Genetic and genomic studies of mouse and human NR2E1 in cortical disorders, aggressive behaviour, and psychiatric disease

Brain and behavioural disorders represent a leading cause of morbidity and suffering worldwide. The 'fierce' mouse has a spontaneous deletion of Nr2e1 that results in a complex phenotype that includes cortical hypoplasia and socially abnormal behaviours. Notably, functional protein and regulatory equivalency of mouse and human NR2E1 has been established. Furthermore, human studies implicate the genomic region containing NR2E1 in mental illness, although a role for NR2E1 in humans is currently unknown. Here, I integrate mouse models and human molecular genetics to understand the involvement of NR2E1 in human brain-behaviour development. First, we test the hypothesis that the spontaneous 'fierce' deletion involves onlyNr2el. It was demonstrated that the 'fierce' mutation results in the loss of all Nr2e1 exons without affecting neighbouring genes. Next, the hypothesis that some humans with cortical malformations will harbour NR2E1 mutations was tested by sequencing the coding, untranslated, splice-site, proximal promoter, and evolutionarily conserved regions of this gene in 60 subjects with microcephaly. Four candidate regulatory mutations were identified. To help interpret these findings, the genomic architecture and molecular evolution of NR2E1 were characterized in 94ethnically-diverse humans and 13 non-human primates, which indicated strong functional constraint. Finally, the hypothesis that some humans with behavioural and psychiatric disorders will harbour mutations in NR2E1 was tested by sequencing the regions outlined above in 126humans with impulsive-aggressive disorders, bipolar disorder, or schizophrenia. Eleven candidate regulatory mutations were identified. Taken together, the findings presented in this thesis are consistent with the proposal that non-coding regulatory mutations may be important to the pathogenesis of brain-behavioural disorders in some humans.Medicine, Faculty ofMedical Genetics, Department ofGraduat