A Mouse Model for the Human Chromosome 16p11.2 Copy Number Variation

Background: A recurrent copy number variation (CNV) on chromosome 16p11.2 resulting in a 550 kilobase genomic deletion is a high penetrance risk factor for autism spectrum disorder (ASD).

Objectives: In order to understand the molecular mechanisms underlying ASD mouse models are a valuable tool. The human chromosome 16p11.2 CNV is amenable to modeling in rodents as all 27 genes in the locus are highly conserved on mouse chromosome 7F3.

Methods: Using Cre-lox technology and two-step homologous recombination, we have generated a mouse model for the human 16p11.2 deletion.

Results: Mice heterozygous for the 27 genes in this region (16p11+/-) display low body weight, and lower survival rate prior to weaning. Adult 16p11+/- animals are less prolific in breeding. Anatomical analysis of the brain suggests increased brain size and deficits in the organization of multiple brain regions including cerebral cortex and cerebellum at early postnatal stages. Behavioral phenotyping of the 16p11+/- mice suggests hyperactivity, altered habituation to a novel environment, and possibly altered social behavior.

Conclusions: Our data suggest a fundamental role of the genes affected by the human 16p11.2 CNV in the development of the central nervous system and in complex behaviors.