CORE Metadata, citation and similar papers at core.ac.uk Provided by Nature Precedings The genetics of colored sequence synesthesia: Evidence of linkage to chromosome 16q and genetic heterogeneity for the condition Stephanie S. Nelson1, Nili Avidan2, Anand K. Sarma1, Rejnal Tushe1, Dianna M. Milewicz2, Kwanghyuk Lee3, Molly Bray4, Suzanne M. Leal3, David M. Eagleman1,5* 1Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA; 2Division of Medical Genetics, Department of Internal Medicine, University of Texas Medical School at Houston, Houston, TX, USA; 3Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; 4Departments of Epidemiology and Genetics, University of Alabama at Birmingham, Birmingham, AL, 5Department of Psychiatry, Baylor College of Medicine, Houston, TX, USA *Correspondence: David Eagleman, PhD, Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA. Email: [email protected] Abstract Synesthesia is a perceptual condition in which normal sensory stimulation can trigger anomalous sensory experiences. For example, synesthetes may experience colors in response to sounds, tastes in response to words, or smells in response to touch. We here focus on colored sequence synesthesia, in which color experiences are triggered by learned ordinal sequences such as letters, numbers, weekdays and months. Although synesthesia has been noted in the scientific literature for over a century, it is understood only at the level of the phenomenology, and not at the molecular and neural levels. We have performed a linkage analysis to identify the first genetic loci responsible for the increased neural crosstalk underlying colored sequence synesthesia. Our analysis has identified a 23 MB region on chromosome 16 as a putative locus for the trait. Our Nature Precedings : doi:10.1038/npre.2009.3987.1 Posted 19 Nov 2009 data provide the first step in understanding neural crosstalk from its molecular basis to its behavioral consequences, opening a new inroad into the understanding of the multisensory brain. Keywords: synesthesia; linkage analysis; chromosome 16 Introduction In synesthesia, ordinary stimuli elicit the year trigger color experiences . We will anomalous perceptual experiences . In one refer to these forms collectively as colored form, known as grapheme-color synesthesia, sequence synesthesia (CSS), since they viewing a letter or digit triggers the visual involve the triggering of color experiences by experience of a specific color ; in closely learned sequences (Figure 1). The particular related forms, days of the week or months of color pairings for each stimulus are 2 idiosyncratic for each synesthete. Grapheme- of these ideas (insufficient pruning and color is one of the most common varieties, increased arborization) have in common is the estimated in random sample studies at >1% of idea that a synesthetic brain harbors an the population (Simner et al 2006), and we abnormal profile of synaptic connections show below that weekday- and month- (Figure 2b). synesthesias are highly correlated. A second hypothesis implicates unusual Synesthetic experiences differ from imagery inhibition as the cause of synesthesia . The in their consistency and automaticity. These idea is that excitation is counterbalanced by associations are often involuntary and inhibition in normal brains, while in synesthetic constant over time, much like the memory of a brains the excitation can overcome the friend’s face upon hearing her name. This is weakened inhibition. In this framework, the thought to occur by an increasing degree of same rich connectivity is present in all brains; crosstalk between brain areas, such that the only difference between normals and activity in one area kindles activity in another. synesthetes is the functioning of the inhibitory 0 A N Sunday January networks (Figure 2c). 1 B O Monday February 2 C P Tuesday March 3 D Q Wednesday April 4 E R Thursday May 5 F S Friday June 6 G T Saturday July 7 H U August 8 I V September 9 J W October Figure 2. Two models of synesthesia. a. K X November Under normal conditions, excitation and L Y December Nature Precedings : doi:10.1038/npre.2009.3987.1 Posted 19 Nov 2009 inhibition are balanced such that activity in one M Z brain area does not lead to activity in another. Figure 1. Data from a representative subject Black lines represent excitatory input, red lines tested at synesthete.org, showing the color represent inhibitory input, and the red neuron experiences triggered by numbers, letters, represents local inhibition by interneurons. b. weekdays and months. An increase of excitatory wiring causes activity One hypothesis of synesthetic crosstalk in one area to kindle activity in the other. c. stipulates that excess connections in newborn When inhibition is decreased, either by brains are insufficiently pruned , leading to diminished input or decreased receptor increased cross-wiring in adulthood. A variant binTdhiensge, tawcoti vhityyp ointh eosnees aarreea i nsdpisretinagdusi sthoa bthlee of this idea is that there is increased outgrowth by behavioral measures , of neurons in a synesthete’s brain. What both electroencephalography and neuroimaging – 3 all of which demonstrate functional with CSS and we have verified the crossactivation but cannot discriminate consistency of these color-sequence between hypotheses of the underlying associations with a host of test batteries. molecular basis. In 1883, Sir Francis Galton observed that Methods synesthesia runs in families and suggested Family characterization that the condition is heritable . Cytowic (1989) To phenotype synesthetes, we leveraged the examined the inheritance patterns of eight fact that synesthetes show greater self-reported families and suggested that consistency than non-synesthetes – that is, synesthesia is transmitted as a dominant trait . when asked to match stimuli to the colors they Ward & Simner (2005), also relying on self- trigger, and then re-tested some time later, report, looked at inheritance patterns in 72 synesthetes are largely consistent in their families of varying size and conjectured that matches, whereas control subjects have a the trait may be inherited on the X– distinguishably worse performance . For chromosome based on their observation that example, when subjects are asked to describe the trait never seemed to pass from father to the color experienced on hearing items from a son . Asher et al (2009) reported two cases of list of words, phrases, and letters, synesthetes male-to-male transmission, which is show 92.3% consistency over a year later, problematic for the X–linked hypothesis while controls cluster around 32% consistency because a single authentic case invalidates it . However, X-linkage remains a possibility if For the purposes of rigorous phenotyping, there is incomplete penetrance. Incomplete we have developed the Synesthesia Battery penetrance seems likely, as evidenced by the (www.synesthete.org), an online battery of finding of identical twins wherein one twin is tests that sensitively discriminates synesthetes synesthetic while the other is not . from non-synesthetes . During the battery, One shortcoming of previous genetic studies participants are serially presented with a full such as Cytowic (1989), Ward & Simner set of graphemes (A-Z, 0-9), three times each Nature Precedings : doi:10.1038/npre.2009.3987.1 Posted 19 Nov 2009 (2005) is the failure to objectively verify the in a random order. For each grapheme, they phenotype. Instead, participants were are asked to choose the best associated color deemed synesthetic based solely on self- from an online palette of 16.7 million colors. report. Furthermore, what counted as a The color choices are then analyzed for ‘pedigree’ was often as small as a single consistency within the session (e.g., did the parent and child. Therefore, at present, the participant choose a similar shade of green mode of inheritance is unknown. each time she saw the letter J?). Controls In an attempt to identify the first gene for display low consistency when associating colored-sequence synesthesia, we have colors to graphemes over 108 trials, while performed a large-scale family linkage synesthetes perform with high accuracy. analysis in synesthetic family pedigrees. We Participants were retested after six months to have limited the present study to individuals ensure consistency. 4 Once we established synesthesia in each Caucasian decent was obtained. Each proband, we investigated the presence of pedigree contained at least four verified CSS synesthesia in other members of the family. All synesthetes, as determined by the participants in this study completed the Synesthesia Battery. The saliva samples Synesthesia Battery to ensure proper were collected using OraGene sample kits classification. Each member of a pedigree (OraGene, DNA Genotek . The samples were was classified in one of three ways: purified according to Oragene DNA purification synesthetic, unknown, or unaffected. protocol and quantified using PicoGreen (Invitrogen, Carlsbad, CA, USA). The Inclusion criteria concentration of all samples was normalized Although synesthesia has been reported in to 50 ng/µl. A single-nucleotide-polymorphism many forms (e.g., tasting shapes, seeing (SNP) array (Linkage-12 BeadChip, Illumina, sounds, etc), for our analysis we included only Inc., San Diego, CA) containing 6,090 SNPs verified colored sequence synesthesias, which was used to genotype 24 affected and 24 here include the