At the Core of Autism: Engineered Models of 16p11.2 CNVs

Background:  Autism is a neurocognitive syndrome characterized by clinical features of repetitive behavior and altered social interactions, as well as a spectrum of co-morbidities such as language impairments, eating problems, and sleep deficits. Copy number variations (CNVs) have been found in patients with autism.  

Objectives:  The goal of our work is to determine whether 16p11.2 CNVs cause autism-like phenotypes. 

Methods:  We used chromosome engineering to generate mice with deletion corresponding to 16p11.2—one of the most prevalent genomic lesions associated with autism—as well as mice with reciprocal duplication of this region. We analyzed these 16p11.2 CNV models for behavioral and brain architectural phenotypes using video monitoring and MRI, respectively.

Results:  We found that mice with altered dosage of the region corresponding to human 16p11.2 have unique phenotypes, with mice heterozygous for its deletion having neuroanatomical and behavioral phenotypes reminiscent of autism. Deletion mice have repetitive behavior, sleep deficits, and difficulty adapting to a new environment. These behavioral phenotypes correspond with alterations in brain architecture, as MRI and histological analyses define perturbations in specific brain regions. Remarkably, we can identify behavioral alterations just two days after birth, suggesting that these phenotypes can be used as endophenotypes to identify affected children before the full-blown features of autism have developed. Throughout this study, we discovered that deletion causes the most severe phenotype, and that duplication has the reciprocal effect. 

Conclusions: These findings provide the first functional evidence that compromised dosage of 16p11.2 is causal in autism-like phenotypes, providing unique models for elucidating the molecular mechanisms involved and for developing new approaches for clinical intervention.