Reciprocal Effects on Neurocognitive and Metabolic Phenotypes in Mouse Models of 16p11.2 Deletion and Duplication Syndromes

摘要

The 16p11.2 600 kb BP4-BP5 deletion and duplication syndromes have been associated with developmental delay; autism spectrum disorders; and reciprocal effects on the body mass index, head circumference and brain volumes. Here, we explored these relationships using novel engineered mouse models carrying a deletion ( Del/+ ) or a duplication ( Dup/+ ) of the Sult1a1-Spn region homologous to the human 16p11.2 BP4-BP5 locus. On a C57BL/6N inbred genetic background, Del/+ mice exhibited reduced weight and impaired adipogenesis, hyperactivity, repetitive behaviors, and recognition memory deficits. In contrast, Dup/+ mice showed largely opposite phenotypes. On a F1 C57BL/6N × C3B hybrid genetic background, we also observed alterations in social interaction in the Del/+ and the Dup/+ animals, with other robust phenotypes affecting recognition memory and weight. To explore the dosage effect of the 16p11.2 genes on metabolism, Del/+ and Dup/+ models were challenged with high fat and high sugar diet, which revealed opposite energy imbalance. Transcriptomic analysis revealed that the majority of the genes located in the Sult1a1-Spn region were sensitive to dosage with a major effect on several pathways associated with neurocognitive and metabolic phenotypes. Whereas the behavioral consequence of the 16p11 region genetic dosage was similar in mice and humans with activity and memory alterations, the metabolic defects were opposite: adult Del/+ mice are lean in comparison to the human obese phenotype and the Dup/+ mice are overweight in comparison to the human underweight phenotype. Together, these data indicate that the dosage imbalance at the 16p11.2 locus perturbs the expression of modifiers outside the CNV that can modulate the penetrance, expressivity and direction of effects in both humans and mice. Author Summary The 16p11.2 BP4-BP5 deletion and duplication syndromes are frequent copy number variants in humans, and are associated with developmental delay and autism spectrum disorders, with a reciprocal effect on head circumference and body mass index. Here we explored gene dosage effect in mouse models and found that the deletion and duplication induced opposite behavioral phenotypes. Notably, we observed that some behavioral phenotypes, such as social interaction, were sensitive to the genetic background. For the metabolism, the energy imbalance and adipocyte phenotypes were mirrored in the deletion and duplication carriers but opposite to the human phenotypes, the deletion mouse carriers were lean whereas the individuals with the deletion were obese. The main cause of the phenotypic features is the copy number variation of the 16p11.2 region with many genetic pathways altered in the striatum and the liver. Thus the final consequences of the rearrangement are likely governed by the interplay between many cellular pathways in both human cases and mouse models.