic diversity, and suggest that individual humans have a highly personalized “barcodes” of functional olfactory receptors (see Figure).

Figure: Personal receptor repertoires
A. A distribution showing the number of OR haplotypes in different individual genomes, coming from different ethnic groups. Every individual genome contains different number of OR haplotypes.
B. About 60% of the human ORs are segregating between intact and pseudogene forms. Every individual have different combination of intact genes.

For the auxiliary olfactory genes, we created the General Olfactory Sensitivity database (GOSdb: http://genome.weizmann.ac.il/GOSdb). This was derived using 11 data sources, including next-generation sequencing of olfactory epithelium (RNAseq) and literature survey. The database contains hundreds of genetic variations candidate determinants of general olfactory sensitivity (GOS) variations and its extreme case, congenital general anosmia (CGA), a heritable inability to sense all odors. The database and its variations assist in an on-going whole exome sequencing study of 66 Jewish families with CGA.


A. Articles

• Keydar, I., Ben-Asher, E., Feldmesser, E., Oshimoto, A., Restrepo, D., Matsunami, H., Chien, M. S., Pinto, J., Gilad, Y., Olender, T. and Lancet, D.  General olfactory sensitivity: candidate genes and their genomic variations. Hum Mutat. 2012 Aug 30. doi: 10.1002/humu.22212.
• Olender, T., Waszak, S.M., Viavant, M., Khen, M., Ben-Asher, E., Reyes, A., Nativ, N., Wysocki, C.J., Ge, D. and Lancet, D.  Personal receptor repertoires: olfaction as a model. BMC Genomics. 2012 Aug 21;13:414. doi: 10.1186/1471-2164-13-414.
• Waszak, S. M., Hasin, Y., Zichner, T., Olender, T., Keydar I., Khen, M., M. Stütz, A.D., Schlattl, A., Lancet, D., and  Korbel, J, O. Systematic inference of copy-number genotypes from personal genome sequencing data reveals extensive olfactory receptor gene content diversity. PLoS Comput Biol 6(11):| e1000988 November (2010)
• Warren, W.C., Clayton, D.F., Ellegren, H., …  Puente, X.S., Olender, T., Lancet, D., Smit, A.F., … Hou, S., Mardis, E.R. and Wilson, R.K.   The genome of a songbird.  Nature 464(7289):757-62. (2010)
• Gottlieb, A., Olender, T., Lancet, D. and Horn, D. Common peptides shed light on evolution of   Olfactory Receptors BMC Evol Biol, 9:91 (2009).
• Olender, T., Lancet, D. and Nebert, D.W. Update on the Olfactory Receptor (OR) Gene Superfamily. Hum Genomics (3): 87–97 (2008).
• Hasin, Y*., Olender, T*., Khen, M., Gonzaga-Jauregui C., M. Kim, P., Eckehart Urban, A., Snyder, M., Gerstein, MB., Lancet, D., and Korbel, JO. High-resolution Copy-Number Variation Map Reflects Human Olfactory Receptor Diversity and Evolution. PLOS Genetics. 4(11):e1000249 (2008).
• Warren, W.C., Hillier, L.W., Marshall Graves, J.A., … Wakefield, M.J., Lancet, D., Olender, T. Huttley, G.A., … Renfree, M.B., Mardis, E.R. and Wilson R.,K.  Genome analysis of platypus reveals signatures of unique evolution. Nature 453 (7192):175-83 (2008).
• Menashe, I., Abaffy, T., Hasin, Y., Goshen, S., Yahalom, V., Luetje, CW. and Lancet, D. Genetic Elucidation of Human Hyperosmia to Isovaleric Acid, PLoS Biology 5(11):e284. (2007).
• Aloni, R., Olender, T. and Lancet,D. Ancient Genomic Architecture for Mammalian Olfactory Receptor Clusters. Genome Biol. 1;7(10):R88. (2006).
• Menashe, I., Aloni, R. and Lancet, D. A probabilistic classifier for olfactory receptor pseudogenes. BMC Bioinformatics. 29;7:393 (2006).
• Feldmesser, E.,  Bercovich, D.,  Avidan, N.,  Halbertal, S.,  Haim, L.,  Gross-Isseroff, R. and Lancet, D. Mutation in olfactory signal transduction genes are not a major cause of human congenital general anosmia. Chem Senses. (2007);32(1):21-30. (2006).
• Feldmesser, E.,  Olender,T.,   Khen, M.,  Yanai , I.,  Ophir, R. and Lancet, D.  Widespread ectopic expression of olfactory receptors genes. BMC Genomics. 7:121 (2006).
• Man, O., Gilad, Y. and Lancet, D.  Prediction of the odorant binding site of olfactory receptor proteins by human-mouse comparisons.  Protein Science 13:240-254 (2004).
• Olender, T., Fuchs, T., Linhart, C., Shamir, R., Adams, M., Kalush, F., Khen, M. and Lancet, D.  The Canine Olfactory Subgenome.  Genomics. 83:361-372 (2004).
• Gilad, Y., Przeworski M. and Lancet, D. Loss of olfactory receptor genes coincides with the acquisition of full trichromatic vision in primates. PLOS Biology. 2(1):120-125 (2004).
• Olender, T., Feldmesser, E., Atarot, T., Eisenstein, M. and Lancet, D.  The olfactory receptor universe – from whole genome analysis to structure and evolution.  Genet Mol Res. 3(4):545-53 (2004).
• Harel, D., Carmel, L. and Lancet, D.  Towards an Odor Communication System. Computational Biology and Chemistry 27:121-133 (2003).
• Gilad, Y. and Lancet, D.  Population differences in the human functional olfactory repertoire.  Molecular Biology and Evolution, 20(3):307-314 (2003).
• Gilad, Y., Man, O., Paabo, S. and Lancet, D.   Human specific loss of olfactory receptor genes.   Proceedings of the National Academy of Sciences (PNAS) 100(6): 3324-3327 (2003).
• Menashe, I., Man, O., Lancet, D. and Gilad, Y.  Different noses for different people. Nature Genetics. 34(2): 143-144 (2003).
• Gilad, Y., Bustamante, C.D., Lancet, D. and Paabo, S.  Natural selection on the olfactory receptor gene family in humans and chimpanzees.  American Journal of Human Genetics. 73:489-501 (2003).
• Carmel, L., Levy, S., Lancet, D. and Harel, D.  A feature extraction method for chemical       sensors in electronic noses.  Sensors and Actuators B: Chemical. 93:67-76 (2003). 
• Carmel, L., Sever, N., Lancet, D. and Harel, D.  An E-Nose Algorithm for Identifying Chemicals and Determining their Concentration. Sensors and Actuators B: Chemical. 93:77-83 (2003).
• Rosenwald, S., Kafri, R. and Lancet, D. Test of a statistical model for molecular recognition in biological repertoires.  Journal of Theoretical Biology,  216:327-336 (2002).
• Lapidot, M., Pilpel, Y., Gilad Y., Falcovitz, A., Haaf, T. and Lancet, D.  Mouse-human Orthology relationships in an Olfactory Receptor Gene Cluster. Genomics, 71:296-306 (2001).
• Glusman, G., Yanai, I., Rubin, I. and Lancet, D. The complete human olfactory subgenome, Genome Research, 11:685-702 (2001).
• Carmel, L, Harel, D. and Lancet, D.  Estimating the size of the olfactory repertoire. Bulleting of Mathematical Biology, 63:1063-1078 (2001).
• Glusman, G., Sosinsky, A., Ben-Asher, E., Avidan, N., Sonkin, D., Bahar, A., Rosenthal, A., Clifton, S., Roe, B., Ferraz, C., Demaille, J. and Lancet, D.  Sequence, structure and evolution of a complete human olfactory receptor gene cluster. Genomics 63: 227-245 (2000).
• Gilad, Y., Segre, D., Skorecki, K., Lancet, D. and Sharon, D.  Dichotomy of single-nucleotide polymorphism haplotypes in olfactory receptor genes and pseudogenes. Nature Genetics, 26:221-224 (2000).
• Sosinsky, A., Glusman, G. and Lancet, D.  The genomic structure of human olfactory receptor genes, Genomics, 70: 49-61 (2000).
• Pilpel, Y. and Lancet D., The Variable and Conserved interfaces of modeled Olfactory Receptor Proteins. Protein Science  8: 969-977 (1999).
• Ben-Arie, N., Lancet, D., Taylor, C., Khen, M., Walker, N., Ledbetter, D.H., Carrozzo, R., Patel,  K., Sheer, D., Lehrach, H. and North, M.A.  Olfactory Receptor Gene Cluster on Human Chromosome 17: Possible Duplication of an Ancestral Receptor Repertoire. Human Mol. Genetics 3: 229-235 (1994).
• Lancet, D., Sadovsky, E. and Seidemann, E.  Probability Model for Molecular Recognition in Biological Receptor Repertoires: Significance to the Olfactory System. Proc. Natl. Acad. Sci., USA 90: 3715-3719 (1993).
• Gross-Isseroff, R., Ophir, D., Bartana, A., Voet, H. and Lancet, D.  Evidence for Genetic Determination in Human Twins of Olfactory Thresholds for a Standard Odorant. Neurosci. Lett. 141: 115-118 (1992).
• Lazard, D., Zupko, K., Poria I., Nef, P., Lazarovits, J., Horn, S., Khen, M. and Lancet, D.  Odorant Signal Termination by Olfactory UDP-Glucuronosyl Transferase. Nature 349: 790-793 (1991).
• Nef, P., Heldman, J., Lazard, D., Margalit, T., Jaye, M., Hanukoglu, I., Lancet, D. Cytochrome P450: cDNA Cloning of a Novel Neuroepithelial Enzyme Possibly Involved in Chemoreception. J. Biol Chem. 264: 6780-6785 (1989).
• Pfeuffer, E., Mollner, S., Lancet, D. and Pfeuffer, T. Olfactory Adenylyl Cyclase: Identification and Purification of a Novel Enzyme Form. J. Biol. Chem. 264:18803-18807  (1989).
• Gross-Isseroff, R. and Lancet, D.  Concentration-Dependent Changes of Perceived Odor Quality. Chemical Senses 13: 191-204 (1988).
• Pace, U. and Lancet, D.  Olfactory GTP-Binding Protein: Signal Transducing Polypeptide of Vertebrate Chemosensory Neurons. Proc. Natl. Acad. Sci. USA 83(13): 4947-4951 (1986).
• Pace, U., Hanski, E., Salomon, Y. and Lancet, D.  Odorant Sensitive Adenylate Cyclase May Mediate Olfactory Reception. Nature 316: 255-258 (1985).
• Lancet, D., Greer, C.A., Kauer, J.S. and Shepherd, G.M.  Mapping of Odor-Related Neuronal activity in the Olfactory Bulb using High Resolution 2-Deoxyglucose Autoradiography. Proc. Natl. Acad. Sci. USA 79: 670-674 (1982).

B.  Reviews and Book Chapters

• Evolutionary Grass Roots for Odor Recognition. Olender, T. and Lancet, D. Chem. Senses 37(7):581-4. Epub 2012 Jun 13 (2012).
• Hasin-Brumshtein, Y., Lancet, D. and Olender, T., Human olfaction: from  genomic variation to  phenotypic diversity, Trends Genet. 25:178-184 (2009).
• Menashe I, Feldmesser E and Lancet D In: Genetic basis of olfactory deficits. In: Genomic Disorders: The Genomic Basis of Disease, Lupski JR and Stankiewicz P,  Eds, Humana Press, Totowa, NJ .Part II 101-113. (2006).
• Man, O., Atarot, T., Olender, T. and Lancet, D. From subgenome analysis to protein structure. Current Opinion in Structural Biology. 13:353-358 (2003).
• Pilpel, Y. and Lancet, D. Good reception in Fruitfly Antennae. Nature, 398 (6725): 285-287 (1999).
• Sharon, D., Glusman, G., Pilpel, Y., Horn-Saban, S. and Lancet, D. Genome Dynamics, Evolution and Protein Modeling in the Olfactory Receptor Gene Superfamily. In: Olfaction and Taste XII an International Symposium Murphy, C., Ed., Annals of the New York Academy of Sciences, 855: 182-193 (1998).
• Pilpel, Y., Sosinsky, A. and Lancet, D., The molecular biology of olfactory receptors. Essays in Biochemistry.  33: 93-104 (1998).
• Lancet, D., Horovitz, A. and Katchalski-Katzir, E.  Molecular Recognition in Biology: Models for Analysis of Protein-Ligand Interactions. In: The Lock and Key Principle. J.P. Behr ed., John Wiley & Sons Ltd., pp. 25-71 (1994).
• Lancet, D.  Most of the Senses Begin to Make some Sense. Nature 353: 799-800 (1991).
• Lancet, D.  The Strong Scent of Success. Nature 351: 275-276 (1991).
• Lancet, D., Lazard, D., Heldman, J., Khen, M. and Nef, P. Molecular transduction in smell and  taste. Cold Spring Harbor Symposia on Quantitative Biology 53:343-348 (1988).
• Lancet, D., Chen, Z., Ciobotariu, A., Eckstein, F., Khen, M., Heldman, J., Ophir, D., Shafir, I. and Pace, U.  Towards a Comprehensive Molecular Analysis of Olfactory Transduction. Annals of the New York Academy of Sciences 510: 27-32 (1988).
• Lancet, D. and Pace, U.  Molecular Basis of Odor Recognition. Trends Biochem. Sci. 12:63-66 (1987).
• Lancet, D.  Vertebrate Olfactory Reception. Ann. Rev. Neurosci. 9:329-355 (1986).
• Lancet, D.  Molecular View of Olfactory Reception. Trends in Neurosci. 7:35-36 (1984).