Genetic Dissection of Behavioral Phenotypes. Lost & Found in Translation

This thesis shows that the exploration of human genetic disorders and animal genetic models can bring understanding of the causes and mechanisms of common psychiatric disorders. The first part of the thesis contains studies on genetic behavioral phenotypes in boys with Klinefelter syndrome, a human genetic disorder characterized by one or more extra X-chromosomes. The second part describes studies that specify genetic behavioral phenotypes using advanced mouse genetic models and techniques. The studies on Klinefelter syndrome (47, XXY) captured signatures of supernumerary X-chromosomes on different levels of phenotype expression such as the specifity of genetic autism phenotypes and the impact of the parent-of-origin of the supernumerary X chromosome psychopathology. The Klinefelter studies further showed that particular cognitive defects can be central to problems in social adaptation. A further challenge was to find genes regulating cognitive functions that influence social outcome. Therefore, a genetic mapping study in mice was started to find loci regulating ‘social cognition’ and to evaluate their function in humans. We used quantitative genetic analysis (using chromosome substitution strains) of temporal aspects of social recognition and discrimination to find genetic loci that relate to social information processing. A quantitative trait locus (QTL) for long-term social discrimination was genetically mapped to a locus harboring Pchd9 (Protocadherin 9), a gene that has been associated to human autism and social behavioral regulation in dogs. Pchd9-deficient mice were generated and confirmed impairments in long-term but not short-term social discrimination, while nonsocial discrimination was intact. We further showed that long-term social behavior impairments in Pchd9-deficient mice were associated with a brain region-specific reduction in cortical thickness in areas of higher order sensory processing. These findings show that complementary genetic mapping of clinically relevant mouse phenotypes may bridge the gap between genotypes and phenotypes in human psychiatric disorders, leading to greater understanding of the underlying biology. Overview of studies in the thesis: Study 1: Describes a general survey of psychopathology in 51 boys with Klinefelter syndrome. Study 2: Proves the specificity of phenotypes in autistic subjects with KS and 22q11 deletion syndrome through statistical comparison of both disorder autistic symptom profiles with the profiles of genetically heterogeneous autism spectrum disorders. Study 3: Investigates cognitive executive functioning in boys with KS and its relation to social functioning. Study 4: Shows that the parent-of origin of the X chromosome influences psychopathogy in KS. Study 5: Searches for core cognitive features in KS by cross-species comparison of recognition deficits in mice with a supernumerary X chromosome to recognition deficits in boys with KS. Study 6: Is a large study that describes the genetic mapping of temporal components of social memory in mice using chromosome substitution strains, leading to the identification of genes involved in social information processing and cortical morphogenesis across species.