OJGen  Vol.5 No.1 , March 2015
Music in DNA: From Williams Syndrome to Musical Genes
Williams syndrome (WS) is a genetic disorder caused by a heterozygous contiguous gene deletion on chromosome 7q11.23. Clinical features of the disease include low IQ and deficit in some cog- nitive domains, and the presence of relatively strong abilities in social drive, face processing, language, and musical skills. The presence of a strong predisposition to the development of musicality in individuals affected by WS leads us to suppose that some genes deleted in this syndrome are somehow involved in the evolution of this ability, and that these genes could act in normal conditions as “suppressors of music ability”. To test this hypothesis, we carried out an “in silico” analysis by using the Ingenuity Pathway Analysis (IPA) software to identify the interaction between genes mapped in the WS critical region and genes previously related to musical ability by literature data. This approach allowed us to identify 3 networks of interaction, involving AVPR1A, NCF1, UNC5C and LAT2 in the first network, STX1A and SLC6A4 in the second one and only WS related genes in the last one. Among these associations, the one involving STX1A and SLC6A4 suggested a possible mechanism of interaction was based on the influence played by STX1A deletion on the serotonin levels through a decrease of SLC6A4 activity.

Cite this paper
Rosa, C. , Cieri, F. , Antonucci, I. , Stuppia, L. and Gatta, V. (2015) Music in DNA: From Williams Syndrome to Musical Genes. Open Journal of Genetics, 5, 12-26. doi: 10.4236/ojgen.2015.51002.
[1]   Huron, D. (2001) Is Music an Evolutionary Adaptation? Annals of the New York Academy of Sciences, 930, 43-61.

[2]   Dowling, W.J. (1986) The Psychology of Music: The Musical Mind. Science, 231, 279-280.

[3]   Darwin, C. (1871) The Descent of Man, and Selection in Relation to Sex, Volume 1. John Murray, Lon-don.

[4]   Zatorre, R. and McGill, J. (2005) Music, the Food of Neuroscience? Nature, 434, 312-315.

[5]   Zatorre, R.J. (2003) Music and the Brain. Annals of the New York Academy of Sciences, 999, 4-14.

[6]   Theusch, E., Basu, A. and Gitschier, J. (2009) Genome-Wide Study of Families with Absolute Pitch Reveals Linkage to 8q24.21 and Locus Heterogeneity. The American Journal of Human Genetics, 85, 112-119.

[7]   Theusch, E. and Gitschier, J. (2011) Absolute Pitch Twin Study and Segregation Analysis. Twin Research and Human Genetics, 14, 173-178. http://dx.doi.org/10.1375/twin.14.2.173

[8]   Vanzella, P. and Schellenberg, E.G. (2010) Absolute Pitch: Effects of Timbre on Note-Naming Ability. PLoS One, 5, e15449.

[9]   Peretz, I., Cummings, S. and Dubé, M.P. (2007) The Genetics of Congenital Amusia (Tone Deafness): A Family-Aggregation Study. The American Journal of Human Genetics, 81, 582-588.

[10]   Strømme, P., Bjørnstad, P.G. and Ramstad, K. (2002) Prevalence Estimation of Williams Syndrome. Journal of Child Neurology, 17, 269-271.

[11]   Ewart, A.K., Morris, C.A., Atkinson, D., Jin, W., Sternes, K., Spallone, P., Stock, A.D., Leppert, M. and Keating, M.T. (1993) Hemizygosity at the Elastin Locus in a Developmental Disorder, Williams Syndrome. Nature Genetics, 5, 11-16. http://dx.doi.org/10.1038/ng0993-11

[12]   Francke, U. (1999) Williams-Beuren Syndrome: Genes and Mechanisms. Human Molecular Genetics, 8, 1947-1954.

[13]   Micale, L., Turturo, M.G., Fusco, C., Augello, B., Jurado, L.A., Izzi, C., Digilio, M.C., Milani, D., Lapi, E., Zelante, L. and Merla, G. (2010) Identification and Characterization of Seven Novel Mutations of Elastin Gene in a Cohort of Patients Affected by Supravalvular Aortic Stenosis. European Journal of Human Genetics, 18, 317-323.

[14]   Bellugi, U., Lichtenberger, L., Mills, D., Galaburda, A. and Korenberg, J.R. (1999) Bridging Cognition, the Brain and Molecular Genetics: Evidence from Williams Syndrome. Trends in Neurosciences, 22, 197-207.

[15]   Gosch, A. and Pankau, R. (1997) Personality Characteristics and Behaviour Problems in Individuals of Different Ages with Williams Syndrome. Developmental Medicine & Child Neurology, 39, 527-533.

[16]   Bellugi, U., Korenberg, J.R. and Klima, E.S. (2001) Williams Syndrome: An Exploration of Neurocognitive and Genetic Features. Journal of Clinical Neurosciences Research, 1, 217-229.

[17]   Don, A.J., Schellenberg, E.G. and Rourke, B.P. (1999) Music and Language Skills of Children with Williams Syndrome. Child Neuropsychology, 5, 154-170.

[18]   Hopyan, T., Dennis, M., Weksberg, R. and Cytrynbaum, C. (2001) Music Skills and the Expressive Interpretation of Music in Children with Williams-Beuren Syndrome: Pitch, Rhythm, Melodic Imagery, Phrasing, and Musical Affect. Child Neuropsychology, 7, 42-53.

[19]   Marler, J.A., Elfenbein, J.L. and Ryals, B.M. (2005) Sensorineural Hearing Loss in Children and Adults with Williams Syndrome. American Journal of Medical Genetics Part A, 138, 318-327.

[20]   Morris, A.C., Mervis, C.B., Hobart, H.H., Gregg, R.G., Bertrand, J., Ensing, G.J., Sommer, A., Moore, C.A., Hopkin, R.J., Spallone, P.A., Keating, M.T., Osborne, L., Kimberley, K.W. and Stock, A.D. (2003) GTF2I Hemizygosity Implicated in Mental Retardation in Williams Syndrome: Genotype-Phenotype Analysis of Five Families with Deletions in the Williams Syndrome Region. American Journal of Medical Genetics Part A, 123A, 45-59.

[21]   Cassidy, S.B. and Morris, C.A. (2002) Behavioral Phenotypes in Genetic Syndromes: Genetic Clues to Human Behavior. Advances in Pediatrics, 49, 59-86.

[22]   Meyer-Lindenberg, A., Buckholtz, J.W., Kolachana, B., Hariri, A.R., Pezawas, L., Blasi, G., Wabnitz, A., Honea, R., Verchinski, B., Callicott, J.H., Egan, M., Mattay, V. and Weinberger, D.R. (2006) Neural Mechanisms of Genetic Risk for Impulsivity and Violence in Humans. Proceedings of the National Academy of Sciences of the United States of America, 103, 6269-6274.

[23]   Järvinen-Pasley, A., Bellugi, U., Reilly, J., Mills, D.L., Galaburda, A., Reiss, A.L. and Korenberg, J.R. (2008) Defining the Social Phenotype in Williams Syndrome: A Model for Linking Gene, the Brain, and Behavior. Development and Psychopathology, 20, 1-35.

[24]   Morris, A.C. (2010) Introduction: Williams Syndrome. American Journal of Medical Genetics Part C, Seminars in Medical Genetics, 154, 203-208.

[25]   Silman, S. and Gelfand, S.A. (1981) The Relationship between Magnitude of Hearing Loss and Acoustic Reflex Threshold Levels. Journal of Speech and Hearing Disorders, 46, 312-316.

[26]   Zarchi, O., Attias, J. and Gothelf, D. (2010) Auditory and Visual Processing in Williams Syndrome. The Israel Journal of Psychiatry and Related Sciences, 47, 125-131.

[27]   Gothelf, D., Farber, N., Raveh, E., Apter, A. and Attias, J. (2006) Hyperacusis in Williams Syndrome. Characteristics and Associated Neuroaudiologic Abnormalities. Neurology, 66, 390-395.

[28]   Pulli, K., Karma, K., Norio, R., Sistonen, P., Göring, H.H. and Järvelä, I. (2008) Genome-Wide Linkage Scan for Loci of Musical Aptitude in Finnish Families: Evidence for a Major Locus at 4q22. Journal of Medical Genetics, 45, 451-456.

[29]   Williams, J. and O’Donovan, M.C. (2006) The Genetics of Developmental Dyslexia. European Journal of Human Genetics, 14, 681-689.

[30]   Kwan, K.Y., Allchorne, A.J., Vollrath, M.A., Christensen, A.P., Zhang, D.S., Woolf, C.J. and Corey, D.P. (2006) TRPA1 Contributes to Cold, Mechanical, and Chemical Nociception but Is Not Essential for Hair-Cell Transduction. Neuron, 50, 277-289.

[31]   Bachner-Melman, R., Dina, C., Zohar, A.H., Constantini, N., Lerer, E., Hoch, S., Sella, S., Nemanov, L., Gritsenko, I., Lichtenberg, P., Granot, R. and Ebstein, R.P. (2005) AVPR1a and SLC6A4 Gene Polymorphisms Are Associated with Creative Dance Performance. PLOS Genetics, 1, e42.

[32]   Granot, R.Y., Frankel, Y., Gritsenko, V., Lererd, E., Gritsenkoc, I., Bachner-Melmane, R., Israelb, S. and Ebstein, R.P. (2007) Provisional Evidence That the Arginine Vasopressin 1a Receptor Gene Is Associated with Musical Memory. Evolution and Human Behavior, 28, 313-318.

[33]   Kim, S.J., Young, L.J., Gonen, D., Veenstra-VanderWeele, J., Courchesne, R., Courchesne, E., Lord, C., Leventhal, B.L., Cook Jr., E.H. and Insel, T.R. (2002) Transmission Disequilibrium Testing of Arginine Vasopressin Receptor 1A (AVPR1a) Polymorphisms in Autism. Molecular Psychiatry, 7, 503-507.

[34]   Yirmiya, N., Rosenberg, C., Levi, S., Salomon, S., Shulman, C., Nemanov, L., Dina, C. and Ebstein, R.P. (2006) Association between the Arginine Vasopressin 1a Receptor (AVPR1a) Gene and Autism in a Family-Based Study: Mediation by Socialization Skills. Molecular Psychiatry, 11, 488-494.

[35]   Meyer-Lindenberg, A., Kolachana, B., Gold, B., Olsh, A., Nicodemus, K.K., Mattay, V., Dean, M. and Weinberger, D.R. (2009) Genetic Variants in AVPR1A Linked to Autism Predict Amygdala Activation and Personality Traits in Healthy Humans. Molecular Psychiatry, 14, 968-975.

[36]   Levitin, D. and Tirovolas, A.K. (2009) Current Advances in the Cognitive Neuroscience of Music. Annals of the New York Academy of Sciences, 1156, 211-231.

[37]   Knafo, A., Israel, S., Darvasi, A., Bachner-Melman, R., Uzefovsky, F., Cohen, L., Feldman, E., Lerer, E., Laiba, E., Raz, Y., Nemanov, L., Gritsenko, I., Dina, C., Agam, G., Dean, B., Bornstein, G. and Ebstein, R.P. (2008) Individual Differences in Allocation of Funds in the Dictator Game Associated with Length of the Arginine Vasopressin 1a Receptor RS3 Promoter Region and Correlation between RS3 Length and Hippocampal mRNA. Genes, Brain and Behavior, 7, 266-275.

[38]   Thompson, R., Gupta, S., Miller, K., Mills, S. and Orr, S. (2004) The Effects of Vasopressin on Human Facial Responses Related to Social Communication. Psychoneuroendocrinology, 29, 35-48.

[39]   Walum, H., Westberg, L., Hen-ningsson, S., Neiderhiser, J.M., Reiss, D., Igl, W., Ganiban, J.M., Spotts, E.L., Pedersen, N.L., Eriksson, E. and Lichtenstein, P. (2008) Genetic Variation in the Vasopressin Receptor 1a Gene (AVPR1A) Associates with Pair-Bonding Behavior in Humans. Proceedings of the National Academy of Sciences of the United States of America, 105, 14153-14156.

[40]   Hammock, E.A.D. and Young, L.J. (2006) Oxytocin, Vasopressin and Pair Bonding: Implications for Autism. Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences, 361, 2187-2198.

[41]   Zeki, S. (2007) The Neurobiology of Love. FEBS Letters, 581, 2575-2579.

[42]   Canli, T. and Lesch, K.P. (2007) Long Story Short: The Serotonin Transporter in Emotion Regulation and Social Cognition. Nature Neuroscience, 10, 1103-1109.

[43]   Wendland, J.R., Martin, B.J., Kruse, M.R., Lesch, K.P. and Murphy, D.L. (2006) Simultaneous Genotyping of Four Functional Loci of Human SLC6A4, with a Reappraisal of 5-HTTLPR and rs25531. Molecular Psychiatry, 11, 224-226.

[44]   Hu, X., Oroszi, G., Chun, J., Smith, T.L., Goldman, D. and Schuckit, M.A. (2005) An Expanded Evaluation of the Relationship of Four Alleles to the Level of Response to Alcohol and Alcholism Risk. Alcoholism: Clinical and Experimental Research, 29, 8-16.

[45]   Donaldson, Z.R., Kondrashov, F.A., Putnam, A., Bai, Y., Stoinski, T.L., Hammock, E.A. and Young, L.J. (2008) Evolution of a Behavior-Linked Microsatellite-Containing Element of the 5’ Flanking Region of the Primate AVPR1A Gene. BMC Evolutionary Biology, 8, 180-188.

[46]   Samuvel, D.J., Jayanthi, L.D., Bhat, N.R. and Ramamoorthy, S. (2005) A Role for p38 Mitogen-Activated Protein Kinase in the Regulation of the Serotonin Transporter: Evidence for Distinct Cellular Mechanisms Involved in Transporter Surface Expression. The Journal of Neuroscience, 25, 29-41.

[47]   Quick, M.W. (2003) Regulating the Conducting States of a Mammalian Serotonin Transporter. Neuron, 40, 537-549.

[48]   Quick, M.W. (2002) Role of Syntaxin 1A on Serotonin Transporter Expression in Developing Thalamocortical Neurons. International Journal of Developmental Neuroscience, 20, 219-224.

[49]   Haase, J., Killian, A.M., Magnani, F. and Williams, C. (2001) Regulation of the Serotonin Transporter by Interacting Proteins. Biochemical Society Transactions, 29, 722-728.

[50]   Curran, M.E., Atkinson, D.L., Ewart, A.K., Morris, C.A., Leppert, M.F. and Keating, M.T. (1993) The Elastin Gene Is Disrupted by a Translocation Associated with Supravalvular Aortic Stenosis. Cell, 73, 159-168.

[51]   Schubert, C. (2009) The Genomic Basis of the Williams-Beuren Syndrome. Cellular and Molecular Life Sciences, 66, 1178-1197.

[52]   Enkhmandakh, B., Makeyev, A.V., Erdenechimeg, L., Ruddle, F.H., Chimge, N.O., Tussie-Luna, M.I., Roy, A.L. and Bayarsaihan, D. (2009) Essential Functions of the Williams Syndrome-Associated TFII-I Genes in Embryonic Development. Proceedings of the National Academy of Sciences of the United States of America, 106, 181-186.

[53]   Edelmann, L., Prosnitz, A., Pardo, S., Bhatt, J., Cohen, N., Lauriat, T., Ouchanov, L., González, P.J., Manghi, E.R., Bondy, P., Esquivel, M., Monge, S., Delgado, M.F., Splendore, A., Francke, U., Burton, B.K. and McInnes, L.A. (2007) An Atypical Deletion of the Williams Syndrome Interval Implicates Genes Associated with Defective Visuospatial Processing and Autism. Journal of Medical Genetics, 44, 136-143.

[54]   Hoogenraad, C.C., Koekkoek, B., Akhmanova, A., Krugers, H., Dortland, B., Miedema, M., van Alphen, A., Kistler, W.M., Jaegle, M., Koutsourakis, M., Van Camp, N., Verhoye, M., van der Linden, A., Kaverina, I., Grosveld, F., De Zeeuw, C.I. and Galjart, N. (2002) Targeted Mutation of Cyln2 in the Williams Syndrome Critical Region Links CLIP-115 Haploinsufficiency to Neurodevelopmental Abnormalities in Mice. Nature Genetics, 32, 116-127.

[55]   Merla, G., Howald, C. and Antonarakis, S.E. (2004) The Subcellular Localization of the ChoRE-Binding Protein, Encoded by the Williams-Beuren Syndrome Critical Region Gene 14, Is Regulated by 14-3-3. Human Molecular Genetics, 13, 1505-1514.

[56]   Burgess, S.C., Iizuka, K., Jeoung, N.H., Harris, R.A., Kashiwaya, Y., Veech, R.L., Kitazume, T. and Uyeda, K. (2008) Carbohydrate-Response Element-Binding Protein Deletion Alters Substrate Utilization Producing an Energy-Deficient Liver. Journal of Biological Chemistry, 283, 1670-1678.

[57]   Cherniske, E.M., Carpenter, T.O., Klaiman, C., Young, E., Bregman, J., Insogna, K., Schultz, R.T. and Pober, B.R. (2004) Multisystem Study of 20 Older Adults with Williams Syndrome. American Journal of Human Genetics, 131, 255-264.

[58]   Merla, G., Brunetti-Pierri, N., Micale, L. and Fusco, C. (2010) Copy Number Variants at Williams-Beuren Syndrome 7q11.23 Region. Human Genetics, 128, 3-26.

[59]   Buznikov, G.A. and Shmukler, Y.B. (1981) Possible Role of “Prenervous” Neurotransmitters in Cellular Interactions of Early Embryogenesis: A Hypothesis. Neurochemical Research, 6, 55-68.

[60]   Lauder, J.M. (1993) Neurotransmitters as Growth Regulatory Signals: Role of Receptors and Second Messengers. Trends in Neurosciences, 16, 233-239.

[61]   Bennett-Clarke, C.A., Leslie, M.J., Lane, R.D. and Rhoades, R.W. (1994) Effect of Serotonin Depletion on Vibrissa-Related Patterns of Thalamic Afferents in the Rat’s Somatosensory Cortex. Journal of Neuroscience, 14, 7594-7607.

[62]   Mazer, C., Muneyyirci, J., Taheny, K., Raio, N., Borella, A. and Whitaker-Azmitia, P. (1997) Serotonin Depletion during Synaptogenesis Leads to Decreased Synaptic Density and Learning Deficits in the Adult Rat: A Possible Model of Neurodevelopmental Disorders with Cognitive Deficits. Brain Research, 760, 68-73.

[63]   Kojic, L., Gu, Q., Douglas, R.M. and Cynader, M.S. (1997) Serotonin Facilitates Synaptic Plasticity in Kitten Visual Cortex: An in Vitro Study. Developmental Brain Research, 101, 299-304.

[64]   Edagawa, Y., Saito, H. and Abe, K. (2001) Endogenous Serotonin Contributes to a Developmental Decrease in Long-Term Potentiation in the Rat Visual Cortex. Journal of Neuroscience, 21, 1532-1537.

[65]   Rhoades, R.W., Bennett-Clarke, C.A., Shi, M.Y. and Mooney, R.D. (1994) Effects of 5-HT on Thalamocortical Synaptic Transmission in the Developing Rat. Journal of Neurophysiology, 72, 2438-2450.

[66]   Borella, A., Bindra, M. and Whitaker-Azmitia, P.M. (1997) Role of the 5-HT1A Receptor in Development of the Neonatal Rat Brain: Preliminary Behavioral Studies. Neuropharmacology, 36, 445-450.

[67]   Breese, G.R., Vogel, R.A. and Mueller, R.A. (1978) Biochemical and Behavioral Alterations in Developing Rats Treated with 5,7-Dihydroxytryptamine. Journal of Pharmacology and Experimental Therapeutics, 205, 587-595.

[68]   Tricklebank, M.D. (1985) The Behavioral Response to 5-HT Receptor Agonists and Subtypes of the Central 5-HT Receptor. Trends in Pharmacological Sciences, 3, 403-407.

[69]   Buwalda, B., Nyakas, C., Vosselman, H.J. and Luiten, P.G. (1995) Effects of Early Postnatal Anoxia on Adult Learning and Emotion in Rats. Behavioural Brain Research, 67, 85-90.

[70]   Nyakas, C., Nuwalda, B., Kramers, R.K.J., Traber, J. and Luiten, P.G. (1994) Postnatal Development of Hippocampal and Neocortical Cholinergic and Serotonergic Innervation in Rat: Effects of Nitrite-Induced Prenatal Hypoxia and Nimodipine Treatment. Neuroscience, 39, 541-559.

[71]   Whitaker-Azmitia, P.M., Borella, A. and Raio, N. (1995) Serotonin Depletion in the Adult Rat Causes Loss of Dendritic Marker MAP-2. A New Animal Model of Schizophrenia? Neuropharmacology, 12, 269-272.

[72]   Blue, M.E., Erzurumlu, R.S. and Jhaveri, S. (1991) A Comparison of Pattern Formation by Thalamocortical and Serotonergic Afferents in the Rat Barrel Field Cortex. Cerebral Cortex, 1, 380-389.

[73]   Cases, O., Vitalis, T., Seif, I., De Maeyer, E., Sotelo, C. and Gaspar, P. (1996) Lack of Barrels in the Somatosensory Cortex of Monoamine Oxidase A Deficient Mice: Role of Serotonin Excess during the Critical Period. Neuron, 16, 297-307.

[74]   Upton, D. and Thompson, P.J. (1999) Twenty Questions Task and Frontal Lobe Dysfunction. Archives of Clinical Neuropsychology, 14, 203-216.

[75]   Salichon, N., Gaspar, P., Upton, A.L., Picaud, S., Hanoun, N., Hamon, M., De Maeyer, E., Murphy, D.L., Mossner, R., Lesch, K.P., Hen, R. and Seif, I. (2001) Excessive Activation of Serotonin (5-HT) 1B Receptors Disrupts the Formation of Sensory Maps in Monoamine Oxidase a and 5-HT Transporter Knock-Out Mice. Journal of Neuroscience, 21, 884-896.