GENES, LANGUAGE, AND MUSICALITY: AN INTERSECTION

Ciências da Saúde, Volume 28 – Edição 135/JUN 2024 / 17/06/2024

REGISTRO DOI: 10.5281/zenodo.11489446

Betina S. Moreschi Antonio,a,b Ricardo Lehtonen Rodrigues Souza,a Stephanie Elisabeth Quadrado,a Liliane M. F. O. Lehtonen-Souza,c Lupe Furtado Alle,a

Abstract

Throughout human history, music and language have evolved and taken distinct forms in diverse cultures, enabling several types of communication. Both music and language systems are complex and have intrigued researchers aiming to uncover their neurobiological bases. This review compiles studies at the intersection of genes, language, and musicality, describing research that investigates the connection between genes and cognition. We conducted a comprehensive literature review, searching relevant published scientific articles in the MEDLINE database via PubMed and SciELO (The Scientific Electronic Library On-Line) using the following combination of terms: (gene OR genes OR genetic OR polymorphism) AND (language OR musicality OR speech OR music) AND (cognition). Potentially eligible studies span from 1990 to 2022. Our review showed that music and language are complex cognitive functions that share many cognitive domains, maintaining close relationships with attention, memory, and motor skills. Although the cognition of music and language can be affected by an individual’s environment, genes play an important role in their development. For instance, the discovery of FOXP2, involved in speech and musical ability, highlights the genetic basis of these skills. Other genes, such as FOXP1, CNTNAP2, AVPR1A, SLC6A4, ITGB3, COMT, DRD2, and DRD4, are also related to elements of verbal fluency and musical perception. Genes play an undeniable role in the development of an individual’s linguistic and musical abilities. Future research should quantitatively address the relationship between genes, language, and musicality.

Introduction

Language, the ability of an individual to convey an idea, is a crucial aspect of communication. Human language is communicated through articulated sounds, written marks, or physical gestures associated with specific ideas. Identifying the universal rules of language and understanding their origin has been a major challenge in neuroscience (Morato, 2001). The acquisition of language constitutes “a privileged arena” (Scarpa, 2001), a prominent place for the debate of genetics, medicine, linguistics, cognitive psychology, neuropsychology, and psycholinguistics. In recent decades, researchers from different areas have joined forces to elucidate the origins and development of language. Despite obvious methodological and applied advances, scientists, linguists, and philosophers remain highly critical of the entire field of evolution. This struggle was led by Noam Chomsky, one of the fathers of modern linguistics and cognitive science (Ravignani et al., 2018).

Chomsky distinguishes between I-languages and E-languages. For him, I-language is the only form of language worth studying because it is outside the variations of time and culture. I-language refers to internal linguistic representations, a universal language of thought also known as universal grammar, which he says is innate. E-language includes multiple languages and sequences of sounds emitted in the outside world, which vary between individuals and cultures. Chomsky (2015) claims that the processes behind the development and evolution of a wide variety of E-language domains cannot be studied empirically and remain a mystery (Chomsky, 2015). In contrast, Ravignani et al. (2018) have criticized and classified as declining the view that the nature, origins, and evolution of language cannot be approached empirically. These authors defend the value of considering the evolution of language when studying the evolution of music. They claim that studying language and music within a common framework provides important insights and testable hypotheses across disciplines. Furthermore, they argue that anti-empiricist views on language have detrimental effects on understanding its origins and evolution.

In addition to these hypotheses, the relationship between genes and language has been investigated for many years, with significant studies demonstrating hereditary transmission and genetic etiology of different language disorders. Often, language disorders cannot be explained because verbal fluency is compromised, despite normal cognitive balance and environmental stimulation. Many of these disorders are multigenerational, suggesting the involvement of genetic factors. However, their etiology at the molecular level is not well understood (Pearce & Rohrmeier, 2012).

The FOXP2 gene, which codes for a protein called forkhead box P2, was discovered in 2001 and was the first gene implicated in speech and language disorders. Neuroscientists investigated the case of a British multigenerational family known as the KE family in the 1990s. The family had the same speech and expression disorder in successive generations, which aroused suspicion of a relationship between dyspraxia, a neurological dysfunction that prevents certain motor functions, and the yet undiscovered FOXP2 gene. Lai et al. (2001) plotted a genetic map of those affected by dyspraxia in the family, identifying mutations in FOXP2. Analysis of the wildtype gene sequence and its comparison with that of the KE family revealed that all affected members had a single nucleotide polymorphism (SNP) in their DNA, with a substitution of the nucleotide guanine (G) for adenine (A). This substitution occurs in the coding region of the gene (exon 14), resulting in the exchange of an amino acid in the protein sequence. Replacement of arginine with histidine in the DNA-binding domain of FOXP2 triggered structural and phenotypic effects in affected individuals. Such a mutation was found in heterozygous individuals in the family; all affected individuals inherited one mutated copy of the FOXP2 gene, the other being normal. This discovery led scientists to a new avenue of investigation of the substrates and mechanisms underlying the development of human speech.

By investigating FOXP2 as a dysfunctional manifestation, scientists were able to establish a relationship between a gene and a language disorder for the first time. The discovery of the FOXP2 gene has also led to a discussion of the (inter)dependence relationships that may exist between language and other cognitive domains. Neuroscience, alongside genetics, has contributed notably to deciphering the links between genes, brain development, cognition, and behavior (Baxter et al., 2007). Sean Kean asks, “How much artistic genius is in our DNA?” in his book The Art of Gene (Kean, 2013). For him, “Art, music, poetry, and painting… there are no more beautiful expressions of neural brilliance. Genetics can illuminate some unexpected aspects of fine arts.”

Music can be a paradigm that helps us understand the interactions between genes and their environment. Singing, improvisation, composing a theme, and dancing involve a series of behavioral, cognitive, and social processes. Similarly, composing, improvising, and organizing music are complex creative functions of the brain in which the involvement of biology remains unknown (Ukkola, 2009). The notion that FOXP2 is a language gene supports the idea that musicality and language share a common point of origin (Leongómez et al., 2022). One study found that the FOXP2 gene appears to affect rhythm perception and production without affecting pitch perception and production skills, which seem to be influenced by independent genetic factors such as congenital amusia (Alcock et al., 2000). Similarly, note detection in melodies may be more significant among identical twins, presenting additional performance for fraternal musical perception, suggesting that genetic influence is more important than shared environments for musical pitch perception (Seesjärvi et al., 2016). In addition to FOXP2, genes like FOXP1, CNTNAP2, AVPR1A, SLC6A4, ITGB3, COMT, DRD2, and DRD4 have been hypothesized to be related to elements of verbal fluency and musical perception (herein referred to as candidate genes).

Relevant published scientific articles were searched in the MEDLINE database via PubMed and Embase until May 2022 using the following combination of terms: (gene OR genes OR genetic OR polymorphism) AND (language OR musicality OR speech OR music) AND (cognition). Potentially eligible studies spanned from 1990 to May 2022. No restrictions on language or year of publication were imposed. Reference lists of the included studies and relevant reviews were also manually searched for potentially eligible studies (snowball method). At the end of the searches of each database, duplicate references were excluded. The exclusion of studies occurred in the following sequence: first, titles and abstracts were independently selected for inclusion by the first two authors, and then full-text articles were recovered to be selected separately for inclusion in the review. A qualitative synthesis of the data extracted from the studies was performed. The research team discussed the data, identified themes, and content categories that fit each theme. This analysis allowed us to identify common findings and unique contributions across all included studies. The results of the linkage and genetic studies are summarized in Table 1.

Table 1. – Molecular data of the selected genes and the phenotypic association of language and music found in the literature review.

Verbal fluency and musicality involve a variety of cognitive and behavioral processes. Candidate genes associated with the development of both these skills should be investigated. Supposing that the candidate genes mentioned above influence cognitive and psychosocial processes, the following research questions were elaborated: Is it possible to confirm the association of these genes with verbal fluency and musicality? In this review, we compiled information on the nine candidate genes mentioned above, their associations with the cognitive functions of language and musicality, and their phenotypic correlations.

Main Text

Genes associated with language and musicality

Several genes have been implicated in language and musicality development. Some are thought to contribute to these traits in non-human species such as birds. In the following section, we discuss the most prominent of these genes, which will later form the focus of our review.

FOXP2

This gene encodes a member of the forkhead box (FOX) family of transcription factors. It is expressed in the fetal and adult brain as well as in several other organs, such as the lungs and gut. FOXP2 plays an important role in the proper development of the speech and language regions of the brain during embryogenesis and may be involved in a variety of biological pathways and cascades that ultimately influence language development. Mutations in this gene cause speech-language disorder 1 (SPCH1), also known as autosomal dominant speech and language disorders, with orofacial dyspraxia. [NCBI–RefSeq, Feb2010].

FOXP1

This gene belongs to subfamily P of the FOX family of transcription factors. FOX transcription factors play an important role in the regulation of tissue- and cell type-specific gene transcription during development and adulthood. This gene can act as a tumor suppressor because it is lost in several tumor types. Furthermore, FOXP1 maps onto a chromosomal region (3p14.1) that is reported to contain tumor suppressor genes. [NCBI – RefSeq, Jul. 2008]. Germ mutations causing intellectual deficit syndrome, severe language delay, and mild dysmorphism (ORPHA:391372)

CNTNAP2

The protein encoded by this gene is part of the neurexin family, members of which function in the vertebrate nervous system as cell-adhesion molecules and receptors. This protein is localized in the juxtapararanodes of myelinated axons and mediates interactions between neurons and glia during nervous system development. It is also involved in the localization of potassium channels within differentiating axons. CNTNAP2 is one of the largest genes in the human genome and encompasses almost 1.5% of chromosome 7. It directly binds to and is regulated by FOXP2. This gene has been implicated in multiple neurodevelopmental disorders, including Gilles de la Tourette syndrome, schizophrenia, epilepsy, autism, ADHD, and intellectual disability. [NCBI – RefSeq, Jul 2017].

AVPR1A

The protein encoded by this gene acts as a receptor for arginine vasopressin. The receptor mediates cell contraction and proliferation, platelet aggregation, release of coagulation factors, and glycogenolysis [NCBI – RefSeq, Jul 2008]. Musical aptitude is related to the AVPR1A haplotype (Ukkola et al. 2009). PMID: 19461995).

SLC6A4

This gene encodes an integral membrane protein that transports the neurotransmitter serotonin from the synaptic spaces into presynaptic neurons. The encoded protein terminates the action of serotonin and recycles it in a sodium dependent manner. There have been conflicting reports in the literature regarding the possible effect of this polymorphism on behavior and induction of depression [NCBI – RefSeq, May 2019]. The polymorphic region linked to the serotonin transporter (5-HTTLPR) of SLC6A4 is involved in the encoding of speech in the human subcortical auditory pathway. (Selinger et al. 2016). PMID: 27798133).

ITGB3

ITGB3 is an integrin beta 3 protein. Integrin beta 3 is found along the alpha IIb chain in platelets. Integrins participate in cell adhesion and cell surface-mediated signaling [NCBI – RefSeq, Jul 2008]. ITGB3 haplotypes indicate a statistically significant association with autism, characterized by different levels of impairment in social interaction and communication associated with language disorders (Napolioni et al., 2010). PMID: 21102624)

COMT

Catechol-O-methyltransferase (COMT) catalyzes the transfer of a methyl group from S-adenosylmethionine to catecholamines, including neurotransmitters dopamine, epinephrine, and norepinephrine. COMT is important for the metabolism of catechol drugs used in the treatment of hypertension, asthma, and Parkinson’s disease. [NCBI – RefSeq, Sep 2008]. It is associated with intelligence, memory, emotional difficulties, and addiction, as well as some musical characteristics, such as pitch recognition and improvisation. (Sugiura et al., 2017. PMID: 27909011)

DRD2

This gene encodes the D2 subtype of dopamine receptor. A missense mutation in this gene causes myoclonus dystonia, and other mutations have been associated with schizophrenia [NCBI – RefSeq, Jul 2008]. The association between the A1 allele of DRD2 and reduced verbal abilities and phonological memory (Beaver et al., 2010. PMID: 20532925).

DRD4

This gene encodes the D4 subtype of dopamine receptor. The D4 subtype is a G protein-coupled receptor that inhibits adenylyl cyclase. Mutations in this gene have been associated with various behavioral phenotypes, including autonomic nervous system dysfunction, attention deficit/hyperactivity disorder, and the personality trait of novelty seeking [NCBI – RefSeq, Jul 2008]. Higher DRD4 receptor expression has been identified in leukocytes from musicians and individuals with autism (Emanuelle et al., 2009. PMID: 20150884).

Cognitive function, language, and musicality

Voice communication mediated by speech and language is a unique characteristic of humans and has been the focus of many studies (Perszyk & Waxman, 2019). Such studies have provided new insights into how the unique human link between language and cognition may have emerged in evolution. Many variations in language functions and speech disorders exist; among them are aphasia, stuttering, articulation disorders, verbal dyspraxia, and specific language disorders. Most language disorders appear in early childhood and, with appropriate intervention, are easily controlled and remedied. However, it is common to find young people and adults with articulation disorders and impaired speech fluency. Many of these disorders are found in multigenerational families, which suggests the involvement of genetic factors. However, their etiology at the molecular level is still not well understood (Kang & Drayna, 2011). Like the British KE family (described above), association studies and genetic molecular analyses for specific language disorders have focused on investigating families in which many individuals from different generations have verbal dyspraxia. Researchers have proposed various theories regarding the origin of this disorder. Hurst et al. (1990) believed that affected family members had verbal developmental dyspraxia, whereas Gopnik et al. (1990, 1991) suggested that dyspraxia is determined by damage related to grammatical competence. The first thesis was strengthened due to a study that included 21 members of the affected KE family and demonstrated the existence of orofacial dyspraxia (related to the temporomandibular joint, chewing, sucking, and swallowing) common to those affected, a problem associated with linguistic and extralinguistic damage, which, by extension, makes it difficult to locate a gene directly associated with language. Later studies that examined the issue from different perspectives, such as behavioral linguistics, neuroimaging methods, and genetic research, made it possible to locate the cause of the condition in the FOXP2 gene (Lai et al., 2001).

KE family members affected and unaffected by dyspraxia participated in studies that involved positron emission tomography (PET) and magnetic resonance imaging (MRI), which made it possible to verify the functional and morphological aspects of the problem. The descriptions of the KE family published since 1990 revealed significant inconsistencies between analyses, which eventually confounded the phenotypic characterization of the KE (Fisher et al., 2003). However, the general picture that results from FOXP2 mutation leads to a discussion about the (inter)dependence relationships between language and other human cognitive domains.

Musical ability, such as verbal fluency, requires a broad cognitive and multisensory spectrum for its development. However, in addition to cognitive, genetic, and physical factors, an environment of exposure to music is also necessary for the development of musical skills. Individuals require access to musical instruments that promote the intrinsic and extrinsic reinforcement of their musical ability. Singing, improvisation, theme composition, and dance are musical activities that involve behavioral, cognitive, and social processes. The concept of musicality is broad because it involves musical skills, including the perception of differences in tone, rhythm, dynamics, and timbres, using voice, the body (in dance), and culture (Mithen, 2009). Developing musicality is important in helping to develop higher mental functions such as auditory processing, linguistic and metalinguistic skills, and cognitive processes.

The human desire to communicate has been a powerful driving force, both in the evolution of auditory function and in how it can be altered by experience during an individual’s lifetime (Kraus & Slater, 2015). The cochlea is responsible for translating acoustic energy into neural activity, which is gradually transformed into the auditory brainstem. This transformation is controlled by different neural response properties, such as pitch, roughness, intensity, and interaural disparities, which are integrated and regulated in the superior olivary complex and inferior colliculus (Sinex, 2008; Langner & Ochse, 2006). Next, the auditory stimulus is pre-processed at the level of the superior colliculus and thalamus, from which auditory information is transmitted to the primary auditory cortex (Kass et al., 1999). Once these auditory characteristics are expressed, the information of the auditory stimulus enters auditory sensory memory, and the Gestalten auditory stage is formed, entailing processes of melodic, rhythmic, tonal, and spatial grouping—a considerable portion of auditory scenario analysis and flow segregation.

Musicians have developed special skills including the ability to improvise, peripheral reading ability, manual dexterity, and processing absolute pitch (AP). Many scientists support the hypothesis that the daily training that musicians perform to maintain or increase these musical skills can lead to functional reorganization of the cerebral cortex (Elbert et al., 1995). The degree of this functional reorganization was determined by the age at which musical training began. Many reports in the literature indicate that more musical processing occurs in the right cerebral hemisphere than in the left cerebral hemisphere. However, some reports indicate that with an increase in musical sophistication, there is a change in musical processing from the right to the left hemisphere. However, this remains a controversial issue (Bever & Chiarello, 2009). In studies by Ohnishi et al. (2001), functional MRIs (fMRIs) demonstrate that musicians and non-musicians exhibit a different pattern of brain activity when they perceive music. This study found significant neuroanatomical distinctions between the two groups. During a passive music listening activity, musicians showed activity in their dominant secondary auditory areas in the left temporal cortex and left dorsolateral prefrontal cortex, whereas non-musicians showed dominant secondary auditory areas on the right.

To determine whether brain asymmetry for speech and music arises from acoustic cues or domain-specific neural networks, researchers (Albouy et al., 2020) selected temporal or spectral modulations in sing-speech stimuli and cross-referenced the song’s verbal and melodic content. The degradation of temporal information impaired speech recognition, but not melody recognition, whereas the degradation of spectral information impaired melody recognition, but not speech recognition. Brain scans revealed a right-left asymmetry in speech and music. Speech content classification occurs exclusively in the left auditory cortex, whereas melodic content classification occurs only in the right auditory cortex (Sammler, 2020). These results suggest a correlation between the acoustic properties of communication signals and the specific characteristics of the neurons that adapt to this effect. Recently, another study (Leongómez et al., 2022) on the universality of musical form and structure suggested that music and its perception are related in complex ways to language or at least are analogous to it. The deep relationship between language and music in terms of shared neural resources is supported by evidence from a variety of studies (Koelsch et al., 2005; Coumel et al., 2019) and has become an important area of research in the cognitive sciences and the reason for years of debate.

Many studies have reported on the current progress of genetics in understanding human cognition, placing genetics in a prominent place in the future of cognitive science. Reviews and arguments have been put forward in genetics and developmental neuroscience, hoping to provide a new perspective on the timeless issues of innate and modularity. They provide different empirical examples and theoretical perspectives on how integration between different levels of description (gene, brain, and cognition) should be achieved (Ramus, 2006).

Genetic basis of language and musicality

Although language (Krawczyk-Becker & Gerkmann, 2018), musical aptitude, and creativity (Pulli et al., 2008; Ukkola, 2009) are learned traits, they also display a percentage of heritability. Studies have identified there are several genetic loci linked to musical aptitude, including genes involved in neurocognitive functions, auditory pathways, and the development of the inner ear (Beccacece, 2021). According to Levitin (2012), music activates regions throughout the brain, not just a single music center. Polymorphisms in the genes involved in serotonin neurotransmission are associated with behavior and musical aptitude. Neuroscientific studies (Ebstein et al., 2010) have shown that music, verbal fluency, and disorders in both cognitive fields can appear multigenerational within families. FOXP2 was the first and most well-studied gene implicated in human speech and language skills (Becker et al., 2018).

Researchers have studied the regulation of FOXP2, its downstream effectors, and its modes of action as transcription factors in brain development and function, providing an integrated view of what is known about critical molecular networks (den Hoed et al., 2021). Alcock et al. (2000) investigated whether FOXP2 gene mutation interferes with other vocal functions, such as singing. Thus, They tested nine affected individuals from the KE family and observed that these individuals had deficiencies in both the perception and production of rhythm in vocal and manual modalities. Therefore, FOXP2 seems to participate in an individual’s perception and creation of rhythms in music, and music and speech may have a common origin (Peretz, 2009). This finding supports the hypothesis that genetic approaches should be used to better understand the genesis of such cognitive domains. FOXP2 likely acts as a pivot for other genes relevant to speech and language phenotypes, making these other candidate genes associated with language disorders (Graham & Fisher, 2013; Pinel et al., 2012).

A recent study highlighted a small subclass of putative targets for FOXP2 through validation and follow-up in animal or cell-based models (Den Hoed et al., 2021). FOXP2 directly binds to the regulatory regions of the CNTNAP2 locus to repress its expression (Vernes et al., 2008; Mendoza & Scharff, 2017). CNTNAP2, as described above, encodes a neurexin protein and is expressed in the developing human cortex; homozygous loss-of-function mutations cause childhood-onset epilepsy, followed by mental retardation and language regression (Strauss et al., 2006). In a study of 180 British families with children with specific language disorders, significant associations were found between the results of the nonsense word repetition test and a group of preselected SNPs in CNTNAP2. Beyond its effects as a transcriptional repressor, FOXP2 has been reported to be a direct activator of VLDLR (very-low-density lipoprotein receptor) expression (Adam et al., 2016; Mendoza & Scharff, 2017).

In gene association research, homozygous disruptions in the VLDLR gene (MIM#224050) have been identified (Dixon-Salazar et al., 2012). Another gene from the P subfamily of the FOX family that is also associated with language disorders is FOXP1 on chromosome 3p14.1. FOXP1 encodes a transcriptional repressor One study revealed that it is implicated in autism spectrum disorders and intellectual disabilities with language impairments (Bacon & Rappold, 2012). Recent studies have described FOXP1 syndrome (FOXP1S), a neurodevelopmental disorder caused by mutations or deletions in FOXP1, and numerous clinical studies have elucidated the role of FOXP1 in neurodevelopment and characterized its phenotype (Lozano R et al., 2021). FOXP1 is associated with “intellectual disability and language impairment with or without autistic features” (OMIM #613670) and is caused by FOXP1 gene deletions and mutations, including nonsense, missense, and in-frame deletions (Meerschaut et al., 2017).

Researchers have identified specific molecularly analogous brain regions for singing and speech in birds and humans. These regions are situated in broader homologous brain regions that specialize in singing and speech (Pfenning et al., 2014). Studies have demonstrated that the learning of speech and song in birds relies on lateral neural pathways that function similarly (Petkov and Jarvis, 2012; Pfenning et al., 2014). Because of the similarities between the mechanisms of development of both functions, songbirds provide a valuable model for behavioral, neural, and molecular analyses of genes involved in verbal communication (Bolhuis et al., 2010). Researchers have determined the potential of neurally expressed FOXP proteins to bind to the regulatory regions of VLDLR and CNTNAP2 and regulate their transcriptional activity in zebra finches. As in humans, FOXP2 represses CNTNAP2 promoter activity and activates the VLDLR promoter activity (Poot, 2015; Vernes et al., 2006). In a recent study, to elucidate the molecular and evolutionary background of musical aptitude, researchers compared genome-wide genotyping data (641 K SNPs) from 148 Finnish individuals characterized by their musical aptitude (Szyfter & Witt, 2020). Gene ontology classification revealed that the positive selection regions contained genes associated with inner ear development, auditory perception, song perception and production (FOXP1), and language development (FOXP1 and VLDLR). Such identification supports the hypothesis that music and language share a common genetic and evolutionary basis (Liu et al., 2016).

In genetic association studies, polymorphisms in genes such as AVPR1A and SLC6A4 were chosen as candidates based on results from other studies. AVPR1A on chromosome 12q has been implicated in music memory and perception, whereas SLC6A4 on chromosome 17q has been associated with music memory and chorus participation (Tan et al., 2014). In humans and other mammals, the hormone arginine vasopressin (AVP) plays a prominent role in the control of higher cognitive functions, such as memory and learning. AVP receptor 1A, encoded by AVPR1A, mediates the influence of AVP on the brain (Granot et al., 2007). Studies have shown an association between AVP and social behavior, vocalization (Winslow & Insel, 1991), autism, and cognition (Vargha-Khadem et al., 1995). AVPR1A is associated with communication disorders and language impairments in children (Israel et al., 2008; Klein et al., 2007; Smith et al., 2005). It is also associated with musical and phonological memories (Mariath et al., 2017; Ukkola et al., 2009).

The biological basis of the ability to engage in any musical activity remains unclear. However, many neuroscientific studies have shown functional and structural differences between the brains of musicians and non-musicians (Kanduri et al. 2015). Significant transcriptional responses were observed only in participants with substantial periods of music training or relatively high musical aptitude scores. This suggests that certain musical skills (innate or acquired through music education) may influence transcriptional responses to listening to music. In the study “The effect of music performance on the transcriptome of professional musicians,” researchers provided evidence of candidate genes and molecular mechanisms underlying musical performance. The SLC6A4 gene (also known as the 5-hydroxy tryptamine transporter, 5-HTT) encodes the serotonin transporter and is expressed in the brain, especially in emotion areas involved in the expression of emotion (Ukkola-Vuoti et al., 2011). The serotonin transporter regulates synaptic concentrations of serotonin and influences many functions such as perception, emotions, and cognitive activities (Li et al., 2013). SLC6A4 and AVPR1A polymorphisms have been associated with artistic creativity and short-term musical memory in professional dancers. A study at the Hebrew University of Israel hypothesized that the epistatic interaction between AVPR1A (RS1 and RS3 promoter microsatellites) and SCL6A4 (the 5-HTT-linked polymorphic region [5-HTTLPR] promoter region and the intron 2 variable number of tandem repeats [VNTR]) contributes to creative dance skills and noted that the association between these genes reflects social-sensory-motor integration (Bachner-Melman et al. 2005). In another study, 523 participants were analyzed for tagging SNPs for AVPR1A and SLC6A4 to determine whether other variants in these genes were associated with single or non-musician status. This study suggests that allelic variants in SLC6A4 and AVPR1A are associated with certain behavioral outcomes, namely choir membership. They found that the STin2.9 and STin2.12 alleles in the SLC6A4 gene were more common in choral singers than in non-musicians, whereas the STin2.10 allele was less common. In the same group, no overall differences were detected in AVPR1A allele frequencies at the RSI, RS3, and AVR polymorphisms. These qualities may be associated with STin2 polymorphism in singers, but not with musical ability. The study concluded that STin2 VNTR in SLC6A4 is associated with choir membership. Allele frequencies in other AVPR1A and SLC6A4 polymorphisms were similar between choral singers and non-musicians. Therefore, a possible interpretation of the results is that genetic factors other than those affecting musical ability alone may influence whether an individual belongs to a choir.

Another study identified that the most studied polymorphism of SLC6A4 is involved in speech coding in the subcortical auditory pathway (Selinger et al., 2016). In this study, serotonin was found to be fundamental for modulating the cerebral response to speech at the cortical and subcortical levels. Participants with low expression of serotonin transporters had higher signal-to-noise ratios and a greater representation of the periodic part of the syllable than participants with medium to high expression. This suggests that individuals with low transporter expression adjust their synaptic activity to the characteristics of the stimulus and, therefore, are less sensitive to sound. These results demonstrated the involvement of 5-HTT-LPR polymorphisms in subcortical auditory coding, suggesting a genetic basis for human subcortical responses to speech sounds. Many studies have shown that coding accuracy at subcortical stages is experience-dependent and can be trained (Skoe & Chandrasekaran, 2014), Researchers in this study suggested that special attention should be paid to the early development of individuals with medium and high expression of 5-HTT to stimulate auditory processing through musical or other auditory training.

To understand music in human evolution and communication, researchers analyzed polymorphisms in genes associated with social bonding and cognitive functions (AVPR1A, SLC6A4, COMT, and DRD2) in 19 Finnish families (n = 343 members) with professional musicians and active amateurs (Ukkola et al., 2009). All individuals were tested with the Karma Music Test (KMT) and Carl the Seashore tests for pitch (SP) and time (ST), which are formal tests of musical ability. The researchers highlighted that high music test scores were significantly associated with creative music function (p < 0.0001). They discovered an overall haplotype association between AVPR1A markers RS1 and RS3 and KMT (p = 0.0008; corrected p = 0.00002), SP (p = 0.0261; corrected p = 0.0072), and combined music test scores (COMB) (p = 0.0056; corrected p = 0.0006). The AVPR1A haplotype AVR+RS1 further suggested a positive association with ST (p = 0.0038; corrected p = 0.00184) and COMB (p = 0.0083; corrected p = 0.0040) using a haplotype-based association test (HBAT). These results suggest that musical aptitude is an innate ability associated with several predisposing genetic variants (Pulli et al. 2008). Several studies have shown evidence of dopaminergic influence on language ability (Gaysina et al., 2013). The substitution of a valine amino acid for methionine in the fourth exon of this gene (Val158Met) reduces its enzymatic activity, thereby modifying COMT-related actions such as executive function, working memory, and emotional processing. Studies have shown that this variation is associated with intelligence (Turnbridge et al., 2006), memory (Shaw, 2007), emotional difficulties, addiction (Taylor, 2013), and some musical characteristics, such as pitch recognition and improvisation (Tan et al., 2014).

Serotonin encodes the β3 integrin (ITGB3) gene, which codes for a signal receptor (Mariath et al., 2017). Autism is a neurodevelopmental disorder characterized by impairments in three core areas: language, social interaction, and restricted or repetitive behaviors (Schuch et al., 2014). Some studies have demonstrated an association between the interaction between ITGB3 and SLC6A4 and autism spectrum disorder. A previous study identified a significant two-way interaction between markers in SLC6A4 and ITGB3, indicating that epistasis between variants in these two genes is associated with an increased risk of autism, even though the markers themselves do not show an individual association with the disease (Napolioni et al., 2011). Although ITGB3 belongs to an interactive network involved in several behavioral and cognitive functions, an association study of the rs15908 polymorphism found no significant association between this gene and musicality scores (Mariath & Silva, 2017).

The dopamine receptor genes DRD2 and DRD4 have been shown to influence behavioral and cognitive functions in genetic association studies (Liu et al., 2016). Attention deficit disorder is regularly comorbid with various communication and language disorders. In a Chinese Han population study, DRD2 was associated with stuttering (Lan et al., 2009); and another study demonstrated an association between the A1 allele of DRD2 and reduced verbal ability in adolescence and early adulthood (Beaver et al., 2010). Certain SNPs (rs11604671, rs2734849, rs1800497, and rs6278) in DRD2 are associated with communication and language disorders in tests of non-verbal and verbal comprehension (Eicher et al., 2013).

DRD4 is also widely expressed in the central nervous system, especially in planning- and reward-related regions. The 48 base pairs VNTR polymorphism in the third exon has nine different alleles (Mariath et al., 2017). The repeat sequence of the DRD4 7R allele is associated with reduced expression of DRD4 compared to that of the 2R and 4R alleles (Naka et al., 2011). This polymorphism has been associated with attention deficit hyperactivity disorder (Camarena et al., 2007), obsessive-compulsive disorder (OCD) (Walitza et al., 2008), impulsivity (Eisenberg et al., 2007), literacy skills, and executive functions (Kegel & Bus, 2013).

People with autism spectrum disorder (ASD) have communication deficits, severe impairments in social functioning, and associated aberrant behaviors. DRD2 and DRD4 influence behavioral and cognitive functions (Mariath, 2017). In a study at the University of Pavia in Italy (Emanuelle et al., 2009), researchers investigated the expression of DRD4 in the peripheral blood lymphocytes of healthy adult musicians and patients with autism spectrum disorder under the hypothesis that the dopaminergic system may contribute to the biological dimensions of musical abilities in both musicians and autistic individuals. The study found that musicians and individuals with autism had greater expression of the DRD4 receptor in lymphocytes than in controls. Research on the evolution of rhythm processing has clarified that dopamine receptors are expressed in mesolimbic and mesocortical pathways. These regions are involved in the reward process, which has connections modulated by the activity of listening to music. Regular rhythm is a central component of human music (Ravignani et al., 2018). It seems likely that musical rhythms incorporated primitive biological elements, and unusual (apomorphic) elements have probably evolved recently.

In a Japanese study on the age-dependent effects of the COMT VAL158Met polymorphism on language function in developing children (Sugiura et al., 2017), researchers noted that subjects with the Met polymorphism in COMT surpassed those with the Val homozygous polymorphism in language capacity during early school years. Homozygous Val probands exhibited significantly less cortical activation than Met carriers during word processing, particularly at an older age. These findings indicate that the effects of the COMT genotype on language ability and cortical language processing may change over a narrow age range of 6–10 years.

Conclusion

The study of language, musicality, and their relationships can contribute to elucidating the cognitive and biological mechanisms, functions, and courses of development. A growing body of evidence suggests that musical activity can improve auditory and cognitive functions, including language skills. The technological evolution of imaging techniques and molecular genetics has enabled great scientific advances. fMRI, for example, can identify brain regions activated in the brain, cognitive processes, or behaviors. When combined with advanced methods of large-scale genetic and genomic analysis (GWAS), fMRI opens new horizons for researchers and their areas of expertise. Combining these techniques can shed light on the missing links between speech and music phenotypes, the intrinsic patterns of brain circuits, and the human genome. Deciphering neurogenetic pathways and genes related to language and musicality can aid in the diagnosis and treatment of language and communication disorders as well as contribute new information regarding the variability of verbal fluency and musicality. Basic studies can identify the genetic risk factors implicated in language developmental disorders, and research can uncover the complex underlying genetic architecture that involves a range of molecular mechanisms.

In this review, we have presented several genes implicated in language and music processing, including FOXP2, mutations that cause serious problems with the sequencing of speech sounds; CNTNAP2, which is associated with typical forms of language impairment; and FOXP1, with alleles connected to the autism phenotype, severe language delay, and motor coordination deficits. Furthermore, we have shown the role of serotonergic neurotransmission genes and related pathways in cognitive function, such as the association of the 5-HTTLPR polymorphism of the SLC6A4 gene with the human subcortical response to speech sounds. Moreover, the same polymorphism, as well as the AVPR1A gene, is associated with musical aptitude, as shown by the tendency to adhere to and participate in choral activities. Another study showed that the serotonin transporter regulates serotonin synaptic concentrations and influences many functions such as perception, emotions, and cognitive activities, and that musical skills (innate or acquired through music education) can influence transcriptional responses to music listening. The study “The effect of music performance on the transcriptome of professional musicians” provides evidence of candidate genes and molecular mechanisms underlying musical performance. We have discussed associations between SCL6A4 and ITGB3 and autism spectrum disorder and reduced language skills despite the benefits of musical aptitude. Polymorphisms in the dopaminergic system genes COMT (VAL158 MET), DRD2 (rs6278), and DRD4 (VNTR) are associated with intelligence, memory, emotional difficulties, and dependence, as well as some musical characteristics, such as pitch recognition and improvisation. Furthermore, these variations are associated with autism, severe speech delay, motor coordination deficits, changes in executive function, working memory, emotional processing, reduced literacy skills, reading difficulties, and stuttering.

The questions raised in research on language and musicality are often interlaced within a common framework, providing important insights and testable hypotheses in both areas. Finally, although genes play an important role in language and music, epigenetics and the environment should not be neglected. Genetic exploration of these two functions can provide useful insights into cognition, behavior, and brain functions. This review aims to contribute to different areas of research involving these two cognitive domains and their relationships to stimulate further genetic studies in other populations to highlight whether clear global differences in genes are associated with musical ability and verbal fluency, and to verify the possible prevalence of the genetic basis of language and musicality in humans.

References

Adam, I., Mendoza, E., Kobalz, U., Wohlgemuth, S. & Scharff, C. (2016). FoxP2 directly regulates the reelin receptor VLDLR developmentally and by singing. Mol Cell Neurosci, 74, 96-105. https://doi.org/10.1016/j.mcn.2016.04.002.

Alcock, K. J., Passingham, R. E., Watkins, K., & Vargha-Khadem, F. (2000). Pitch and timing abilities in inherited speech and language impairment. Brain and language, 75(1), 34-46.

Bachner-Melman, R., Dina, C., Zohar, A. H., Constantini, N., Lerer, E., Hoch, S., Sella, S., Nemanov, L., Gritsenko, I., Lichtenberg, P., Granot, R., & Ebstein, R. P. (2005). AVPR1A and SLC6A4 gene polymorphisms are associated with creative dance performance. PLoS Genetics, 1(3), e42. https://doi.org/10.1371/journal.pgen.0010042

Bacon, C., & Rappold, G. A. (2012). The distinct and overlapping phenotypic spectra of FOXP1 and FOXP2 in cognitive disorders. Human Genetics 131(11), 1687-1698. https://doi.org/10.1007/s00439-012-1193-z

Baxter, S.D., Royer, J.A., Hardin, J.W., Guinn, C.H., & Smith, A.F. (2007). Fourth-grade children are less accurate in reporting school breakfast than school lunch during 24-hour dietary recalls. J Nutr Educ Behav, 39, 126-133.

Beaver, K. M., Delisi, M., Vaughn, M. G., & Wright, J. P. (2010). Association between the A1 allele of the DRD2 gene and reduced verbal abilities in adolescence and early adulthood. Journal of Neural Transmission, 117(7), 827-830. https://doi.org/10.1007/s00702-010-0421-8

Beccacece, L., Abondio, P., Cilli, E., Restani, D., & Luiselli, D. (2021). Human Genomics and the Biocultural Origin of Music. Int J Mol Sci. 22(10), 5397. https://doi.org/10.3390/ijms22105397.

Becker, M., Devanna, P., Fisher, S.E., & Vernes, S.C. (2018) Mapping of Human FOXP2 Enhancers Reveals Complex Regulation. Front Mol Neurosci, 11, 47. https://doi.org/10.3389/fnmol.2018.00047

Bever, T.G. & Chiarello, R.J. (2009). Cerebral dominance in musicians and non-musicians. 1974. J Neuropsychiatry Clin Neurosci. 21(1), 94-97. https://doi.org/10.1176/jnp.21.1.94.

Bolhuis, J. J., Tattersall, I., Chomsky, N., & Berwick, R. C. (2014). How could language have evolved? PLoS biology, 12(8), e1001934.

Camarena, B., Loyzaga, C., Aguilar, A., Weissbecker, K., & Nicolini, H. (2007). Association study between the dopamine receptor D (4) gene and obsessive-compulsive disorder. European Neuropsychopharmacology, 17(6-7), 406-409. https://doi.org/10.1016/j.euroneuro.2006.08.001

Chomsky, N. (2016). What kind of creatures are we? Columbia University Press.

Coumel, M., Christiner, M., & Reiterer, S.M. (2019). Second Language Accent Faking Ability Depends on Musical Abilities, Not on Working Memory. Front Psychol. 12, 10:257. https://doi.org/10.3389/fpsyg.2019.00257.

Den Hoed, J., Devaraju, K., & Fisher, S.E., (2021). Molecular networks of the FOXP2 transcription factor in the brain. EMBO Rep, 22(8):e52803. https://doi.org/10.15252/embr.202152803.

Dixon-Salazar, T.J., Silhavy, J.L., Udpa, N., Schroth, J., Bielas, S., Schaffer,… & Gleeson, J.G. (2012). Exome sequencing can improve diagnosis and alter patient management. Sci Transl Med. 13, 4(138), 138ra78. https://doi.org/10.1126/scitranslmed.3003544.

Ebstein, R.P., Israel, S., Chew, S.H., Zhong, S., & Knafo, A. Genetics of human social behavior. Neuron, 65(6), 831-44. https://doi.org/10.1016/j.neuron.2010.02.020.

Eicher, J. D., Powers, N. R., Cho, K., Miller, L. L., Mueller, K. L., Ring, S. M., Tomblin, J. B., & Gruen, J. R. (2013). Associations of prenatal nicotine exposure and the dopamine related genes ANKK1 and DRD2 to verbal language. PLoS ONE, 8(5), e63762. https://doi.org/10.1371/journal.pone.0063762

Eisenberg, D. T., Mackillop, J., Modi, M., Beauchemin, J., Dang, D., Lisman, S. A., Lum, J. K., & Wilson, D. S. (2007). Examining impulsivity as an endophenotype using a behavioral approach: A DRD2 TaqI A and DRD4 48-bp VNTR association study. Behavioral and Brain Functions, 3, 2. https://doi.org/10.1186/1744-9081-3-2

Elbert, T., Pantev, C., Wienbruch, C., Rockstroh, B., & Taub, E. (1995). Increased cortical representation of the fingers of the left hand in string players. Science, 270, 305-307

Emanuelle, E., Boso, M., Cassola, F., Broglia, D., Bonoldi, I., Mancini, L., Marini, M., & Politi, P. (2009). Increased dopamine DRD4 receptor mRNA expression in lymphocytes of musicians and autistic individuals: Bridging the music-autism connection. Neuroendocrinology Letters, 31(1), 122-125.

Fisher, S. E., Lai, C. S. L., & Monaco, A. P. (2003). Deciphering the genetic basis of speech and language disorders. Annual Review of Neuroscience, 26, 57-80. https://doi.org/10.1146/annurev.neuro.26.041002.131144

Gaysina, D., Fergusson, D. M., Leve, L. D., Horwood, J., Reiss, D., Shaw, D. S., Elam, K. K., Natsuaki, M. N., Neiderhiser, J. M., & Harold, G. T. (2013). Maternal smoking during pregnancy and offspring conduct problems: evidence from 3 independent genetically sensitive research designs. JAMA Psychiatry, 70(9), 956-963. https://doi.org/10.1001/jamapsychiatry.2013.127

Gene [Internet]. Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information; 2004–[cited Jul. and Sep. 2008, Feb. 2010, Jul. 2017, and May 2019]. Available from: https://www.ncbi.nlm.nih.gov/gene/

Gopnik, M. (1990) Genetic basis of grammar defect. Nature, 347(6288), 26.

Gopnik, M. (1990) Feature-blind grammar and dysphasia. Nature, 344(6268), 715.

Gopnik, M. & Crago, M. B., (1991). Familial aggregation of a developmental language disorder. Cognition, 39(1), 1-50.

Graham, S. A., & Fisher, S. E. (2013). Decoding the genetics of speech and language. Current Opinion in Neurobiology, 23(1), 43-51. https://doi.org/10.1016/j.conb.2012.11.006

Granot, R., Frankel, Y., Gritsenko, V., Lerer, E., Gritsenko, I., Bachner-Melman, R., Israel, S., & Ebstein, R. P. (2007). Provisional evidence that the arginine vasopressin 1a receptor gene is associated with musical memory. Evolution and Human Behavior, 28(5), 313-318. https://doi.org/10.1016/j.evolhumbehav.2007.05.003

Hurst, J. A., Baraitser, M., Auger, E., Graham, F., & Norell, S. (1990). An extended family with a dominantly inherited speech disorder. Dev Med Child Neurol, 32, 352-355.

Israel, S., Lerer, E., Shalev, I., Uzefovsky, F., Reibold, M., Bachner-Melman, R., Granot, R., Bornstein, G., Knafo, A., Yirmiya, N., Ebstein, R. P., Neumann, I. D., & Landgraf, R. (2008). Molecular genetic studies of the arginine vasopressin 1a receptor (AVPR1A) and the oxytocin receptor (OXTR) in human behaviour: from autism to altruism with some notes in between. Progress in Brain Research, 170, 435-449. https://doi.org/10.1016/S0079-6123(08)00434-2

Kanduri, C., Kuusi, T., Ahvenainen, M., Philips, A. K., Lähdesmäki, H., & Järvelä, I. (2015). The effect of music performance on the transcriptome of professional musicians. Scientific Reports, 5, 9506. https://doi.org/10.1038/srep09506

Kang, C., & Drayna, D. (2011) Genetics of Speech and Language Disorders. Annu Rev Genomics Hum Genet, 12, 145-164.

Kass, J. H., Hackett, T. A., & Tramo, M. J. (1999). Auditory processing in primate cerebral cortex. Current Opinion in Neurobiology, 9(2), 164-170. https://doi.org/10.1016/s0959-4388(99)80022-

Kean, S. (2013). The Violinist’s Genetics–and Other Stories from Love, War, and Genius. São Paulo: Jorge Zahar.

Kegel, C. A. T., & Bus, A. G. (2013). Links between DRD4, executive attention, and alphabetic skills in a nonclinical sample. Journal of Child Psychology and Psychiatry, 54(3), 305-312. https://doi.org/10.1111/j.1469-7610.2012.02604.x

Klein, T. A., Neumann, T., Reuter, J., Hennig, M., von Cramon, J. Y., & Ullsperger, D. (2007). Genetically determined differences in learning from errors. Science, 318(5856), 1642-1645. https://doi.org/10.1126/science.1145044

Koelsch, S., & Siebel, W. A. (2005). Towards a neural basis of music perception. Trends in Cognitive Sciences, 9(12), 578-584. https://doi.org/10.1016/j.tics.2005.10.001

Kraus, N., Slater, J. (2015). Music and language: relations and disconnections. Handb Clin Neurol, 129, 207-222. doi: 10.1016/B978-0-444-62630-1.00012-3.

 Krawczyk-Becker, M. & Gerkmann, T. (2018). Nonlinear Speech Enhancement Under Speech PSD Uncertainty, EEE International Conference on Acoustics, Speech and Signal Processing (ICASSP), 641-645, doi: 10.1109/ICASSP.2018.8461810 .

Lai, C. S., Fisher, S. E, Hurst, J. A., Vargha-Khadem, F., & Monaco, A. P. (2001) A forkhead-domain gene is mutated in a severe speech and language disorder. Nature, 413(6855), 519-523. https://doi.org/10.1038/35097076.

Lan, J., Song, M., Pan, C., Zhuang, G., Wang, Y., Ma, W., Chu, Q., Lai, Q., Xu, F., Li, Y., Liu, L., & Wang, W. (2009). Association between dopaminergic genes (SLC6A3 and DRD2) and stuttering among Han Chinese. Journal of Human Genetics, 54(8), 457-460. https://doi.org/10.1038/jhg.2009.60

Langner, G., & Ochse, M. (2006). The neural basis of pitch and harmony in the auditory system. Musicae Scientiae, [In press]. https://doi.org/10.1177/102986490601000109

Leongómez, J.D., Havlíček, J., & Roberts, S. C. (2022) Musicality in human vocal communication: an evolutionary perspective. Philos Trans R Soc Lond B Biol Sci, 377(1841), 20200391. https://doi.org/10.1098/rstb.2020.0391

Levitin, D. J. (2012). What does it mean to be musical? Neuron, 73(4), 633-637. https://doi.org/10.1016/j.neuron.2012.01.017

Li, W., Cressy, M., Qin, H., Fulga, T., Van Vactor, D., & Dubnau, J. (2013). MicroRNA-276a functions in ellipsoid body and mushroom body neurons for naive and conditioned olfactory avoidance in Drosophila. The Journal of Neuroscience, 33(13), 5821-5833. https://doi.org/10.1523/JNEUROSCI.4004-12.2013

Liu, X., Kanduri, C., Oikkonen, J., Karma, K., Raijas, P., Ukkola-Vuoti, L., Teo, Y-Y., & Järvelä, I. (2016). Detecting signatures of positive selection associated with musical aptitude in the human genome. Scientific Reports, 6, 21198. https://doi.org/10.1038/srep21198

Lozano, R., Gbekie, C., Siper, P. M., Srivastava, S., Saland, J. M., Sethuram, S., Tang, L., Drapeau, E., Frank, Y., Buxbaum, J. D., & Kolevzon, A. (2021). FOXP1 syndrome: a review of the literature and practice parameters for medical assessment and monitoring. J Neurodev Disord, 13(1), 18. https://doi.org/10.1186/s11689-021-09358-1.

Mariath, L. M., Silva, A. M., Kowalski, T. W., Gattino, G. S., Araujo, G. A., Figueiredo, F. G., Tagliani-Ribeiro, A., Roman, T., Vianna F. S. L., Schuler-Faccini, L., & Schuch, J. B. (2017). Music genetics research: Association with musicality of a polymorphism in the AVPR1A gene. Genetics and Molecular Biology, 40(2), 421-429. https://doi.org/10.1590/1678-4685-GMB-2016-0021

Meerschaut, I.,Rochefort, D.,Revençu, N.,Pètre, J.,, Corsello, C., Rouleau, G. A., Hamdan, F. F., Michaud, J. L., Morton, J., Radley, J., Ragge, N., García-Miñaúr, S., Lapunzina, P., Bralo, M. P., Mori, M. Á., Moortgat, S., Benoit, V., Mary, S., Bockaert, N.,… Callewaert, B. (2017). foxp1 related intellectual disability syndrome: A recognisable entity. Journal of Medical Genetics, 54(9), 613–623. https://doi.org/10.1136/jmedgenet-2017-104579

Mendoza, E., & Scharff, C. (2017). Protein-Protein Interaction Among the FoxP Family Members and their Regulation of Two Target Genes, VLDLR and CNTNAP2 in the Zebra Finch Song System. Front Mol Neurosci, 10, 112. doi: 10.3389/fnmol.2017.00112.

Mithen, S. J. (2009). Thoughtful foragers: A study of prehistoric decision making. Cambridge University Press.

Morato, E. (2001). Neurolinguistic, In F. Mussalin & A. C. Bentes (Eds.), Introduction to linguistics: Domains and borders (pp. 143-171). Cortez.

Morley, A. P., Narayanan, M., Mines, R., Molokhia, A., Baxter, S., Craig, G., Lewis, C. M., & Craig, I. (2012). AVPR1A and SLC6A4 polymorphisms in choral singers and non-musicians: A gene association study. PLoS One, 7(2), e31763. https://doi.org/10.1371/journal.pone.0031763

Naka, I., Nishida, N., & Ohashi, J. (2011). No evidence for strong recent positive selection favoring the 7-repeat allele of VNTR in the DRD4 gene. PLoS One, 6(8), e24410. https://doi.org/10.1371/journal.pone.0024410

Napolioni, V., Lombardi, F., Sacco, R., Curatolo, P., Manzi, B., Alessandrelli, R.,…,., …, & Persico, A. M., (2011). Family-based association study of ITGB3 in autism spectrum disorder and its endophenotypes. Eur J Hum Genet, 19(3), 353-359. https://doi.org/10.1038/ejhg.2010.180.

Ohnishi, T., Matsuda, H., Asada, T., Aruga, M., Hirakata, M.,…& Imabayashi, E. (2001). Functional anatomy of musical perception in musicians. Cereb Cortex, 11(8), 754-760.

Orphanet. [Internet]. Rrare diseases; gene; FOXP1– – forkhead box P1[accessed 2022 Jun 28]. Available at: https://www.orpha.net/consor/cgi-bin/Disease_Genes.php

Pearce, M., & Rohrmeier, M. (2012). Music cognition and the cognitive sciences. Topics in Cognitive Science, 4(4), 468-484. https://doi.org/10.1111/j.1756-8765.2012.01226.x

Peretz, I. (2009). Music, language, and modularity framed in action. Psychologica Belgica, 49(2-3), 157-175. https://doi.org/10.5334/pb-49-2-3-157

Perszyk, D. R., & Waxman, S.R. (2019). Infants’ advances in speech perception shape their earliest links between language and cognition. Sci Rep. 9(1), 3293. doi: 10.1038/s41598-019-39511-9.

Pfenning, A.R., Hara, E., Whitney, O., Rivas, M.V., Wang, R., Roulhac, P.L.,…, & Jarvis, E. D. (2014). Convergent transcriptional specializations in the brains of humans and song-learning birds. Science, 346 (6215), 1256846. doi: 10.1126/science.1256846.

Pinel, P., Fauchereau, F., Moreno, A., Barbot, A., Lathrop, M., Zelenika,…,, …, & Dehaene, S. (2012). Genetic variants of FOXP2 and KIAA0319/TTRAP/THEM2 locus are associated with altered brain activation in distinct language-related regions. The Journal of Neuroscience, 32(3), 817-825. https://doi.org/10.1523/JNEUROSCI.5996-10.2012

Petkov, C. I., & Jarvis, E. D. (2012). Birds, primates, and spoken language origins: behavioral phenotypes and neurobiological substrates. Frontiers in evolutionary neuroscience, 4, 12.

Poot, M. (2015) Connecting the CNTNAP2 Networks with Neurodevelopmental Disorders. Mol Syndromol, 6(1), 7-22. https://doi.org/10.1159/000371594

Pulli, K., Karma, K., Norio, R., Sistonen, P., Göring, H. H., & Järvelä, I. (2008). Genome-wide linkage scan for loci of musical aptitude in Finnish families: evidence for a major locus at 4q22. J Med Genet, 45(7), 451-456. https://doi.org/10.1136/jmg.2007.056366.

Ramus F. Genes, brain, and cognition: a roadmap for the cognitive scientist. Cognition. 2006 Sep; 101(2):247-69. doi: 10.1016/j.cognition.2006.04.003.

Ravignani, A., Thompson, B., & Filippi, P. (2018). The evolution of musicality: What can be learned from language evolution research? Frontiers in Neuroscience, 12, 20. https://doi.org/10.3389/fnins.2018.00020

Reuter, M., Roth, S., Holve, K., & Hennig, J. (2006). Identification of first candidate genes for creativity: A pilot study. Brain Research, 1069(1), 190-197. https://doi.org/1016/j.brainres.2005.11.046

Sammler, D. (2020) Splitting speech and music. Science. Feb 28; 367(6481):974-976. doi: 10.1126 /science.aba 7913.

Scarpa, E. M. (2001). Acquisition of language, In: F. Mussalim & A. C. Bentes (Eds.), Introduction to linguistics: Domains and borders (pp. 203-232). Cortez.

Schuch, J. B., Muller, D., Endres, R. G., Bosa, C. A., Longo, D.,…,& Roman, T. (2014). The role of β3 integrin gene variants in Autism Spectrum Disorders—diagnosis and symptomatology. Gene, 553(1), 24-30. https://doi.org/10.1016/j.gene.2014.09.058.

Selinger, L., Zarnowiec, K., Via, M., Clemente, I. C., & Escera, C. (2016). Involvement of the serotonin transporter gene in accurate subcortical speech encoding. The Journal of Neuroscience, 36(42), 10782-10790. https://doi.org/10.1523/JNEUROSCI.1595-16.2016

Seesjärvi E, Särkämö T, Vuoksimaa E, Tervaniemi M, Peretz I, Kaprio J. (2016). The Nature and Nurture of Melody: A Twin Study of Musical Pitch and Rhythm Perception. Behav Genet. Jul; 46(4):506-15. doi: 10.1007/s10519-015-9774.

Shaw, P. (2007). Intelligence and the developing human brain. Bioessays, 29(10), 962-973. https://doi.org/10.1002/bies.20641

Sinex, D. G. (2008). Responses of cochlear nucleus neurons to harmonic and mistuned complex tones. Hearing Research, 238(1-2), 39-48. https://doi.org/10.1016/j.heares.2007.11.001

Skoe, E. & Chandrasekaran, B. (2014). The layering of auditory experiences in driving experience-dependent subcortical plasticity. Hear Res, 311, 36-48. doi: 10.1016/j.heares.2014.01.002.

Smith, S. D., Pennington, B. F., Boada, R., & Shriberg, L. D. (2005). Linkage of speech sound disorder to reading disability loci. Journal of Child Psychology and Psychiatry, 46(10), 1057-1066. https://doi.org/10.1111/j.1469-7610.2005.01534.x

Strauss, K. A., Puffenberger, E. G., Huentelman, M. J., Gottlieb, S., Dobrin, S. E., Parod, J. M., Stephan, D. A., & Morton, D. H. (2006). Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2. The New England Journal of Medicine, 354(13), 1370-1377. https://doi.org/10.1056/NEJMoa052773

Sugiura, L., Toyota, T., Matsuba-Kurita, H., Iwayama, Y., Mazuka, R., Yoshikawa, T., & Hagiwara, H. (2017). Age-dependent effects of catechol-O-methyltransferase (COMT) gene Val158Met polymorphism on language function in developing children. Cerebral Cortex, 27(1), 104-116. https://doi.org/10.1093/cercor/bhw371

Szyfter, K. & Witt, M.P., (2020). How far musicality and perfect pitch are derived from genetic factors? J Appl Genet, 61(3), 407-414. https://doi.org/10.1007/s13353-020-00563-7.

Tan, Y. T., McPherson, G. E., Peretz, I., Berkovic, S. F., & Wilson, S. J. (2014). The genetic basis of music ability. Frontiers in Psychology, 5, 658. https://doi.org/10.3389/fpsyg.2014.00658

Taylor, S. (2013). Molecular genetics of obsessive-compulsive disorder: A comprehensive meta-analysis of genetic association studies. Molecular Psychiatry, 18(7), 799-805. https://doi.org/10.1038/mp.2012.76

Tunbridge, E. M., Harrison, P. J., & Weinberger, D. R. (2006). Catechol-o-methyltransferase, cognition and psychosis: Val158Met and beyond. Biological Psychiatry, 60(2), 141-151. https://doi.org/10.1016/j.biopsych.2005.10.024

Ukkola, L.T., Onkamo, P., Raijas, P., Karma, K., & Järvelä, I. (2009). Musical aptitude is associated with AVPR1A-haplotypes. PLoS One, 4, e5534. https://doi.org/10.1371/journal.pone.0005534

Ukkola-Vuoti, L., Oikkonen, J., Onkamo, P., Karma, K., Raijas, P., & Järvelä, I. (2011). Association of the arginine vasopressin receptor 1A (AVPR1A) haplotypes with listening to music. Journal of Human Genetics, 56(4), 324-329. https://doi.org/10.1038/jhg.2011.13

Vargha-Khadem, F., Watkins, K., Alcock, K., Fletcher, P., & Passingham, R. (1995). Praxic and nonverbal cognitive deficits in a large family with a genetically transmitted speech and language disorder. Proceedings of the National Academy of Sciences of the United States of America, 92(3), 930-933. https://doi.org/1073/pnas.92.3.930

Vernes, S. C., Nicod, J., Elahi, F. M., Coventry, J. A., Kenny, N., Coupe, A. M.,…., … & Fisher, S. E. (2006). Functional genetic analysis of mutations implicated in a human speech and language disorder. Human molecular genetics, 15(21), 3154-3167.

Vernes, S. C., Newbury, D. F., Abrahams, B. S., Winchester, L., Nicod, J., Groszer, M., Alarcón, M., Oliver, P. L., Davies, K. E., Geschwind, D. H., Monaco, A. P., & Fisher, S. E. (2008). A functional genetic link between distinct developmental language disorders. The New England Journal of Medicine, 359(22), 2337-2345. https://doi.org/10.1056/NEJMoa0802828

Walitza, S., Scherag, A., Renner, T. J., Hinney, A., Remschmidt, H., Herpertz-Dahlmann, B., Schulz, E., Schafer, H., Lange, K. W., Wewetzer, C., & Gerlach, M. (2008). Transmission disequilibrium studies in early onset of obsessive-compulsive disorder for polymorphisms in genes of the dopaminergic system. Journal of Neural Transmission, 115(7), 1071-1078. https://doi.org/10.1007/s00702-008-0051-6

Winslow, J., & Insel, T. R. (1991). Vasopressin modulates male squirrel monkeys’ behavior during social separation. European Journal of Pharmacology, 200(1), 95-101. https://doi.org/10.1016/0014-2999(91)90671-c

Yan, W., Shen, Q., & Yiqiang, Z. (2003). Induction of very low-density lipoprotein receptor (VLDLR) transcription by VLDL is mediated by the extracellular signal-regulated kinase signaling pathway. J. Huazhong Univ. Sci. Technol. [Med. Sci.],23, 97-100. https://doi.org/10.1007/BF0285992

aDepartment of Genetics, Federal University of Paraná-UFPR
bSpeech Therapist – UMULTI – Hospital Complex of Clinics – CHC-UFPR/EBSERH – Curitiba–PR, Brasil
cMasters Student Department of Genetics, Federal University of Paraná-UFPR – Curitiba–PR, Brasil