We used data from studies of copy-number variants (CNVs), singlegene associations, growth-signaling pathways, and intermediate phenotypes associated with brain growth to evaluate four alternative hypotheses for the genomic and developmental relationships between autism and schizophrenia: (i) autism subsumed in schizophrenia, (ii) independence, (iii) diametric, and (iv) partial overlap. Data from CNVs provides statistical support for the hypothesis that autism and schizophrenia are associated with reciprocal variants, such that at four loci, deletions predispose to one disorder, whereas duplications predispose to the other. Data from single-gene studies are inconsistent with a hypothesis based on independence, in that autism and schizophrenia share associated genes more often than expected by chance. However, differentiation between the partial overlap and diametric hypotheses using these data is precluded by limited overlap in the specific genetic markers analyzed in both autism and schizophrenia. Evidence from the effects of risk variants on growth-signaling pathways shows that autism-spectrum conditions tend to be associated with upregulation of pathways due to loss of function mutations in negative regulators, whereas schizophrenia is associated with reduced pathway activation. Finally, data from studies of head and brain size phenotypes indicate that autism is commonly associated with developmentally-enhanced brain growth, whereas schizophrenia is characterized, on average, by reduced brain growth. These convergent lines of evidence appear most compatible with the hypothesis that autism and schizophrenia represent diametric conditions with regard to their genomic underpinnings, neurodevelopmental bases, and phenotypic manifestations as reflecting under-development versus dysregulated over-development of the human social brain.genetics | evolution | psychiatry T he Swiss psychiatrist Eugen Bleuler coined the terms "schizophrenia", for the splitting of psychic functions, and "autism", for withdrawal from external reality in patients with schizophrenia, almost exactly a century ago (1). Ever since 1943, when Leo Kanner (2) coopted autism to refer to a new condition involving "disturbance of affective contact" manifested in children, the relationship between schizophrenia and Kanner's autism has remained unclear (3). Kanner originally conceived autism as an early, distinct subtype of schizophrenia (model 1A) (Fig. 1A), a view he later renounced in favor of a model, which was also supported by Rutter (4) with the conditions as distinct, separate, and unrelated (model 1B) (Fig. 1B). Under each of these two hypotheses, autism and schizophrenia may each grade more or less smoothly, and independently, into so-called normality. Schizophrenia and autism have also been considered as diametric, or opposite sets of conditions (model 1C) (Fig. 1C) along a spectrum of social-brain phenotypes from hypodevelopment in autism, to normality, to hyperdevelopment in schizophrenia (5). By a fourth model, autism overlaps broadly yet...