Opposite phenotypic effects and genetic dosage in mouse models of 16p11.2 deletion and duplication syndromes

The 16p11.2 deletion and duplication syndromes have been associated with developmental delay and autism spectrum disorders, and a reciprocal effect on body mass index. Here we explored these links with new engineered mouse models carrying a deletion (Del/+) and duplication (Dup/+) of the whole 16p11.2 homologous Sult1a1-Spn region. On a pure genetic background, compared to wild-types, Del/+ mice carrying the deletion showed weight and adipogenesis deficits, hyperactivity, repetitive behaviors, and recognition memory deficits, whereas Dup/+ mice showed the opposite phenotypes and Del/Dup individuals displayed no changes. Alterations in social interaction were also observed in Del/+ and Dup/+ animals on a mixed genetic background. Transcriptomic analysis revealed that the majority of genes located on the Sult1a1-Spn were dosage-sensitive and potentially implicated in the opposite phenotypes described above on the neurocognitive aspect. Nevertheless, the outcome of the 16p11 region genetic dosage on metabolism depends on different genetic contributions between human and mouse. We did transcriptomic analysis of animals carrying rearrangements for the 16p11.2 homologous region after behavioral characterisation.