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.

1. 1. Abu-Khalil A
   2. Fu L
   3. Grove EA
   4. Zecevic N
   5. Geschwind DH

   (2004) Wnt genes define distinct boundaries in the developing human brain: implications for human forebrain patterning

   The Journal of Comparative Neurology 474:276–288.

   https://doi.org/10.1002/cne.20112

   • PubMed
   • Google Scholar
2. 1. Akalin A
   2. Kormaksson M
   3. Li S
   4. Garrett-Bakelman FE
   5. Figueroa ME
   6. Melnick A
   7. Mason CE

   (2012) methylKit: a comprehensive R package for the analysis of genome-wide DNA methylation profiles

   Genome Biology 13:R87.

   https://doi.org/10.1186/gb-2012-13-10-r87

   • PubMed
   • Google Scholar
3. 1. Alqadah A
   2. Hsieh YW
   3. Chuang CF

   (2013) microRNA function in left-right neuronal asymmetry: perspectives from C. elegans

   Frontiers in Cellular Neuroscience 7:158.

   https://doi.org/10.3389/fncel.2013.00158

   • PubMed
   • Google Scholar
4. 1. Annett M

   (1998) Handedness and cerebral dominance: the right shift theory

   The Journal of Neuropsychiatry and Clinical Neurosciences 10:459–469.

   https://doi.org/10.1176/jnp.10.4.459

   • PubMed
   • Google Scholar
5. 1. Armour JA
   2. Davison A
   3. McManus IC

   (2014) Genome-wide association study of handedness excludes simple genetic models

   Heredity 112:221–225.

   https://doi.org/10.1038/hdy.2013.93

   • PubMed
   • Google Scholar
6. 1. Arning L
   2. Ocklenburg S
   3. Schulz S
   4. Ness V
   5. Gerding WM
   6. Hengstler JG
   7. Falkenstein M
   8. Epplen JT
   9. Güntürkün O
   10. Beste C

   (2013) PCSK6 VNTR polymorphism is associated with degree of handedness but not direction of handedness

   PLoS One 8:e67251.

   https://doi.org/10.1371/journal.pone.0067251

   • PubMed
   • Google Scholar
7. 1. Arning L
   2. Ocklenburg S
   3. Schulz S
   4. Ness V
   5. Gerding WM
   6. Hengstler JG
   7. Falkenstein M
   8. Epplen JT
   9. Güntürkün O
   10. Beste C

   (2015) Handedness and the X chromosome: the role of androgen receptor CAG-repeat length

   Scientific Reports 5:8325.

   https://doi.org/10.1038/srep08325

   • PubMed
   • Google Scholar
8. 1. Bisazza A
   2. Rogers LJ
   3. Vallortigara G

   (1998) The origins of cerebral asymmetry: a review of evidence of behavioural and brain lateralization in fishes, reptiles and amphibians

   Neuroscience and Biobehavioral Reviews 22:411–426.

   https://doi.org/10.1016/S0149-7634(97)00050-X

   • PubMed
   • Google Scholar
9. 1. Brandler WM
   2. Morris AP
   3. Evans DM
   4. Scerri TS
   5. Kemp JP
   6. Timpson NJ
   7. St Pourcain B
   8. Smith GD
   9. Ring SM
   10. Stein J
   11. Monaco AP
   12. Talcott JB
   13. Fisher SE
   14. Webber C
   15. Paracchini S

   (2013) Common variants in left/right asymmetry genes and pathways are associated with relative hand skill

   PLoS Genetics 9:e1003751.

   https://doi.org/10.1371/journal.pgen.1003751

   • PubMed
   • Google Scholar
10. 1. Casey MB
    2. Martino CM

    (2000) Asymmetrical hatching behaviors influence the development of postnatal laterality in domestic chicks (Gallus gallus)

    Developmental Psychobiology 37:13–24.

    https://doi.org/10.1002/1098-2302(200007)37:1<13::AID-DEV3>3.0.CO;2-M

    • PubMed
    • Google Scholar
11. 1. Cirillo J
    2. Rogasch NC
    3. Semmler JG

    (2010) Hemispheric differences in use-dependent corticomotor plasticity in young and old adults

    Experimental Brain Research 205:57–68.

    https://doi.org/10.1007/s00221-010-2332-1

    • PubMed
    • Google Scholar
12. 1. Cochella L
    2. Hobert O

    (2012) Embryonic priming of a miRNA locus predetermines postmitotic neuronal left/right asymmetry in C. elegans

    Cell 151:1229–1242.

    https://doi.org/10.1016/j.cell.2012.10.049

    • PubMed
    • Google Scholar
13. 1. Colby KM
    2. Parkison C

    (1977) Handedness in autistic children

    Journal of Autism and Childhood Schizophrenia 7:3–9.

    https://doi.org/10.1007/BF01531110

    • PubMed
    • Google Scholar
14. 1. Corballis MC

    (2009) The evolution and genetics of cerebral asymmetry

    Philosophical Transactions of the Royal Society B: Biological Sciences 364:867–879.

    https://doi.org/10.1098/rstb.2008.0232

    • Google Scholar
15. 1. Corballis MC

    (2014) Left brain, right brain: facts and fantasies

    PLoS Biology 12:e1001767.

    https://doi.org/10.1371/journal.pbio.1001767

    • PubMed
    • Google Scholar
16. 1. Day JJ
    2. Kennedy AJ
    3. Sweatt JD

    (2015) DNA methylation and its implications and accessibility for neuropsychiatric therapeutics

    Annual Review of Pharmacology and Toxicology 55:591–611.

    https://doi.org/10.1146/annurev-pharmtox-010814-124527

    • PubMed
    • Google Scholar
17. 1. de Vries JI
    2. Visser GH
    3. Prechtl HF

    (1985) The emergence of fetal behaviour. II. quantitative aspects

    Early Human Development 12:99–120.

    https://doi.org/10.1016/0378-3782(85)90174-4

    • PubMed
    • Google Scholar
18. 1. De Winter FL
    2. Zhu Q
    3. Van den Stock J
    4. Nelissen K
    5. Peeters R
    6. de Gelder B
    7. Vanduffel W
    8. Vandenbulcke M

    (2015) Lateralization for dynamic facial expressions in human superior temporal sulcus

    NeuroImage 106:340–352.

    https://doi.org/10.1016/j.neuroimage.2014.11.020

    • PubMed
    • Google Scholar
19. 1. Demaree HA
    2. Everhart DE
    3. Youngstrom EA
    4. Harrison DW

    (2005) Brain lateralization of emotional processing: historical roots and a future incorporating "dominance"

    Behavioral and Cognitive Neuroscience Reviews 4:3–20.

    https://doi.org/10.1177/1534582305276837

    • PubMed
    • Google Scholar
20. 1. Denny K

    (2009) Handedness and depression: evidence from a large population survey

    Laterality 14:246–255.

    https://doi.org/10.1080/13576500802362869

    • PubMed
    • Google Scholar
21. 1. Denny K

    (2011) Handedness and drinking behaviour

    British Journal of Health Psychology 16:386–395.

    https://doi.org/10.1348/135910710X515705

    • PubMed
    • Google Scholar
22. 1. DePristo MA
    2. Banks E
    3. Poplin R
    4. Garimella KV
    5. Maguire JR
    6. Hartl C
    7. Philippakis AA
    8. del Angel G
    9. Rivas MA
    10. Hanna M
    11. McKenna A
    12. Fennell TJ
    13. Kernytsky AM
    14. Sivachenko AY
    15. Cibulskis K
    16. Gabriel SB
    17. Altshuler D
    18. Daly MJ

    (2011) A framework for variation discovery and genotyping using next-generation DNA sequencing data

    Nature Genetics 43:491–498.

    https://doi.org/10.1038/ng.806

    • PubMed
    • Google Scholar
23. 1. Dragovic M
    2. Hammond G

    (2005) Handedness in schizophrenia: a quantitative review of evidence

    Acta Psychiatrica Scandinavica 111:410–419.

    https://doi.org/10.1111/j.1600-0447.2005.00519.x

    • PubMed
    • Google Scholar
24. 1. Duecker F
    2. Formisano E
    3. Sack AT

    (2013) Hemispheric differences in the voluntary control of spatial attention: direct evidence for a right-hemispheric dominance within frontal cortex

    Journal of Cognitive Neuroscience 25:1332–1342.

    https://doi.org/10.1162/jocn_a_00402

    • PubMed
    • Google Scholar
25. 1. Elias LJ
    2. Saucier DM
    3. Guylee MJ

    (2001) Handedness and depression in university students: a sex by handedness interaction

    Brain and Cognition 46:125–129.

    https://doi.org/10.1016/S0278-2626(01)80048-8

    • PubMed
    • Google Scholar
26. 1. Eriksson N
    2. Macpherson JM
    3. Tung JY
    4. Hon LS
    5. Naughton B
    6. Saxonov S
    7. Avey L
    8. Wojcicki A
    9. Pe'er I
    10. Mountain J

    (2010) Web-based, participant-driven studies yield novel genetic associations for common traits

    PLoS Genetics 6:e1000993.

    https://doi.org/10.1371/journal.pgen.1000993

    • PubMed
    • Google Scholar
27. 1. Falasca NW
    2. D'Ascenzo S
    3. Di Domenico A
    4. Onofrj M
    5. Tommasi L
    6. Laeng B
    7. Franciotti R

    (2015) Hemispheric lateralization in top-down attention during spatial relation processing: a Granger causal model approach

    European Journal of Neuroscience 41:914–924.

    https://doi.org/10.1111/ejn.12846

    • PubMed
    • Google Scholar
28. 1. Forrester GS
    2. Pegler R
    3. Thomas MS
    4. Mareschal D

    (2014) Handedness as a marker of cerebral lateralization in children with and without autism

    Behavioural Brain Research 268:14–21.

    https://doi.org/10.1016/j.bbr.2014.03.040

    • PubMed
    • Google Scholar
29. 1. Francks C
    2. Maegawa S
    3. Laurén J
    4. Abrahams BS
    5. Velayos-Baeza A
    6. Medland SE
    7. Colella S
    8. Groszer M
    9. McAuley EZ
    10. Caffrey TM
    11. Timmusk T
    12. Pruunsild P
    13. Koppel I
    14. Lind PA
    15. Matsumoto-Itaba N
    16. Nicod J
    17. Xiong L
    18. Joober R
    19. Enard W
    20. Krinsky B
    21. Nanba E
    22. Richardson AJ
    23. Riley BP
    24. Martin NG
    25. Strittmatter SM
    26. Möller HJ
    27. Rujescu D
    28. St Clair D
    29. Muglia P
    30. Roos JL
    31. Fisher SE
    32. Wade-Martins R
    33. Rouleau GA
    34. Stein JF
    35. Karayiorgou M
    36. Geschwind DH
    37. Ragoussis J
    38. Kendler KS
    39. Airaksinen MS
    40. Oshimura M
    41. DeLisi LE
    42. Monaco AP

    (2007) LRRTM1 on chromosome 2p12 is a maternally suppressed gene that is associated paternally with handedness and schizophrenia

    Molecular Psychiatry 12:1129–1139.

    https://doi.org/10.1038/sj.mp.4002053

    • PubMed
    • Google Scholar
30. 1. Frasnelli E
    2. Vallortigara G
    3. Rogers LJ

    (2012) Left-right asymmetries of behaviour and nervous system in invertebrates

    Neuroscience and Biobehavioral Reviews 36:1273–1291.

    https://doi.org/10.1016/j.neubiorev.2012.02.006

    • PubMed
    • Google Scholar
31. 1. Frässle S
    2. Krach S
    3. Paulus FM
    4. Jansen A

    (2016) Handedness is related to neural mechanisms underlying hemispheric lateralization of face processing

    Scientific Reports 6:27153.

    https://doi.org/10.1038/srep27153

    • PubMed
    • Google Scholar
32. 1. Friederici AD

    (2011) The brain basis of language processing: from structure to function

    Physiological Reviews 91:1357–1392.

    https://doi.org/10.1152/physrev.00006.2011

    • PubMed
    • Google Scholar
33. 1. Geschwind DH
    2. Miller BL

    (2001) Molecular approaches to cerebral laterality: development and neurodegeneration

    American Journal of Medical Genetics 101:370–381.

    https://doi.org/10.1002/1096-8628(20010715)101:4<370::AID-AJMG1223>3.0.CO;2-G

    • PubMed
    • Google Scholar
34. 1. Giammattei J
    2. Arndt J

    (2012) Hemispheric asymmetries in the activation and monitoring of memory errors

    Brain and Cognition 80:7–14.

    https://doi.org/10.1016/j.bandc.2012.04.003

    • PubMed
    • Google Scholar
35. 1. Guo H
    2. Ingolia NT
    3. Weissman JS
    4. Bartel DP

    (2010) Mammalian microRNAs predominantly act to decrease target mRNA levels

    Nature 466:835–840.

    https://doi.org/10.1038/nature09267

    • PubMed
    • Google Scholar
36. 1. Habib R
    2. Nyberg L
    3. Tulving E

    (2003) Hemispheric asymmetries of memory: the HERA model revisited

    Trends in Cognitive Sciences 7:241–245.

    https://doi.org/10.1016/S1364-6613(03)00110-4

    • PubMed
    • Google Scholar
37. 1. Hampson E
    2. Sankar JS

    (2012) Hand preference in humans is associated with testosterone levels and androgen receptor gene polymorphism

    Neuropsychologia 50:2018–2025.

    https://doi.org/10.1016/j.neuropsychologia.2012.04.027

    • PubMed
    • Google Scholar
38. 1. Hardie SM
    2. Wright L
    3. Clark L

    (2016) Handedness and social anxiety: Using Bryden's research as a catalyst to explore the influence of familial sinistrality and degree of handedness

    Laterality 12:1–19.

    https://doi.org/10.1080/1357650x.2015.1131712

    • Google Scholar
39. 1. Hawrylycz MJ
    2. Lein ES
    3. Guillozet-Bongaarts AL
    4. Shen EH
    5. Ng L
    6. Miller JA
    7. van de Lagemaat LN
    8. Smith KA
    9. Ebbert A
    10. Riley ZL
    11. Abajian C
    12. Beckmann CF
    13. Bernard A
    14. Bertagnolli D
    15. Boe AF
    16. Cartagena PM
    17. Chakravarty MM
    18. Chapin M
    19. Chong J
    20. Dalley RA
    21. Daly BD
    22. Dang C
    23. Datta S
    24. Dee N
    25. Dolbeare TA
    26. Faber V
    27. Feng D
    28. Fowler DR
    29. Goldy J
    30. Gregor BW
    31. Haradon Z
    32. Haynor DR
    33. Hohmann JG
    34. Horvath S
    35. Howard RE
    36. Jeromin A
    37. Jochim JM
    38. Kinnunen M
    39. Lau C
    40. Lazarz ET
    41. Lee C
    42. Lemon TA
    43. Li L
    44. Li Y
    45. Morris JA
    46. Overly CC
    47. Parker PD
    48. Parry SE
    49. Reding M
    50. Royall JJ
    51. Schulkin J
    52. Sequeira PA
    53. Slaughterbeck CR
    54. Smith SC
    55. Sodt AJ
    56. Sunkin SM
    57. Swanson BE
    58. Vawter MP
    59. Williams D
    60. Wohnoutka P
    61. Zielke HR
    62. Geschwind DH
    63. Hof PR
    64. Smith SM
    65. Koch C
    66. Grant SG
    67. Jones AR

    (2012) An anatomically comprehensive atlas of the adult human brain transcriptome

    Nature 489:391–399.

    https://doi.org/10.1038/nature11405

    • PubMed
    • Google Scholar
40. 1. Hepper PG
    2. McCartney GR
    3. Shannon EA

    (1998) Lateralised behaviour in first trimester human foetuses

    Neuropsychologia 36:531–534.

    https://doi.org/10.1016/S0028-3932(97)00156-5

    • PubMed
    • Google Scholar
41. 1. Hepper PG
    2. Shahidullah S
    3. White R

    (1990) Origins of fetal handedness

    Nature 347:431.

    https://doi.org/10.1038/347431b0

    • PubMed
    • Google Scholar
42. 1. Hepper PG
    2. Shahidullah S
    3. White R

    (1991) Handedness in the human fetus

    Neuropsychologia 29:1107–1111.

    https://doi.org/10.1016/0028-3932(91)90080-R

    • PubMed
    • Google Scholar
43. 1. Hepper PG
    2. Wells DL
    3. Lynch C

    (2005) Prenatal thumb sucking is related to postnatal handedness

    Neuropsychologia 43:313–315.

    https://doi.org/10.1016/j.neuropsychologia.2004.08.009

    • PubMed
    • Google Scholar
44. 1. Hepper PG

    (2013) The developmental origins of laterality: fetal handedness

    Developmental Psychobiology 55:588–595.

    https://doi.org/10.1002/dev.21119

    • PubMed
    • Google Scholar
45. 1. Hicks RA
    2. Pellegrini RJ

    (1978) Handedness and anxiety

    Cortex 14:119–121.

    https://doi.org/10.1016/S0010-9452(78)80014-8

    • PubMed
    • Google Scholar
46. 1. Hirnstein M
    2. Hugdahl K

    (2014) Excess of non-right-handedness in schizophrenia: meta-analysis of gender effects and potential biases in handedness assessment

    The British Journal of Psychiatry 205:260–267.

    https://doi.org/10.1192/bjp.bp.113.137349

    • PubMed
    • Google Scholar
47. 1. Hsieh YW
    2. Chang C
    3. Chuang CF

    (2012) The microRNA mir-71 inhibits calcium signaling by targeting the TIR-1/Sarm1 adaptor protein to control stochastic L/R neuronal asymmetry in C. elegans

    PLoS Genetics 8:e1002864.

    https://doi.org/10.1371/journal.pgen.1002864

    • PubMed
    • Google Scholar
48. 1. Hu HY
    2. Guo S
    3. Xi J
    4. Yan Z
    5. Fu N
    6. Zhang X
    7. Menzel C
    8. Liang H
    9. Yang H
    10. Zhao M
    11. Zeng R
    12. Chen W
    13. Pääbo S
    14. Khaitovich P

    (2011) MicroRNA expression and regulation in human, chimpanzee, and macaque brains

    PLoS Genetics 7:e1002327.

    https://doi.org/10.1371/journal.pgen.1002327

    • PubMed
    • Google Scholar
49. 1. Johnston RJ
    2. Hobert O

    (2003) A microRNA controlling left/right neuronal asymmetry in Caenorhabditis elegans

    Nature 426:845–849.

    https://doi.org/10.1038/nature02255

    • PubMed
    • Google Scholar
50. 1. Kadakkuzha BM
    2. Puthanveettil SV

    (2013) Genomics and proteomics in solving brain complexity

    Molecular BioSystems 9:1807–1821.

    https://doi.org/10.1039/c3mb25391k

    • PubMed
    • Google Scholar
51. 1. Karlebach G
    2. Francks C

    (2015) Lateralization of gene expression in human language cortex

    Cortex 67:30–36.

    https://doi.org/10.1016/j.cortex.2015.03.003

    • PubMed
    • Google Scholar
52. 1. Kazemian M
    2. Ren M
    3. Lin JX
    4. Liao W
    5. Spolski R
    6. Leonard WJ

    (2015) Comprehensive assembly of novel transcripts from unmapped human RNA-Seq data and their association with cancer

    Molecular Systems Biology 11:826.

    https://doi.org/10.15252/msb.156172

    • PubMed
    • Google Scholar
53. 1. Knecht S
    2. Dräger B
    3. Deppe M
    4. Bobe L
    5. Lohmann H
    6. Flöel A
    7. Ringelstein EB
    8. Henningsen H

    (2000) Handedness and hemispheric language dominance in healthy humans

    Brain 123 Pt 12:2512–2518.

    https://doi.org/10.1093/brain/123.12.2512

    • PubMed
    • Google Scholar
54. 1. Krueger F
    2. Andrews SR

    (2011) Bismark: a flexible aligner and methylation caller for Bisulfite-Seq applications

    Bioinformatics 27:1571–1572.

    https://doi.org/10.1093/bioinformatics/btr167

    • PubMed
    • Google Scholar
55. 1. Kundakovic M
    2. Champagne FA

    (2015) Early-life experience, epigenetics, and the developing brain

    Neuropsychopharmacology 40:141–153.

    https://doi.org/10.1038/npp.2014.140

    • PubMed
    • Google Scholar
56. 1. Langel J
    2. Hakun J
    3. Zhu DC
    4. Ravizza SM

    (2014) Functional specialization of the left ventral parietal cortex in working memory

    Frontiers in Human Neuroscience 8:440.

    https://doi.org/10.3389/fnhum.2014.00440

    • PubMed
    • Google Scholar
57. 1. Langmead B
    2. Trapnell C
    3. Pop M
    4. Salzberg SL

    (2009) Ultrafast and memory-efficient alignment of short DNA sequences to the human genome

    Genome Biology 10:R25.

    https://doi.org/10.1186/gb-2009-10-3-r25

    • PubMed
    • Google Scholar
58. 1. Le Grand R
    2. Mondloch CJ
    3. Maurer D
    4. Brent HP

    (2003) Expert face processing requires visual input to the right hemisphere during infancy

    Nature Neuroscience 6:1108–1112.

    https://doi.org/10.1038/nn1121

    • PubMed
    • Google Scholar
59. 1. Leach EL
    2. Prefontaine G
    3. Hurd PL
    4. Crespi BJ

    (2014) The imprinted gene LRRTM1 mediates schizotypy and handedness in a nonclinical population

    Journal of Human Genetics 59:332–336.

    https://doi.org/10.1038/jhg.2014.30

    • PubMed
    • Google Scholar
60. 1. Li Q
    2. Bian S
    3. Liu B
    4. Hong J
    5. Toth M
    6. Sun T

    (2013) Establishing brain functional laterality in adult mice through unilateral gene manipulation in the embryonic cortex

    Cell Research 23:1147–1149.

    https://doi.org/10.1038/cr.2013.106

    • PubMed
    • Google Scholar
61. 1. Liu Y
    2. Siegmund KD
    3. Laird PW
    4. Berman BP

    (2012) Bis-SNP: combined DNA methylation and SNP calling for Bisulfite-seq data

    Genome Biology 13:R61.

    https://doi.org/10.1186/gb-2012-13-7-r61

    • PubMed
    • Google Scholar
62. 1. Logue DD
    2. Logue RT
    3. Kaufmann WE
    4. Belcher HM

    (2015) Psychiatric disorders and left-handedness in children living in an urban environment

    Laterality 20:249–256.

    https://doi.org/10.1080/1357650X.2014.961927

    • PubMed
    • Google Scholar
63. 1. Lyle KB
    2. Chapman LK
    3. Hatton JM

    (2013) Is handedness related to anxiety? new answers to an old question

    Laterality 18:520–535.

    https://doi.org/10.1080/1357650X.2012.720259

    • PubMed
    • Google Scholar
64. 1. Mandal MK
    2. Bhushan B
    3. Kumar A
    4. Gupta P

    (2000) Side-bias in alcohol and heroin addicts

    Alcohol and Alcoholism 35:381–383.

    https://doi.org/10.1093/alcalc/35.4.381

    • PubMed
    • Google Scholar
65. 1. Manns M
    2. Freund N
    3. Leske O
    4. Güntürkün O

    (2008) Breaking the balance: ocular BDNF-injections induce visual asymmetry in pigeons

    Developmental Neurobiology 68:1123–1134.

    https://doi.org/10.1002/dneu.20647

    • PubMed
    • Google Scholar
66. 1. Manns M
    2. Güntürkün O

    (2009) Dual coding of visual asymmetries in the pigeon brain: the interaction of bottom-up and top-down systems

    Experimental Brain Research 199:323–332.

    https://doi.org/10.1007/s00221-009-1702-z

    • PubMed
    • Google Scholar
67. 1. Maynard FM
    2. Bracken MB
    3. Creasey G
    4. Ditunno JF
    5. Donovan WH
    6. Ducker TB
    7. Garber SL
    8. Marino RJ
    9. Stover SL
    10. Tator CH
    11. Waters RL
    12. Wilberger JE
    13. Young W

    (1997)

    International standards for neurological and functional classification of spinal cord injury. american spinal injury association

    Spinal Cord 35:266–274.

    • PubMed
    • Google Scholar
68. 1. McKenna A
    2. Hanna M
    3. Banks E
    4. Sivachenko A
    5. Cibulskis K
    6. Kernytsky A
    7. Garimella K
    8. Altshuler D
    9. Gabriel S
    10. Daly M
    11. DePristo MA

    (2010) The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data

    Genome Research 20:1297–1303.

    https://doi.org/10.1101/gr.107524.110

    • PubMed
    • Google Scholar
69. 1. McManus IC

    (1985) Handedness, language dominance and aphasia: a genetic model

    Psychological Medicine Monograph Supplement 8:3–40.

    https://doi.org/10.1017/S0264180100001879

    • Google Scholar
70. 1. Medland SE
    2. Duffy DL
    3. Spurdle AB
    4. Wright MJ
    5. Geffen GM
    6. Montgomery GW
    7. Martin NG

    (2005) Opposite effects of androgen receptor CAG repeat length on increased risk of left-handedness in males and females

    Behavior Genetics 35:735–744.

    https://doi.org/10.1007/s10519-005-6187-3

    • PubMed
    • Google Scholar
71. 1. Medland SE
    2. Duffy DL
    3. Wright MJ
    4. Geffen GM
    5. Hay DA
    6. Levy F
    7. van-Beijsterveldt CE
    8. Willemsen G
    9. Townsend GC
    10. White V
    11. Hewitt AW
    12. Mackey DA
    13. Bailey JM
    14. Slutske WS
    15. Nyholt DR
    16. Treloar SA
    17. Martin NG
    18. Boomsma DI

    (2009) Genetic influences on handedness: data from 25,732 australian and dutch twin families

    Neuropsychologia 47:330–337.

    https://doi.org/10.1016/j.neuropsychologia.2008.09.005

    • PubMed
    • Google Scholar
72. 1. Medland SE
    2. Duffy DL
    3. Wright MJ
    4. Geffen GM
    5. Martin NG

    (2006) Handedness in twins: joint analysis of data from 35 samples

    Twin Research and Human Genetics 9:46–53.

    https://doi.org/10.1375/twin.9.1.46

    • PubMed
    • Google Scholar
73. 1. Melsbach G
    2. Wohlschläger A
    3. Spiess M
    4. Güntürkün O

    (1996) Morphological asymmetries of motoneurons innervating upper extremities: clues to the anatomical foundations of handedness?

    International Journal of Neuroscience 86:217–224.

    https://doi.org/10.3109/00207459608986712

    • PubMed
    • Google Scholar
74. 1. Mittwoch U

    (2008) Different gene expressions on the left and the right: a genotype/phenotype mismatch in need of attention

    Annals of Human Genetics 72:2–9.

    https://doi.org/10.1111/j.1469-1809.2007.00402.x

    • PubMed
    • Google Scholar
75. 1. Nagel BJ
    2. Herting MM
    3. Maxwell EC
    4. Bruno R
    5. Fair D

    (2013) Hemispheric lateralization of verbal and spatial working memory during adolescence

    Brain and Cognition 82:58–68.

    https://doi.org/10.1016/j.bandc.2013.02.007

    • PubMed
    • Google Scholar
76. 1. Nikolova YS
    2. Hariri AR

    (2015) Can we observe epigenetic effects on human brain function?

    Trends in Cognitive Sciences 19:366–373.

    https://doi.org/10.1016/j.tics.2015.05.003

    • PubMed
    • Google Scholar
77. 1. Nowakowska C
    2. Sachs GS
    3. Zarate CA
    4. Marangell LB
    5. Calabrese JR
    6. Goldberg JF
    7. Ketter TA

    (2008) Increased rate of non-right-handedness in patients with bipolar disorder

    The Journal of Clinical Psychiatry 69:866–867.

    https://doi.org/10.4088/JCP.v69n0522g

    • PubMed
    • Google Scholar
78. 1. Ocklenburg S
    2. Arning L
    3. Gerding WM
    4. Epplen JT
    5. Güntürkün O
    6. Beste C

    (2013b) FOXP2 variation modulates functional hemispheric asymmetries for speech perception

    Brain and Language 126:279–284.

    https://doi.org/10.1016/j.bandl.2013.07.001

    • PubMed
    • Google Scholar
79. 1. Ocklenburg S
    2. Arning L
    3. Gerding WM
    4. Epplen JT
    5. Güntürkün O
    6. Beste C

    (2013d) Cholecystokinin A receptor (CCKAR) gene variation is associated with language lateralization

    PLoS One 8:e53643.

    https://doi.org/10.1371/journal.pone.0053643

    • PubMed
    • Google Scholar
80. 1. Ocklenburg S
    2. Arning L
    3. Gerding WM
    4. Hengstler JG
    5. Epplen JT
    6. Güntürkün O
    7. Beste C
    8. Akkad DA

    (2016) Left-Right axis differentiation and functional lateralization: a haplotype in the methyltransferase encoding gene SETDB2 might mediate handedness in healthy adults

    Molecular Neurobiology 53:6355–6361.

    https://doi.org/10.1007/s12035-015-9534-2

    • Google Scholar
81. 1. Ocklenburg S
    2. Arning L
    3. Hahn C
    4. Gerding WM
    5. Epplen JT
    6. Güntürkün O
    7. Beste C

    (2011b) Variation in the NMDA receptor 2B subunit gene GRIN2B is associated with differential language lateralization

    Behavioural Brain Research 225:284–289.

    https://doi.org/10.1016/j.bbr.2011.07.042

    • PubMed
    • Google Scholar
82. 1. Ocklenburg S
    2. Beste C
    3. Arning L
    4. Peterburs J
    5. Güntürkün O

    (2014b) The ontogenesis of language lateralization and its relation to handedness

    Neuroscience and Biobehavioral Reviews 43:191–198.

    https://doi.org/10.1016/j.neubiorev.2014.04.008

    • PubMed
    • Google Scholar
83. 1. Ocklenburg S
    2. Beste C
    3. Güntürkün O

    (2013c) Handedness: a Neurogenetic shift of perspective

    Neuroscience and Biobehavioral Reviews 37:2788–2793.

    https://doi.org/10.1016/j.neubiorev.2013.09.014

    • PubMed
    • Google Scholar
84. 1. Ocklenburg S
    2. Güntürkün O
    3. Beste C

    (2011a) Lateralized neural mechanisms underlying the modulation of response inhibition processes

    NeuroImage 55:1771–1778.

    https://doi.org/10.1016/j.neuroimage.2011.01.035

    • PubMed
    • Google Scholar
85. 1. Ocklenburg S
    2. Güntürkün O
    3. Beste C

    (2012) Hemispheric asymmetries and cognitive flexibility: an ERP and sLORETA study

    Brain and Cognition 78:148–155.

    https://doi.org/10.1016/j.bandc.2011.11.001

    • PubMed
    • Google Scholar
86. 1. Ocklenburg S
    2. Hirnstein M
    3. Beste C
    4. Güntürkün O

    (2014a) Lateralization and cognitive systems

    Frontiers in Psychology 5:1143.

    https://doi.org/10.3389/fpsyg.2014.01143

    • PubMed
    • Google Scholar
87. 1. Ocklenburg S
    2. Ströckens F
    3. Güntürkün O

    (2013a) Lateralisation of conspecific vocalisation in non-human vertebrates

    Laterality 18:1–31.

    https://doi.org/10.1080/1357650X.2011.626561

    • PubMed
    • Google Scholar
88. 1. Okada Y
    2. Nonaka S
    3. Tanaka Y
    4. Saijoh Y
    5. Hamada H
    6. Hirokawa N

    (1999) Abnormal nodal flow precedes situs inversus in iv and inv mice

    Molecular Cell 4:459–468.

    https://doi.org/10.1016/S1097-2765(00)80197-5

    • PubMed
    • Google Scholar
89. 1. Oldfield RC

    (1971) The assessment and analysis of handedness: the Edinburgh inventory

    Neuropsychologia 9:97–113.

    https://doi.org/10.1016/0028-3932(71)90067-4

    • PubMed
    • Google Scholar
90. 1. Orme JE

    (1970) Left-handedness, ability and emotional instability

    British Journal of Social and Clinical Psychology 9:87–88.

    https://doi.org/10.1111/j.2044-8260.1970.tb00646.x

    • PubMed
    • Google Scholar
91. 1. Pinel P
    2. Fauchereau F
    3. Moreno A
    4. Barbot A
    5. Lathrop M
    6. Zelenika D
    7. Le Bihan D
    8. Poline JB
    9. Bourgeron T
    10. Dehaene S

    (2012) Genetic variants of FOXP2 and KIAA0319/TTRAP/THEM2 locus are associated with altered brain activation in distinct language-related regions

    Journal of Neuroscience 32:817–825.

    https://doi.org/10.1523/JNEUROSCI.5996-10.2012

    • PubMed
    • Google Scholar
92. 1. Pletikos M
    2. Sousa AM
    3. Sedmak G
    4. Meyer KA
    5. Zhu Y
    6. Cheng F
    7. Li M
    8. Kawasawa YI
    9. Sestan N

    (2014) Temporal specification and bilaterality of human neocortical topographic gene expression

    Neuron 81:321–332.

    https://doi.org/10.1016/j.neuron.2013.11.018

    • PubMed
    • Google Scholar
93. 1. Preslar J
    2. Kushner HI
    3. Marino L
    4. Pearce B

    (2014) Autism, lateralisation, and handedness: a review of the literature and meta-analysis

    Laterality 19:64–95.

    https://doi.org/10.1080/1357650X.2013.772621

    • PubMed
    • Google Scholar
94. Book

    1. Rogers LJ
    2. Vallortigara G
    3. Andrew RJ

    (2012)

    Divided Brains, The Biology and Behaviour of Brain Asymmetries

    Cambrige [England], New York: Cambridge University Press.

    • Google Scholar
95. 1. Rogers LJ

    (1982) Light experience and asymmetry of brain function in chickens

    Nature 297:223–225.

    https://doi.org/10.1038/297223a0

    • PubMed
    • Google Scholar
96. 1. Roth TL

    (2012) Epigenetics of neurobiology and behavior during development and adulthood

    Developmental Psychobiology 54:590–597.

    https://doi.org/10.1002/dev.20550

    • PubMed
    • Google Scholar
97. 1. Rysstad AL
    2. Pedersen AV

    (2016) Brief report: Non-right-Handedness within the autism spectrum disorder

    Journal of Autism and Developmental Disorders 46:1110–1117.

    https://doi.org/10.1007/s10803-015-2631-2

    • PubMed
    • Google Scholar
98. 1. Savitz J
    2. van der Merwe L
    3. Solms M
    4. Ramesar R

    (2007) Lateralization of hand skill in bipolar affective disorder

    Genes, Brain and Behavior 6:698–705.

    https://doi.org/10.1111/j.1601-183X.2006.00299.x

    • PubMed
    • Google Scholar
99. 1. Scerri TS
    2. Brandler WM
    3. Paracchini S
    4. Morris AP
    5. Ring SM
    6. Richardson AJ
    7. Talcott JB
    8. Stein J
    9. Monaco AP

    (2011) PCSK6 is associated with handedness in individuals with dyslexia

    Human Molecular Genetics 20:608–614.

    https://doi.org/10.1093/hmg/ddq475

    • PubMed
    • Google Scholar
100. 1. Schaafsma SM
     2. Riedstra BJ
     3. Pfannkuche KA
     4. Bouma A
     5. Groothuis TG

     (2009) Epigenesis of behavioural lateralization in humans and other animals

     Philosophical Transactions of the Royal Society B: Biological Sciences 364:915–927.

     https://doi.org/10.1098/rstb.2008.0244

     • PubMed
     • Google Scholar
101. 1. Sepeta LN
     2. Berl MM
     3. Wilke M
     4. You X
     5. Mehta M
     6. Xu B
     7. Inati S
     8. Dustin I
     9. Khan O
     10. Austermuehle A
     11. Theodore WH
     12. Gaillard WD

     (2016) Age-dependent mesial temporal lobe lateralization in language fMRI

     Epilepsia 57:122–130.

     https://doi.org/10.1111/epi.13258

     • PubMed
     • Google Scholar
102. 1. Shiratori H
     2. Hamada H

     (2014) Tgfβ signaling in establishing left-right asymmetry

     Seminars in Cell & Developmental Biology 32:80–84.

     https://doi.org/10.1016/j.semcdb.2014.03.029

     • PubMed
     • Google Scholar
103. 1. Skiba M
     2. Diekamp B
     3. Güntürkün O

     (2002) Embryonic light stimulation induces different asymmetries in visuoperceptual and visuomotor pathways of pigeons

     Behavioural Brain Research 134:149–156.

     https://doi.org/10.1016/S0166-4328(01)00463-6

     • PubMed
     • Google Scholar
104. 1. Somers M
     2. Ophoff RA
     3. Aukes MF
     4. Cantor RM
     5. Boks MP
     6. Dauwan M
     7. de Visser KL
     8. Kahn RS
     9. Sommer IE

     (2015) Linkage analysis in a dutch population isolate shows no major gene for left-handedness or atypical language lateralization

     Journal of Neuroscience 35:8730–8736.

     https://doi.org/10.1523/JNEUROSCI.3287-14.2015

     • PubMed
     • Google Scholar
105. 1. Sommer I
     2. Ramsey N
     3. Kahn R
     4. Aleman A
     5. Bouma A

     (2001) Handedness, language lateralisation and anatomical asymmetry in schizophrenia: meta-analysis

     The British Journal of Psychiatry 178:344–351.

     https://doi.org/10.1192/bjp.178.4.344

     • PubMed
     • Google Scholar
106. 1. Sperling W
     2. Frank H
     3. Martus P
     4. Mader R
     5. Barocka A
     6. Walter H
     7. Lesch M

     (2000) The concept of abnormal hemispheric organization in addiction research

     Alcohol and Alcoholism 35:394–399.

     https://doi.org/10.1093/alcalc/35.4.394

     • PubMed
     • Google Scholar
107. 1. Stock AK
     2. Beste C

     (2014) Lateralization of spatial information processing in response monitoring

     Frontiers in Psychology 5:22.

     https://doi.org/10.3389/fpsyg.2014.00022

     • PubMed
     • Google Scholar
108. 1. Ströckens F
     2. Güntürkün O
     3. Ocklenburg S

     (2013) Limb preferences in non-human vertebrates

     Laterality 18:536–575.

     https://doi.org/10.1080/1357650X.2012.723008

     • PubMed
     • Google Scholar
109. 1. Sun T
     2. Patoine C
     3. Abu-Khalil A
     4. Visvader J
     5. Sum E
     6. Cherry TJ
     7. Orkin SH
     8. Geschwind DH
     9. Walsh CA

     (2005) Early asymmetry of gene transcription in embryonic human left and right cerebral cortex

     Science 308:1794–1798.

     https://doi.org/10.1126/science.1110324

     • PubMed
     • Google Scholar
110. 1. Tat MJ
     2. Azuma T

     (2016) The effect of cognitive load on hemispheric asymmetries in true and false memory

     Laterality 21:50–75.

     https://doi.org/10.1080/1357650X.2015.1073297

     • PubMed
     • Google Scholar
111. 1. ten Donkelaar HJ
     2. Lammens M
     3. Wesseling P
     4. Hori A
     5. Keyser A
     6. Rotteveel J

     (2004) Development and malformations of the human pyramidal tract

     Journal of Neurology 251:1429–1442.

     https://doi.org/10.1007/s00415-004-0653-3

     • PubMed
     • Google Scholar
112. 1. Trapnell C
     2. Williams BA
     3. Pertea G
     4. Mortazavi A
     5. Kwan G
     6. van Baren MJ
     7. Salzberg SL
     8. Wold BJ
     9. Pachter L

     (2010) Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation

     Nature Biotechnology 28:511–515.

     https://doi.org/10.1038/nbt.1621

     • PubMed
     • Google Scholar
113. 1. Tsang TE
     2. Kinder SJ
     3. Tam PP

     (1999)

     Experimental analysis of the emergence of left-right asymmetry of the body axis in early postimplantation mouse embryos

     Cellular and Molecular Biology 45:493–503.

     • PubMed
     • Google Scholar
114. 1. Turecki G
     2. Meaney MJ

     (2016) Effects of the social environment and stress on glucocorticoid receptor gene methylation: A systematic review

     Biological Psychiatry 79:87–96.

     https://doi.org/10.1016/j.biopsych.2014.11.022

     • PubMed
     • Google Scholar
115. 1. Vaiserman AM

     (2015) Epigenetic programming by early-life stress: Evidence from human populations

     Developmental Dynamics 244:254–265.

     https://doi.org/10.1002/dvdy.24211

     • PubMed
     • Google Scholar
116. 1. Vallortigara G
     2. Rogers LJ

     (2005) Survival with an asymmetrical brain: advantages and disadvantages of cerebral lateralization

     Behavioral and Brain Sciences 28:575–589.

     https://doi.org/10.1017/S0140525X05000105

     • PubMed
     • Google Scholar
117. 1. van Dyck LI
     2. Pittman BP
     3. Blumberg HP

     (2012) Non-right-handedness in adolescents and adults with bipolar disorder

     Bipolar Disorders 14:571–572.

     https://doi.org/10.1111/j.1399-5618.2012.01037.x

     • PubMed
     • Google Scholar
118. 1. Versace E
     2. Vallortigara G

     (2015) Forelimb preferences in human beings and other species: multiple models for testing hypotheses on lateralization

     Frontiers in Psychology 6:233.

     https://doi.org/10.3389/fpsyg.2015.00233

     • PubMed
     • Google Scholar
119. 1. Vlachos IS
     2. Zagganas K
     3. Paraskevopoulou MD
     4. Georgakilas G
     5. Karagkouni D
     6. Vergoulis T
     7. Dalamagas T
     8. Hatzigeorgiou AG

     (2015) DIANA-miRPath v3.0: deciphering microRNA function with experimental support

     Nucleic Acids Research 43:W460–W466.

     https://doi.org/10.1093/nar/gkv403

     • Google Scholar
120. 1. Vuoksimaa E
     2. Koskenvuo M
     3. Rose RJ
     4. Kaprio J

     (2009) Origins of handedness: a nationwide study of 30,161 adults

     Neuropsychologia 47:1294–1301.

     https://doi.org/10.1016/j.neuropsychologia.2009.01.007

     • PubMed
     • Google Scholar
121. 1. Wang HQ
     2. Tuominen LK
     3. Tsai CJ

     (2011) SLIM: a sliding linear model for estimating the proportion of true null hypotheses in datasets with dependence structures

     Bioinformatics 27:225–231.

     https://doi.org/10.1093/bioinformatics/btq650

     • PubMed
     • Google Scholar
122. 1. Wang J
     2. Duncan D
     3. Shi Z
     4. Zhang B

     (2013) WEB-based GEne SeT AnaLysis Toolkit (WebGestalt): update 2013

     Nucleic Acids Research 41:W77–W83.

     https://doi.org/10.1093/nar/gkt439

     • Google Scholar
123. 1. Warden CD
     2. Yuan Y
     3. Wu X

     (2013)

     Optimal calculation of RNA-Seq Fold-Change values

     International Journal of Computational Bioinformatics and In Silico Modeling 2:285–292.

     • Google Scholar
124. 1. Willems RM
     2. Van der Haegen L
     3. Fisher SE
     4. Francks C

     (2014) On the other hand: including left-handers in cognitive neuroscience and neurogenetics

     Nature Reviews Neuroscience 15:193–201.

     https://doi.org/10.1038/nrn3679

     • PubMed
     • Google Scholar
125. 1. Wright L
     2. Hardie SM

     (2012) Are left-handers really more anxious?

     Laterality 17:629–642.

     https://doi.org/10.1080/1357650X.2011.615126

     • PubMed
     • Google Scholar
126. 1. Yi H
     2. Xue L
     3. Guo MX
     4. Ma J
     5. Zeng Y
     6. Wang W
     7. Cai JY
     8. Hu HM
     9. Shu HB
     10. Shi YB
     11. Li WX

     (2010) Gene expression atlas for human embryogenesis

     The FASEB Journal 24:3341–3350.

     https://doi.org/10.1096/fj.10-158782

     • PubMed
     • Google Scholar
127. 1. Zappia JV
     2. Rogers LJ

     (1983) Light experience during development affects asymmetry of forebrain function in chickens

     Developmental Brain Research 313:93–106.

     https://doi.org/10.1016/0165-3806(83)90204-3

     • PubMed
     • Google Scholar
128. 1. Zhang B
     2. Kirov S
     3. Snoddy J

     (2005) WebGestalt: an integrated system for exploring gene sets in various biological contexts

     Nucleic Acids Research 33:W741–W748.

     https://doi.org/10.1093/nar/gki475

     • Google Scholar

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.

• 36,795

  views

• 2,171

  downloads

• 97

  citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.