Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism. Mus musculus

Recurrent Copy Number Variations (CNVs) of human 16p11.2 have been associated with a variety of developmental/neurocognitive syndromes. In particular, deletion of 16p11.2 is found in patients with autism, developmental delay, and obesity. Patients with deletions or duplications have a wide range of clinical features, and siblings carrying the same deletion often have diverse symptoms. To study the consequence of 16p11.2 CNVs in a systematic manner, we used chromosome engineering to generate mice harboring deletion of the chromosomal region corresponding to 16p11.2, as well as mice harboring the reciprocal duplication. These 16p11.2 CNV models have dosage-dependent changes in gene expression, viability, brain architecture, and behavior. For each phenotype, the consequence of the deletion is more severe than that of the duplication. Of particular note is that half of the 16p11.2 deletion mice die postnatally; those that survive to adulthood are healthy and fertile, but have alterations in the hypothalamus and exhibit a ‘behavior trap’ phenotype—a specific behavior characteristic of rodents with lateral hypothalamic and nigrostriatal lesions. Our findings indicate that 16p11.2 CNVs cause both brain and behavioral anomalies, providing new insight into human neurodevelopmental disorders. Overall design: We analyzed gene expression profiles in the brain and determined whether expression corresponded with gene dosage. We measured mRNA intensities in 37 microarray hybridizations representing four brain regions (olfactory bulbs, cortex, cerebellum and brain stem; 5 samples were hybridized twice for estimation of technical errors) in two df/+ mice heterozyous for the deletion of the chromosomal region syntenic to human 16p11.2, three +/+ (wild type) mice and three dp/+ mice heterozyous for the duplication of the chromosomal region syntenic to human 16p11.2. All mice were F1 C57BL/6N: 129Sv hybrid males; therefore, other than the engineered CNV, their genomes were identical.