Compared to the almost infinite complexity of vertebrate cognition and behavior, the number of genes influencing central nervous system development is staggeringly small (Kadakkuzha and Puthanveettil, 2013). Thus, understanding the molecular mechanism underlying the epigenetics of vertebrate central nervous system architecture has become an issue central to neuroscience (Kundakovic and Champagne, 2015).

One fundamental principle of brain organization is lateralization, i.e. structural or functional difference between the left and the right hemisphere of the brain (Corballis, 2014). Lateralization is a conserved feature across the vertebrate lineage (Ströckens et al., 2013; Ocklenburg et al., 2013a; Bisazza et al., 1998; Rogers et al., 2012; Versace and Vallortigara, 2015) and recent studies strongly suggest it is also present in invertebrates (Frasnelli et al., 2012). This ubiquity of behavioral and brain lateralization strongly supports the idea that lateralized central nervous system organization provides an evolutionary advantage (Vallortigara and Rogers, 2005). Suggestions about why a lateralized brain would increase an organism’s fitness include avoidance of unnecessary duplication of neuronal activity in both hemispheres, faster neuronal processing due to not being constrained by slow callosal transfer of information between the hemispheres and better coordination of unilateral behaviors in swarms or other social groups of animals (Vallortigara and Rogers, 2005; Corballis, 2009). In humans, hemispheric asymmetries have been shown in almost all major cognitive systems (Ocklenburg et al., 2014a) including language (Friederici, 2011; Sepeta et al., 2016), memory (Giammattei and Arndt, 2012; Tat and Azuma, 2016; Habib et al., 2003), attention (Falasca et al., 2015; Duecker et al., 2013), emotional processing (Demaree et al., 2005), face perception (De Winter et al., 2015), working memory (Langel et al., 2014; Nagel et al., 2013) and executive functions (Ocklenburg et al., 2011a, 2012; Stock and Beste, 2014).

By far the most widely investigated manifestation of lateralization in humans is handedness (Corballis, 2014). Importantly, handedness is related to the lateralized organization of cognitive systems in the human brain (Ocklenburg et al., 2014b; Frässle et al., 2016). For example, left-hemispheric language dominance is found in 96% of right-handed subjects, but only in 73% of left-handed subjects (Knecht et al., 2000). The relevance of handedness has recently been highlighted by Willems et al. (Willems et al., 2014), who state that it is one of the most important factors influencing the individual brain organization and that explicit inclusion of left-handers in experimental studies has strongly improved our understanding of language, motor behavior and visual processing. Handedness might not only be a behavioral proxy for individual brain organization, but is also interesting from a clinical perspective: A variety of neuropsychiatric and developmental disorders like autism spectrum disorders (Colby and Parkison, 1977; Forrester et al., 2014; Preslar et al., 2014; Rysstad and Pedersen, 2016), depression (Denny, 2009; Elias et al., 2001; Logue et al., 2015), bipolar disorder (van Dyck et al., 2012; Nowakowska et al., 2008), anxiety disorders (Logue et al., 2015; Hicks and Pellegrini, 1978; Orme, 1970; Wright and Hardie, 2012; Hardie et al., 2016; Lyle et al., 2013), schizophrenia (Hirnstein and Hugdahl, 2014; Dragovic and Hammond, 2005; Sommer et al., 2001) or alcoholism (Denny, 2011; Mandal et al., 2000; Sperling et al., 2000) has been associated with left- and mixed-handedness. Thus, understanding the ontogenesis of handedness and hemispheric asymmetries in general could potentially yield important insights into pathogenesis of these disorders.

However, despite their importance for many aspects of brain organization, the ontogenetic background of brain asymmetries is still far from being understood. Initially, single gene theories have been suggested to explain the emergence of handedness as a function of one gene with two alleles (Annett, 1998; McManus, 1985). However, recent genome wide association studies failed to detect any genome-wide significant single nucleotide polymorphisms, refuting single gene theories (Armour et al., 2014; Eriksson et al., 2010). Candidate gene studies revealed a number of genes that display an association with handedness, among them leucine rich repeat transmembrane neuronal 1 (LRRTM1) (Francks et al., 2007), proprotein convertase subtilisin/kexin type 6 (PCSK6) (Scerri et al., 2011; Arning et al., 2013; Brandler et al., 2013) and the androgen receptor gene (AR) (Arning et al., 2015; Hampson and Sankar, 2012; Medland et al., 2005). However, these genes explain only a fraction of the variance in handedness data. Moreover, a number of studies has suggested that only about one quarter of the variance in handedness is attributed to genetic variation, whereas the remaining 75% of variance are explained by non-shared environmental factors (Medland et al., 2006, 2009; Vuoksimaa et al., 2009). These findings highlight the importance of integrating both genetic variation and epigenetic processes modulating gene expression when investigating the ontogenesis of hemispheric asymmetries (Geschwind and Miller, 2001).

Asymmetric gene expression in the fetal cortex has been suggested as the molecular basis of left-right differences in hand-use: Sun et al. (Sun et al., 2005) compared gene expression levels in the right and left perisylvian cortex of the human fetus. At 12 gestational weeks, the authors identified 27 consistently asymmetrically expressed genes, which are mostly responsible for gene expression regulation, signal transduction, and cortical development. One of the consistently asymmetrically expressed genes was LIM Domain Only 4 (LMO4). Further investigation revealed that unilateral variation of Lmo4 expression in embryonic mice suppresses neurogenesis in one hemisphere, leading to the asymmetric functional area formation, neuronal production and axonal projection as well as altered paw preference (Li et al., 2013). Analysis of gene expression in the adult human brain yielded less clear results, since two independent studies found no differences in gene expression between analogous regions across the cerebral hemispheres (Hawrylycz et al., 2012; Pletikos et al., 2014). In a recent study, Karlebach and Francks reanalyzed both datasets and showed that subtle lateralization at single gene level translates to stronger asymmetries at the level of functional gene ontology (GO) groups. The authors found lateralized gene sets to be associated with neuronal electrophysiology, synaptic transmission, nervous system development, and glutamate receptor activity (Karlebach and Francks, 2015).

However, recent research indicates that cortical tissue might not be the optimal choice to investigate the relation of gene expression asymmetries and behavioral asymmetries. Ontogenetically, handedness starts early in development since coordinated hand movements begin 8 weeks post conception (PC), i.e. 10 weeks gestational age, when 85% of fetuses exhibit more right arm than left arm movements (Hepper et al., 1998; de Vries et al., 1985). Investigation of thumb sucking in 274 fetuses revealed that at 13 weeks PC 90% prefer to suck their right thumb whereas only 10% suck their left thumb more often (Hepper et al., 1990, 1991). Interestingly, a follow up study of 75 infants revealed that thumb sucking preference is significantly positively correlated with subsequent handedness: The 60 children showing a right thumb preference were right-handed whereas out of the 15 children displaying a left thumb preference, five were right-handed and 10 were left-handed (Hepper et al., 2005). Importantly, the motor cortex is not yet functionally linked to the spinal cord at that stage of development as the outgrowth of corticospinal projections does not enter the anterior spinal cord before 15 weeks PC (ten Donkelaar et al., 2004). This implies that handedness is unlikely to be under brain control (Hepper et al., 1991) and asymmetrical hand movements have to arise from spinal activity patterns. Thus, it is likely that spinal rather than cortical gene expression asymmetries represent the molecular basis of handedness.

Asymmetrical gene expression patterns are likely to be influenced by epigenetic variation. The most important epigenetic mechanism is DNA methylation. Binding of methyl (-CH₃) groups to CpG sites or islands causes a reduction or prevention of transcription and thus gene expression. DNA methylation is confirmed to be involved in the development of basic central nervous system functions like synaptic function, neuronal plasticity, learning and memory (Nikolova and Hariri, 2015; Day et al., 2015; Roth, 2012). Especially intrauterine stressors have been shown to influence DNA methylation (Turecki and Meaney, 2016; Vaiserman, 2015), which is particularly interesting in the context of handedness ontogenesis. Moreover, a recent study showed that methylation plays a role in the ontogenesis of handedness: methylation levels in a CpG block in the promoter region of LRRTM1 were associated with atypical handedness (Leach et al., 2014).

Post-transcriptionally, gene expression is further regulated by microRNAs (miRNAs) that are composed of small, 21–25 nucleotide, non-coding RNAs. In humans and other mammals, miRNAs primarily cause destabilization of target mRNAs instead of reduced translation (Guo et al., 2010). This has also been shown to be relevant for hemispheric asymmetries, as neuronal asymmetries in the nematode Caenorhabditis elegans are controlled for by different miRNAs (Alqadah et al., 2013; Cochella and Hobert, 2012; Johnston and Hobert, 2003; Hsieh et al., 2012).

Pronounced changes in spatiotemporal expression profiles are a key feature of human embryogenesis (Yi et al., 2010) and formation of functional asymmetries in vertebrates has been shown to strongly depend on critical periods in early development (Le Grand et al., 2003; Zappia and Rogers, 1983). To investigate the molecular determinants of human behavioral asymmetries we analyzed asymmetries in genome-wide mRNA expression, miRNA expression and DNA methylation patterns in human fetal spinal cord tissue. Importantly, we specifically wanted to investigate the spinal cord segments innervating arms and hands. While rostral cervical segments (C2–C5) innervate the head, neck and shoulder region, the subsequent segments directly innervate arms and hands with C6 innervating the thumb, C7 innervating the middle finger and C8 innervating the little finger. T1 innervates the medial site of the antecubital fossa (Maynard et al., 1997). Based on the findings on the start of left-right asymmetries in coordinated hand movements (Hepper et al., 1998; de Vries et al., 1985), we focused on fetal tissue samples obtained between 8 and 12 weeks PC.

We hypothesized that gene expression asymmetries between the left and right spinal cord start at 8 weeks PC, as this is the starting point of coordinated asymmetrical hand movements. Based on the findings about the role of non-genetic influence factors for handedness development, we also assumed a pronounced modulation of these mRNA expression asymmetries by asymmetric DNA methylation and asymmetric miRNA expression.

Hemispheric asymmetries in brain and behavior are a major organizational principle in the vertebrate central nervous system, but their ontogenesis is not well understood (Ocklenburg et al., 2014b). While it is general consensus that both genetic and epigenetic factors play a role (Ocklenburg et al., 2013c), it is unclear, which molecular processes underlie the epigenetic modulation of gene expression asymmetries, a potential origin of behavioral asymmetries (Sun et al., 2005; Karlebach and Francks, 2015). To elucidate this question we analyzed asymmetries in genome-wide mRNA expression, miRNA expression and DNA methylation patterns in human fetal tissue samples. Importantly, we focused on spinal cord, not brain, tissue. Eight weeks after conception, human fetuses exhibit pronounced lateralized motor behavior of the arms. As cortical control of this behavior is unlikely (Hepper et al., 1998; de Vries et al., 1985; Hepper et al., 2005; ten Donkelaar et al., 2004), it has been suggested that it is under spinal control (Hepper, 2013).

In line with our hypothesis, our findings suggest that gene expression asymmetries in the spinal cord segments innervating the hands and arms might be critical for the ontogenesis of functional asymmetries. For the first time we show that the left and right cervical and anterior thoracal segments of the fetal spinal cord do show biologically relevant gene expression differences. Importantly, these gene expression asymmetries are highly developmental stage-specific. At eight weeks after conception, gene expression asymmetries between the two halves of the spinal cord were most pronounced, with 3.29% of all transcripts showing biologically relevant left-right gene expression differences, largely higher towards the right side and involved in numerous GO categories contributing to neurodevelopment. At 10 weeks PC, this number decreased substantially to 0.05% and further so at 12 weeks PC (0.01%). While the findings for 10 and 12 weeks PC are largely comparable to what has been reported for gene expression asymmetries in the fetal cerebral cortex (Sun et al., 2005; Karlebach and Francks, 2015), the data for eight weeks PC indicate a substantial increase over previous reports of gene expression asymmetries in CNS tissue that goes along with the first onset of coordinated hand movements.

In line with the suggestion that non-shared environmental influences account for more than 75% of the variance in functional hemispheric asymmetries in humans (Medland et al., 2009), we could show that a large part of these gene expression asymmetries is regulated by epigenetic processes.

On the one hand, we could show that DNA methylation of CpG islands shows substantial asymmetries that are related to RNA expression asymmetries. In week 8 tissue samples, there was a strong left-lateralization of CpG island methylation, indicating a stronger repression of gene transcription in the left spinal cord. This is well in line with our finding of increased overall right-sided gene expression at that time point. Direct comparison of the location of asymmetrically methylated CpG islands and asymmetrically expressed genes indicated that 27% of the variance in asymmetrical gene expression at week 8 could be explained by differential methylation. In week 10 tissue samples, methylation asymmetries are massively decreased as compared to week eight, also in line with the gene expression data. Week 12 is difficult to interpret as here only one sample was analyzed, greatly increasing the number of asymmetrically methylated CpG sites.

On the other hand, we could also show that the asymmetries in gene expression are modulated by miRNA expression asymmetries. Particularly interesting was our finding that for the miRNAs asymmetrically expressed towards the right spinal cord at week eight, KEGG pathway analysis revealed a substantial effect of the TGF-β signaling pathway. This is an intriguing finding, as both nodal growth differentiation factor (Nodal) and left-right determination factor (Lefty), two of the key proteins for establishing bodily left–right asymmetry during development are part of the TGF-β superfamily (Mittwoch, 2008; Shiratori and Hamada, 2014). Importantly, TGF-β signaling has directly been linked to handedness, as proprotein convertase subtilisin/kexin type 6 (PCSK6), one of the major candidate genes for handedness, encodes for a protease that cleaves NODAL (Scerri et al., 2011).

Our data collection was limited to weeks 8 to 12 PC and for future studies, it could potentially be interesting to include tissue samples from even earlier stages to get a more detailed picture of the developmental trajectory. Also, independent replication in larger samples is needed in order to make more in-depth functional conclusions. As limb preferences have been reported in many non-human primates, but the strong 90 to 10 distribution of right- and left-handedness in humans seems to be rather unique, comparative analysis of primate tissue samples might yield unique insights into the evolution of the molecular basis of hemispheric asymmetries.

One potential issue with the interpretation of our data is to what extent the observed gene expression asymmetries are linked to visceral situs and not necessarily nervous system asymmetries. A particular interesting experiment in this regard would be to investigate spinal cord gene expression asymmetries in the inversus viscerum (iv) line of mouse mutants (Okada et al., 1999). These mutants show randomized visceral laterality and by comparing spinal cord gene expression asymmetries between animals with normal and atypical visceral asymmetries a potential impact of visceral asymmetries on spinal cord gene expression could easily be identified.

Taken together, these results are a strong indicator of epigenetic influences on human spinal cord gene expression asymmetries, a potential precursor of handedness. In birds, it has been shown that a behavioral preference for turning the head to the right, caused by epigenetic modulation during a critical period just before hatch, induces not only motor, but also visual and cognitive asymmetries (Casey and Martino, 2000; Manns and Güntürkün, 2009; Rogers, 1982; Skiba et al., 2002). Based on our data, a similar model is conceivable in humans. As week eight after conception represents the onset of coordinated hand movements and behavioral asymmetries of the hands occur first at this time point (Hepper et al., 1998; de Vries et al., 1985), we assume that a certain time frame before 10 weeks PC represents the critical period for handedness formation. During this period, asymmetrical DNA methylation and posttranscriptional regulation by asymmetrically expressed miRNAs lead to a spike in RNA expression asymmetries in the spinal segments innervating the arms and hands. These expression asymmetries of genes relevant for CNS development could lead to a differential development of neuronal circuits influencing the right arm and hand, causing the described behavioral asymmetries. For example, it has been shown that spinal cord segments innervating the right arm contain motoneurons with larger somata than left arm segments. In contrast, there are no size differences in left and right segments innervating the upper trunk (Melsbach et al., 1996). Furthermore, at eight weeks PC, the spinal cord and motor cortex are functionally not connected (ten Donkelaar et al., 2004), also supporting that behavioral asymmetries in arm use at that stage are controlled for by the spinal cord. At a later developmental stage when the spinal cord and motor cortex are functionally connected, the established behavioral asymmetry then could lead to asymmetries in use-dependent neuronal plasticity processes (Cirillo et al., 2010) in the motor cortex, ultimately leading to the cortical correlates of handedness (Ocklenburg et al., 2013c). This process could start at around 14 weeks PC, as asymmetric fetal hand use at that stage strongly correlates with later handedness at school age (Hepper et al., 1990, 2005). Unlike models assuming that handedness is primarily controlled by allelic variations in one or more candidate genes (Annett, 1998), our suggestion is in line with the finding that more than 75% of the variance in handedness data is explained for by non-shared environmental influences (Medland et al., 2009). Moreover, our data do not contradict neither linkage studies in extended left-handed pedigrees nor genome-wide association studies which were unable to identify allelic variants that explain more than a fraction of the variance in handedness data (Armour et al., 2014; Eriksson et al., 2010; Somers et al., 2015). Whereas our findings suggest that a large part of these influencing factors act prenatally, there remain several important peri- and postnatal environmental factors like social modulation to shape actual handedness (Schaafsma et al., 2009).

In summary, we could show pronounced, time sensitive gene expression asymmetries in human fetal spinal tissue that overlap with the onset of behavioral asymmetries. Thus, our data suggest a spinal, not a cortical, beginning of hemispheric asymmetries. The observed gene expression asymmetries were modulated by asymmetric CpG island methylation and asymmetries in miRNA expression, suggesting that these processes form the molecular basis of asymmetry epigenetics. In conclusion, our data strongly suggest a multifactorial model for the ontogenesis of hemispheric asymmetries, including both multiple genetic and epigenetic factors.

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Author details

1. Sebastian Ocklenburg

   Institute of Cognitive Neuroscience, Department Biopsychology, Ruhr University Bochum, Bochum, Germany

   Contribution

   SO, Conceptualization, Formal analysis, Supervision, Writing—original draft, Project administration, Writing—review and editing

   Contributed equally with

   Judith Schmitz

   For correspondence

   sebastian.ocklenburg@rub.de

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0001-5882-3200

2. Judith Schmitz

   Institute of Cognitive Neuroscience, Department Biopsychology, Ruhr University Bochum, Bochum, Germany

   Contribution

   JS, Data curation, Software, Formal analysis, Visualization, Writing—original draft, Writing—review and editing

   Contributed equally with

   Sebastian Ocklenburg

   Competing interests

   The authors declare that no competing interests exist.

3. Zahra Moinfar

   Department of Neuroanatomy and Molecular Brain Research, Ruhr University Bochum, Bochum, Germany

   Contribution

   ZM, Data curation, Investigation, Writing—review and editing

   Competing interests

   The authors declare that no competing interests exist.

4. Dirk Moser

   Department of Genetic Psychology, Ruhr University Bochum, Bochum, Germany

   Contribution

   DM, Data curation, Investigation, Methodology, Writing—review and editing

   Competing interests

   The authors declare that no competing interests exist.

5. Rena Klose

   Institute of Cognitive Neuroscience, Department Biopsychology, Ruhr University Bochum, Bochum, Germany

   Contribution

   RKl, Formal analysis, Writing—review and editing

   Competing interests

   The authors declare that no competing interests exist.

6. Stephanie Lor

   Institute of Cognitive Neuroscience, Department Biopsychology, Ruhr University Bochum, Bochum, Germany

   Contribution

   SL, Formal analysis, Writing—review and editing

   Competing interests

   The authors declare that no competing interests exist.

7. Georg Kunz

   Department of Obstetrics and Gynecology, St. Johannes Hospital, Dortmund, Germany

   Contribution

   GK, Methodology, Project administration, Writing—review and editing

   Competing interests

   The authors declare that no competing interests exist.

8. Martin Tegenthoff

   Department of Neurology, University Hospital Bergmannsheil, Bochum, Germany

   Contribution

   MT, Methodology, Project administration, Writing—review and editing

   Competing interests

   The authors declare that no competing interests exist.

9. Pedro Faustmann

   Department of Neuroanatomy and Molecular Brain Research, Ruhr University Bochum, Bochum, Germany

   Contribution

   PF, Data curation, Investigation, Writing—review and editing

   Competing interests

   The authors declare that no competing interests exist.

10. Clyde Francks

    1. Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, Netherlands
    2. Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, Netherlands

    Contribution

    CF, Formal analysis, Validation, Methodology, Writing—review and editing

    Competing interests

    The authors declare that no competing interests exist.

11. Jörg T Epplen

    Department of Human Genetics, Ruhr University Bochum, Bochum, Germany

    Contribution

    JTE, Data curation, Validation, Investigation, Writing—review and editing

    Competing interests

    The authors declare that no competing interests exist.

12. Robert Kumsta

    Department of Genetic Psychology, Ruhr University Bochum, Bochum, Germany

    Contribution

    RKu, Conceptualization, Formal analysis, Investigation, Methodology, Writing—review and editing

    Competing interests

    The authors declare that no competing interests exist.

13. Onur Güntürkün

    1. Institute of Cognitive Neuroscience, Department Biopsychology, Ruhr University Bochum, Bochum, Germany
    2. Stellenbosch Institute for Advanced Study (STIAS), Wallenberg Research Centre at Stellenbosch University, Stellenbosch, South Africa

    Contribution

    OG, Conceptualization, Resources, Formal analysis, Supervision, Funding acquisition, Project administration, Writing—review and editing

    Competing interests

    The authors declare that no competing interests exist.

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