Annett's right‐shift theory proposes that human cerebral dominance (the functional and anatomical asymmetry or torque along the antero‐posterior axis) and handedness are determined by a single “right‐shift” gene. Familial transmission of handedness and specific deviations of cerebral dominance in sex chromosome aneuploidies implicate a locus within an X–Y homologous region of the sex chromosomes. The Xq21.3/Yp11.2 human‐specific region of homology includes the protocadherin 11X/Y ( PCDH11X/Y ) gene pair, which encode cell adhesion molecules subject to accelerated evolution following the separation of the human and chimpanzee lineages six million years ago. PCDH11X and PCDH11Y , differentially regulated by retinoic acid, are highly expressed in the ventricular zone, subplate, and cortical plate of the developing cerebral cortex. Both proteins interact with β‐catenin, a protein that plays a role in determining axis formation and regulating cortical size. In this way, the PCDH11X/Y gene pair determines cerebral asymmetry by initiating the right shift in Homo sapiens .

Protocadherins 11X and 11Y are cell adhesion molecules of the δ1-protocadherin family. Pcdh11X is present throughout the mammalian radiation; however, 6 million years ago (MYA), a reduplicative translocation of the Xq21.3 block onto what is now human Yp11 created the Homo sapiens-specific PCDH11Y. Therefore, modern human females express PCDH11X whereas males express both PCDH11X and PCDH11Y. PCDH11X/Y has been subject to accelerated evolution resulting in human-specific changes to both proteins, most notably 2 cysteine substitutions in the PCDH11X ectodomain that may alter binding characteristics. The PCDH11X/Y gene pair is postulated to be critical to aspects of human brain evolution related to the neural correlates of language. Therefore, we raised antibodies to investigate the temporal and spatial expression of PCDH11X/Y in cortical and sub-cortical areas of the human fetal brain between 12 and 34 postconceptional weeks. We then used the antibodies to determine if this expression was consistent in a series of adult brains. PCDH11X/Y immunoreactivity was detectable at all developmental stages. Strong expression was detected in the fetal neocortex, ganglionic eminences, cerebellum, and inferior olive. In the adult brain, the cerebral cortex, hippocampal formation, and cerebellum were strongly immunoreactive, with expression also detectable in the brainstem.

Annett's right-shift theory proposes that human cerebral dominance (the functional and anatomical asymmetry or torque along the antero-posterior axis) and handedness are determined by a single “right-shift” gene. Familial transmission of handedness and specific deviations of cerebral dominance in sex chromosome aneuploidies implicate a locus within an X–Y homologous region of the sex chromosomes. The Xq21.3/Yp11.2 human-specific region of homology includes the protocadherin 11X/Y ( PCDH11X/Y ) gene pair, which encode cell adhesion molecules subject to accelerated evolution following the separation of the human and chimpanzee lineages six million years ago. PCDH11X and PCDH11Y , differentially regulated by retinoic acid, are highly expressed in the ventricular zone, subplate, and cortical plate of the developing cerebral cortex. Both proteins interact with β-catenin, a protein that plays a role in determining axis formation and regulating cortical size. In this way, the PCDH11X/Y gene pair determines cerebral asymmetry by initiating the right shift in Homo sapiens .

Review of the first comprehensive meta-analysis of VBM (voxel-based morphometry) studies in schizophrenia indicates asymmetrical reductions of anterior cingulate gyrus to the right, and medial temporal lobe (including the uncus) and para-hippocampal gyrus to the left. In subsequent meta-analyses of schizophrenia and bipolar disorder change in these limbic structures is systematically related to change in the insula. Deficits in insula (and para-hippocampal gyrus) to the left, and dorsal anterior cingulate gyrus to the right are greater in schizophrenic psychoses whereas deficits in anterior cingulate to the left and insula to the right are greater in bipolar illness. Thus (1) brain structures implicated in schizophrenia include those implicated in bipolar disorder, (2) the variation that separates the prototypical psychoses may be a subset of that relating to the structural asymmetry (the "torque") characteristic of the human brain, and (3) the meta-analysis of Bora et al. (2012) indicates that laterality of involvement of the insula and cingulate gyrus across the spectrum of bipolar and schizophrenic psychoses is critically dependent upon the sex ratio. Thus structural change underlying the continuum of psychosis relates to the interaction of laterality and sex.

How differences between the two sides of the brain (or ‘laterality’) relate to level of function are important components of theories of the origin and purpose of hemispheric asymmetry, although different measures show different relationships, and this heterogeneity makes discerning any underlying relationships a difficult task. There are some exceptions, for example it has been concluded that increasing lateralization (eg of hand skill or planum temporale area) occurs at the expense of the non-dominant hemisphere. However, we have previously demonstrated this latter relationship to be an artefact: a consequence of plotting two variables against each other, that are not independent of each other [Leask, S. J., & Crow, T. J. (1997) How far does the brain lateralize? An unbiased method for determining the optimum degree of hemispheric specialisation. Neuropsychologia, 36, 1275–1282; Mazoyer, B. M., & Tzourio-Mazoyer, N. G. (2004). Title Planum temporale asymmetry and models of dominance for language: a reappraisal. Neuroreport, 15, 1057–1059]. Two approaches to discerning any underlying relationships are presented in data from over 20,000 10- and 11-year olds from the 1958 and 1970 UK national cohort studies. These demonstrate that maximal performance, both cognitive and hand function, is found in association with one particular degree of functional lateralization.

Francks et al. (2007, p. 1129) claim to have identified The first potential genetic influence on human handedness and the first putative genetic effect on variability in human brain asymmetry and a gene that underlies much of human cognition, behaviour and emotion (p. 1129). We criticise this claim on the basis that the authors have made unjustified assumptions concerning mode of transmission both of psychosis and relative hand skill, that they have failed to establish a parent of origin effect, and have overlooked previous findings concerning the genetic basis of handedness and asymmetry. We suggest that some of these errors relate to the application of linkage disequilibrium to detect variation that is common in the population and relates to the characteristic that defines the species. While we agree (and indeed first proposed) that the variation underlying psychosis is intrinsically related to the cerebral torque, which we take to be the anatomical basis of language, we are unconvinced by the data for LRRTM1 presented by Francks et al. We consider that a stronger case can be mounted for the Protocadherin11X/Y gene pair located in the hominid specific Xq21.3/Yp11.2 region of homology that was generated by a duplication from the X between 6 and 5 million years ago and that has been subject to a number of chromosomal and sequence changes. This gene pair can account for relationships between relative hand skill and verbal and non-verbal ability that are sex dependent, and morphological changes in the brain in psychosis that reflect interactions between sex and laterality, which are already established in the literature.

The 5‐hydroxytryptamine (5‐HT, serotonin) system has been implicated in the pathophysiology and treatment of schizophrenia. In this study, we addressed the hypothesis that a deficit of 5‐HT neurones, either inherited or acquired, is central to the developmental pathology of the disorder. We examined putative 5‐HT neurones of the dorsal raphe nucleus (DRN) in post mortem, formalin‐fixed tissue from 15 schizophrenic patients and 20 control subjects matched for age and gender. No significant difference was detected between these groups in the number or size (cross‐sectional area or diameter) of tryptophan‐hydroxylase‐immunoreactive cell profiles viewed in transverse sections collected from the level of the trochlear decussation to the emergence of the trigeminal nerve. Profile number was not affected by age, gender, side of the brainstem (left or right) or post mortem interval; however, time in formalin correlated negatively with the number of neurones counted. Moreover, a significant negative correlation was detected between time in formalin and the levels of immunoreaction product (optical density), which in turn correlated positively with our profile counts. A positive correlation was found between the age of subjects and our estimates of cell size. Our results do not support the proposal that an abnormality in the number and/or size of DRN 5‐HT neurones is central to the aetiopathology of schizophrenia.

Despite evidence for an abnormality of noradrenergic function in schizophrenia, it remains unclear whether the number of noradrenergic neurones is normal in patients with the disorder. In postmortem, formalin-fixed tissue from 15 schizophrenic patients and 18 controls matched for age and gender, we made estimates of the number and size of tyrosine-hydroxylase-immunoreactive cells in the locus coeruleus (LC). No significant difference was detected between these groups in the cross-sectional area or diameter of immunoreactive cell profiles. Profile number was not significantly affected by gender, side of the brainstem (left or right), postmortem interval or time in formalin; however, the levels of immunoreaction product (optical density) correlated significantly with our profile counts, which were lower on average in the schizophrenic group. When optical density was included as a covariate in our comparison (a repeated-measures analysis of variance) of schizophrenic and control cases, we found no difference between these groups in the number of neurones counted. An age-related decrease in profile number was detected, but no effect of age on our estimates of cell size was apparent. Our results highlight the importance of accounting for potential confounding variables, including variations in the quality of immunostaining, in investigations of this type. The findings presented here concur with previous studies suggesting that noradrenergic dysfunction in schizophrenia is not associated with an anatomical abnormality at the level of the LC.