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.
Music is one of the most mysterious aspects of human nature (Charles Darwin―The Origin of Species; 1859).
Music represents a universally diffused practice, endowed of ubiquity in time and culture. For this reason, it comes immediate to wonder which function music has in people’s life. Some authors attribute the importance of music to social factors, as cohesion and group cooperation [
Despite naturalness and diffusion of music, musical executive competence is characterized by strong differences among individuals, which can be located on a continuum where it is possible to find competences ranging from very scarce to excellent with the majority of people located in the middle with modest production skills. The existence of individual differences in musical competence has driven the interest of researchers to clarify the basis of this variability, especially as concerning the different role played by biological and experiential factors. A biological basis in the development of music ability is supported by the existence of specific behavioural features, like absolute pitch (AP) and congenital amusia, for which a genetic influence has clearly been individualized [
A very peculiar condition strongly suggesting the presence of genes related to the individual musical ability is represented by the great musical abilities existing in individuals affected by Williams syndrome (WS). WS (OMIM 194050) is a multisystem genomic disorder affecting 1/7500 -1/10,000 live births caused by a heterozygous contiguous gene deletion on chromosome 7q11.23 [
Individuals with WS are characterized by low IQ, ranging from 40 to 100 (mean = 61, SD = 11), and deficit in some cognitive domains including conceptual reasoning, problem solving, and spatial cognition [
Studies about this rare syndrome have suggested various candidate genes for the intellectual disability, like GTF2I [
To verify this hypothesis, we carried out a study to identify the interaction between genes mapped in the WS critical region and genes previously related to musical ability by literature data.
The present study has been organized in three steps. In the first part of the study, we analyzed the functions played by genes mapped within the WS critical region in order to verify their possible roles in the development of musical competence. To this aim, we carried out a review of the most recent literature by means of Pubmed, using “William syndrome” “genes” “critical region” and “deletion” as key words.
In the second step of the study, we performed a search of literature data in order to identify other genes, outside the WS critical region, which have been previously suggested as involved in the development of musical ability. Also in this case a literature review was carried out by Pubmed, using “genes” and “music” as specific key words.
Finally, we carried out an “in silico” analysis in order to highlight the presence of functional correlation among genes mapped in the critical region for the WS and those evidenced in literature as involved in musical competences. For this part of the study, we used the Ingenuity Pathways Analysis (IPA) software, allowing classifying genes detected in the first two steps of the study on the basis of their biological functions and detecting the functional networks connecting genes among them.
Literature data evidence that the following genes are removed by the deletion on 7q11.23: ELN, LIMK1, GTF2I, STX1A, BAZ1A, CYLN2, GTF2IRD1, NCF1, RFC2, FZD9, FKBP6, TBL2, BCL7B, CLDN4, EIF4H, LAT2, WBSCR11, STAG3L, PMS2L, GATS-L, WBSCR19, GTF2IRD2, POM121, NSUN5, TRIM50, FKBP6, FZD9, BAZ1B, BCL7B, TBL2, MLXIPL, VPS37D, DNAJC30, WBSCR22, WBSCR26, ABHD11, CLDN3 and CLDN4, EIF4H, LAT2, RFC2, CLIP2, WBSCR23.
Although no one of these genes has been so far suggested as a candidate for musical abilities, all these genes are expressed in the nervous system, and thus all of them have been considered in the present study as potentially involved in the regulation of other genes mapped outside the WS critical region and directly affecting the development of musical abilities.
Furthermore, some evidences have argued that a haploinsufficiency of the ELN gene may also be involved in the peripheral impairments mediating hyperacusis. Since the elastase enzyme destroys the stereocilia tip links [
A few studies have been performed about genetic component in musical skills.
Considering the possibility that music was an innate ability, Pulli et al. [
One more candidate gene that appears to play a role in “structural-musical abilities” is TRPA1, a member of the transient receptor potential (TRP) family of ion channels, mainly expressed by cells of the inner ear [
Unlike UNC5C and TRPA1, related to physical and structural characteristics that “allow to listen the music”, other two polymorphic genes have been directly associated to social aspects of musical abilities: the arginine vasopressin 1a receptor (AVPR1a) and the serotonin transporter (SLC6A4) related by literature to several social, emotional and behavioral traits, including musical abilities, musical aptitude and musical memories [
AVPR1a gene has been shown to affect many emotional and social traits. Microsatellite repeat regions (RS1 and RS3) located in the human AVPR1a gene promoter have been associated with autism spectrum disorders [
SLC6A4 promoter region polymorphism (5-HTTLPR) is one of the most important genes in emotion regulation and social cognition. It contains a regulatory variation (Short Variant, S, and Long Variant, L) that have been associated with anxiety-related traits and susceptibility for depression [
AVPR1A and SLC6A4 have been directly correlated both to social cognition and musical abilities in different studies. Bachner-Melman et al. [
In order to investigate genetic contribution of musical abilities, Granot et al. [
Moreover, Donaldson et al. [
Results of the second step of our study evidenced four candidate genes for musical abilities: (UNC5C, TRP1A, AVPR1a and SLC6A4), all considered in the third step of our investigation, aimed to explore the presence of a relation between genes related to music by literature data and deleted genes in WS.
After the identification of genes selectively involved to Williams syndrome and musical abilities, we employed Ingenuity Pathway Analysis (IPA) to further investigate key biological functions and networks linked to these genes. IPA analysis revealed that the main functions involved were: Cardiovascular Disease, Developmental Disorder, Endocrine System Disorders, Hereditary Disorder, Organismal Injury and Abnormalities, Renal and Urological Disease, Behavior showing a p-value ranging from 1.91E−08 to 4.45E−02 (
We employed IPA to study how the selected genes were interacting in specific networks. IPA predicts functional networks based on known protein-protein and functional interactions. IPA infers and ranks networks by a score, expressed as a numerical value, which is a probabilistic fit between the amount of focus genes that are potentially eligible for a network composition and present on a given gene list, the size of the network, as well as all the molecules present in the Ingenuity Knowledge Base that can be part of such a network.
IPA analysis of the selected genes generated 3 networks with a score of 27, 24 and 21.
In the first top network (
Cardiovascular Disease | 1.91E−08 - 4.11E−02 | ELN, MLXIPL, NCF1, EIF4H, SLC6A4, BAZ1B, LIMK1 |
---|---|---|
Developmental Disorder | 1.91E−08 - 4.11E−02 | ELN, MLXIPL, NCF1, PMS2, SLC6A4, LIMK1 |
Endocrine System Disorders | 1.91E−08 - 4.45E−02 | ELN, MLXIPL, PMS2, BAZ1B, CLDN3, LIMK1 |
Hereditary Disorder | 1.91E−08 - 3.77E−02 | ELN, MLXIPL, NCF1, SLC6A4, PMS2, AVPR1A, LIMK1 |
Organismal Injury and Abnormalities | 1.91E−08 - 4.11E−02 | ELN, NCF1, MLXIPL, LAT2, PMS2, TRPA1, SLC6A4, LIMK1 |
Renal and Urological Disease | 1.91E−08 - 1.9E−02 | ELN, MLXIPL, SLC6A4, LIMK1 |
Behavior | 1.16E−06 - 4.45E−02 | NCF1, SLC6A4, TRPA1, FZD9, STX1A, GTF2IRD1, AVPR1A, LIMK1 |
UNC5C). The analysis of this network evidenced an indirect relationship among Williams and music related genes (AVPR1A to NCF1 and UNC5C to LAT2) but, as mentioned, these were non significant for our purpose.
The second network (
Interestingly, as depicted, we observed a direct correlation between STX1A and SLC6A4 (5-HTT), a Williams and music related genes, respectively. This direct correlation is supported by four Source Ingenuity Expert Findings [
The third network includes only ten Williams related genes (BAZ1B, BCL7B, CLDN3, CLDN4, DNAJC30, FKBP6, GTF2IRD2, LIMK1, MLXIPL, WBSCR22) and no music related genes, and it doesn’t reveal any interesting gene-gene relationship (
SLC6A4, the serotonin transporter gene, is involved in the formation of neural circuits. Factors regulating the expression of serotonin transporter could have a role in cortical development. Syntaxin 1A (STX1A) can be one
Symbol | Entrez Gene Name | Entrez Gene | Location |
---|---|---|---|
ABHD11 | abhydrolase domain containing 11 | 83451 | Cytoplasm |
CEP55 | centrosomal protein 55kDa | Cytoplasm | |
CETN2 | centrin, EF-hand protein, 2 | Nucleus | |
CLASP1 | cytoplasmic linker associated protein 1 | Cytoplasm | |
CLASP2 | cytoplasmic linker associated protein 2 | Cytoplasm | |
CLIP2 | CAP-GLY domain containing linker protein 2 | 7461 | Cytoplasm |
COL4A3BP | collagen, type IV, alpha 3 (Goodpasture antigen) binding protein | Cytoplasm | |
DSCAM | Down syndrome cell adhesion molecule | Plasma Membrane | |
EIF4H | eukaryotic translation initiation factor 4H | 7458 | Cytoplasm |
GYG1 | glycogenin 1 | Cytoplasm | |
ITSN1 | intersectin 1 (SH3 domain protein) | Cytoplasm | |
LAT2 | linker for activation of T cells family, member 2 | 7462 | Plasma Membrane |
MAPRE3 | microtubule-associated protein, RP/EB family, member 3 | Cytoplasm | |
MRPL23 | mitochondrial ribosomal protein L23 | Cytoplasm | |
MRPL40 | mitochondrial ribosomal protein L40 | Cytoplasm | |
MRPS21 | mitochondrial ribosomal protein S21 | Cytoplasm | |
MVB12A | multivesicular body subunit 12A | Cytoplasm | |
NSUN5 | NOP2/Sun domain family, member 5 | 55695 | Unknown |
PLCG1 | phospholipase C, gamma 1 | Cytoplasm | |
POM121/POM121C | POM121 transmembranenucleoporin | 9883 | Nucleus |
SARS2 | seryl-tRNAsynthetase 2, mitochondrial | Cytoplasm | |
TBL2 | transducin (beta)-like 2 | 26608 | Plasma Membrane |
TRIM50 | tripartite motif containing 50 | 135892 | Unknown |
TRPA1 | transient receptor potential cation channel, subfamily A, member 1 | 8989 | Plasma Membrane |
TSG101 | tumor susceptibility gene 101 | Cytoplasm | |
UBC | ubiquitin C | Cytoplasm | |
UBE2D1 | ubiquitin-conjugating enzyme E2D 1 | Cytoplasm | |
UNC5C | unc-5 homolog C (C. elegans) | 8633 | Plasma Membrane |
USP44 | ubiquitin specific peptidase 44 | Nucleus | |
VPS28 | vacuolar protein sorting 28 homolog (S. cerevisiae) | Cytoplasm | |
VPS37A | vacuolar protein sorting 37 homolog A (S. cerevisiae) | Cytoplasm | |
VPS37B | vacuolar protein sorting 37 homolog B (S. cerevisiae) | Cytoplasm | |
VPS37C | vacuolar protein sorting 37 homolog C (S. cerevisiae) | Cytoplasm | |
VPS37D | vacuolar protein sorting 37 homolog D (S. cerevisiae) | 155382 | Cytoplasm |
WBSCR27 | Williams Beuren syndrome chromosome region 27 | 155368 | Unknown |
Symbol | Entrez Gene Name | Entrez Gene | Location |
---|---|---|---|
ADRBK1 | adrenergic, beta, receptor kinase 1 | Cytoplasm | |
AP4S1 | adaptor-related protein complex 4, sigma 1 subunit | Cytoplasm | |
ATAD5 | ATPase family, AAA domain containing 5 | Extracellular Space | |
AVPR1A | arginine vasopressin receptor 1A | 552 | Plasma Membrane |
AVPR2 | arginine vasopressin receptor 2 | Plasma Membrane | |
DSCC1 | defective in sister chromatid cohesion 1 homolog (S. cerevisiae) | Nucleus | |
ELN | elastin | 2006 | Extracellular Space |
FKBP10 | FK506 binding protein 10, 65 kDa | Cytoplasm | |
FZD9 | frizzled family receptor 9 | 8326 | Plasma Membrane |
GAA | glucosidase, alpha; acid | Cytoplasm | |
Gpcr | Unknown | ||
GTF2I | general transcription factor IIi | 2969 | Nucleus |
GTF2IRD1 | GTF2I repeat domain containing 1 | 9569 | Nucleus |
HSF1 | heat shock transcription factor 1 | Nucleus | |
Igh | immunoglobulin heavy chain complex | Unknown | |
MAGEH1 | melanoma antigen family H, 1 | Cytoplasm | |
MLH1-PMS2 | Nucleus | ||
NCF1 | neutrophil cytosolic factor 1 | 653361 | Cytoplasm |
OTUB2 | OTU domain, ubiquitin aldehyde binding 2 | Unknown | |
PMS2 | PMS2 postmeiotic segregation increased 2 (S. cerevisiae) | 5395 | Nucleus |
PSD3 | pleckstrin and Sec7 domain containing 3 | Cytoplasm | |
RFC2 | replication factor C (activator 1) 2, 40kDa | 5982 | Nucleus |
RFTN1 | raftlin, lipid raft linker 1 | Plasma Membrane | |
RUSC1 | RUN and SH3 domain containing 1 | Cytoplasm | |
SLC6A4 | solute carrier family 6 (neurotransmitter transporter, serotonin), member 4 | 6532 | Plasma Membrane |
SLC6A9 | solute carrier family 6 (neurotransmitter transporter, glycine), member 9 | Plasma Membrane | |
SLU7 | SLU7 splicing factor homolog (S. cerevisiae) | Nucleus | |
SMAD3 | SMAD family member 3 | Nucleus | |
SRC | v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian) | Cytoplasm | |
STAG3 | stromal antigen 3 | 10734 | Nucleus |
STX1A | syntaxin 1A (brain) | 6804 | Cytoplasm |
STXBP2 | syntaxin binding protein 2 | Plasma Membrane | |
STXBP6 | syntaxin binding protein 6 (amisyn) | Cytoplasm | |
SUV420H2 | suppressor of variegation 4-20 homolog 2 (Drosophila) | Nucleus | |
UBC | ubiquitin C | Cytoplasm |
Symbol | Entrez Gene Name | Entrez Gene | Location |
---|---|---|---|
ACACB | acetyl-CoA carboxylase beta | Cytoplasm | |
ACLY | ATP citrate lyase | Cytoplasm | |
ATAD5 | ATPase family, AAA domain containing 5 | Extracellular Space | |
BAZ1A | bromodomain adjacent to zinc finger domain, 1A | Nucleus | |
BAZ1B | bromodomain adjacent to zinc finger domain, 1B | 9031 | Nucleus |
BAZ2A | bromodomain adjacent to zinc finger domain, 2A | Nucleus | |
BCL7A | B-cell CLL/lymphoma 7A | Unknown | |
BCL7B | B-cell CLL/lymphoma 7B | 9275 | Unknown |
CDC42BPA | CDC42 binding protein kinase alpha (DMPK-like) | Cytoplasm | |
Cldn | Plasma Membrane | ||
CLDN1 | claudin 1 | Plasma Membrane | |
CLDN3 | claudin 3 | 1365 | Plasma Membrane |
CLDN4 | claudin 4 | 1364 | Plasma Membrane |
CLDN5 | claudin 5 | Plasma Membrane | |
CLDN8 | claudin 8 | Plasma Membrane | |
DNAJC30 | DnaJ (Hsp40) homolog, subfamily C, member 30 | 84277 | Cytoplasm |
ELAVL1 | ELAV (embryonic lethal, abnormal vision, Drosophila)-like 1 (Hu antigen R) | Cytoplasm | |
FGF21 | fibroblast growth factor 21 | Extracellular Space | |
FKBP6 | FK506 binding protein 6, 36kDa | 8468 | Nucleus |
GTF2IRD2 | GTF2I repeat domain containing 2 | 84163 | Unknown |
HNF4A | hepatocyte nuclear factor 4, alpha | Nucleus | |
LIMK1 | LIM domain kinase 1 | 3984 | Cytoplasm |
MID1IP1 | MID1 interacting protein 1 | Cytoplasm | |
MLXIPL | MLX interacting protein-like | 51085 | Nucleus |
MYO1A | myosin IA | Cytoplasm | |
NME7 | NME/NM23 family member 7 | Cytoplasm | |
PHF10 | PHD finger protein 10 | Nucleus | |
PHF21A | PHD finger protein 21A | Nucleus | |
SMARCA4 | SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 | Nucleus | |
SS18 | synovial sarcoma translocation, chromosome 18 | Nucleus | |
SUMO2 | SMT3 suppressor of mif two 3 homolog 2 (S. cerevisiae) | Nucleus | |
TJP1 | tight junction protein 1 | Plasma Membrane | |
TP53 | tumor protein p53 | Nucleus | |
VHL | vonHippel-Lindau tumor suppressor, E3 ubiquitin protein ligase | Nucleus | |
WBSCR22 | Williams Beuren syndrome chromosome region 22 | 114049 | Nucleus |
of these factors, being involved in synaptic transmission. Particularly, a physic interaction between SERT and STX1A could be responsible for modulation of serotonin reuptake. SERT function is reduced by the deletion of STX1A in WS, suggesting a different development of specific cognitive skills such as music abilities.
Since 1990, technological development has largely modified our approach to biological and medical information. For instance, genome-wide association studies (GWASs) have revolutionized the field of human quantitative genetics and genome sequencing and gene expression data were used to identify gene modifications and modulations related to specific phenotypes. However, these experimental efforts to measure the functions of genes, especially those of unknown function, which are very challenging and very expensive in terms of time, effort, and money. Nowadays the use of appropriate hardware and software makes it possible to simulate static or dynamic, even complex, physiological or cellular processes to unravel the molecular pathways which are modulated by diverse set of genes in the hope of discovering information that would prompt future studies.
Analysis in silico, made through computer programs, represents an important new research method that allows the examination of a large amount of data not possible in a different way, if not with great human and economical efforts. For this reason we used this method to verify the initial hypothesis of this work, especially using IPA software to verify the possibility that some deleted gene in Williams syndrome acted, in normal conditions, as suppressor of other genes that were able to influence the development of musical skills.
Many studies have investigated genotype-phenotype correlation in WS individuals, but a clear, direct link has been established only for the elastin gene (ELN) responsible for the SVAS [
For this reason, it can be interesting to consider the observed direct correlation between STX1A and SLC6A4, the serotonin transporter gene. Neocortex receives serotoninergic innervations at the beginning of the development, suggesting an important role of serotonin in the formation of neural circuits [
Levels of serotonin during the development influence the neural morphology [
Since in normal conditions, STX1A influence serotonin levels, the results of research suggest that the lack of STX1A could cause alterations of 5HT levels justifying a different development of specific cognitive skills.
Specific cognitive abilities are involved in listening, processing and producing music, so musicality can be considered as a particular form of cognitive profile.
For this reason, it cannot be excluded the involvement of serotonin not only in the development of basic cog- nitive abilities but also in musical abilities.