Copy number variants (CNV) are hemizygous deletions, duplication or triplication of chromosomal loci up to a few million bases pairs and are associated with unprecedented high levels of psychiatric disorders. Our group has focused on human chromosome 22q11.2 for which hemizygous deletion is associated with elevated rates of schizophrenia and ASD. As almost all genes affected at 22q11.2 are conserved in the mouse genome, it has been possible to develop genetic mouse models of 22q11 CNVs with construct validity and experimentally manipulate the doses of 22q11.2-encoded genes individually and as segments, a necessary prerequisite to establish a cause-effect relationship. While there are admittedly species differences in brain structure, circuits and neurons between humans and mice, mouse models present a valid platform for delving into mechanisms underlying dimensions of psychiatric disorders. Our data present potential mechanistic bases of the association between 22q11.2 CNV and psychiatric disorders in which some, but not all, 22q11.2-encoded genes have non-identical phenotypic targets for neuronal and behavioral dimensions and such phenotypic expression is modified by genetic background and environmental factors. Our observations and segmental genetic models can be tested for other CNVs. These potential mechanisms underlying dimensions of mental illness in mice remain hypothetical until their ultimate validity is evaluated by mechanism-based therapeutic intervention in humans.
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