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 [1] ; others consider music as a valid tool to express feelings, being able to arouse deep and meaningful emotions [2] . Darwin proposed in 1871 that singing was used to attract the opposite sex [3] . Furthermore, music provides a tool to study numerous aspects of neuroscience from motor-skill learning to emotion [4] .

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 [5] - [7] . AP is the ability to identify or produce isolated musical tones [8] . This condition can be considered as a complex trait, depending on both genetic factors and exposure to musical training during childhood [5] . On the other hand, congenital amusia, also known as “tone-deafness”, is a deficit of music perception that, in absence of deafness or any other cognitive disorder, determines the inability to correctly reproduce sounds. The hereditary component of the congenital amusia has been demonstrated within 9 amusic families, where 39% of first-degree relatives had the same disorder, against 3% only in control families [9] .

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 [10] . The common deletion region ranges in size from 1.5 to 1.8 Mb between the polymorphic markers D7S1816 and D7S489B and encompasses approximately 28 genes, including Elastin (ELN), LIM1 kinase (LIMK1), Frizzled (FZD9, previously called FZD3), and Syntaxin1A (STX1A) [11] [12] . A clear genotype-phenotype correlation has been established in WS only for the ELN gene, which is responsible for the vascular and connective tissue abnormalities [13] .

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 [14] . However, the most interesting aspect of WS cognitive profile is the presence of relatively strong abilities in four specific domains: social drive [15] , face processing, language [16] , and musical skills [17] [18] . Individuals with WS show unique communication strengths and impairments that are challenging to treat in community, educational, and vocational settings. Many issues regarding characteristics of auditory sensitivity in WS remain to be resolved [19] .

Studies about this rare syndrome have suggested various candidate genes for the intellectual disability, like GTF2I [20] . Since WS has a clearly defined genetic etiology, playing for sure a role in the determination of the characteristic cognitive and behavioral profile, investigators have used this syndrome as a model to elucidate gene-brain-behavior relationships [21] - [24] . In this view, the existence of a strong predisposition to the development of musicality in individuals affected by WS lead us to suppose that some genes deleted in this syndrome are somehow involved in the evolution of this ability. The general hypothesis of this study is that genes deleted in WS act in normal conditions, in healthy people, as “suppressors of music ability”. Assuming this hypothesis is correct, the consequence should be that musical behaviour is expressed naturally and at a superior level in individuals where these genes are inactive.

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.

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 [50] [51] . Moreover, mouse models have suggested other genotype-phenotype correlations, such as those between craniofacial abnormalities and GTF2I and GTF2IRD1 genes [52] , tooth anomalies and visuo-spatial deficit, associated to GTF2I, GTF2IRD1 and GTF2IRD2 genes [53] , as well as deficits in motor coordination, associated with CLIP2 gene [54] . Likewise, the function of the carbohydrate response element-binding protein (MLXIPL, a.k.a. ChREBP or WBSCR14) in the regulation of the expression of enzymes involved in glucose and lipid metabolism [55] [56] suggests that haploinsufficiency of this gene is associated with the higher relative body fat, silent diabetes and/or impaired glucose tolerance found in WS adult individuals [57] . The molecular substrates underlying the other clinical features of 7q11.23 CNVs, including the neurocognitive phenotypes, are still debated [58] .

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 [59] [60] .

Levels of serotonin during the development influence the neural morphology [61] and density of synaptic contacts [62] . Levels of serotonin are important also in modulation of synaptic plasticity [63] [64] , neural activity [65] and neural maturation [66] . Experimental manipulation in serotonin levels during the first post-natal development can produce characteristic behavioural syndromes [67] [68] and long term cognitive damages [69] - [71] . Furthermore, changes in normal serotonergic signalling reveal a crucial role of serotonin system in the formation of sensitive maps of somatosensorial [72] [73] and visual [74] [75] systems. Then, SERT regulation in neocortex 5HT levels can have serious physiological, anatomical and behavioural effects. Reduction of STX1A results in decreased function and expression of SERT. Reduction of STX1A is related to a decrease of SERT function. STX1A acts like a positive regulator of synaptic signalling [48] .

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.