Reciprocal copy number variation (CNV), or duplication or deletion, of the 16p11.2 region of chromosome 16 causes a multi-system genomic disorder. While there has been a concerted research effort to characterize the clinical symptoms of this disorder, we still do not understand the mechanisms driving many of the phenotypes observed. Michael Talkowski and his colleagues aim to investigate the tissue-specific transcriptional consequences of deletion and duplication of the genes within the 16p11.2 microdeletion or duplication segment in mouse models harboring deletion or duplication of the syntenic genomic segment 7qf3.

In 2014, Talkowski and his collaborators showed that changes in gene expression predictably occur for all genes within the 16p11.2 region in a dosage-dependent manner in the presence of a CNV¹. The same is true for many genes outside of the 16p11.2 region, and these differentially expressed networks are enriched for genes that have been implicated in autism. They found this to be true in tissue derived from lymphoblasts in people, and from the cortex of the mouse models created by Alea Mills at Cold Spring Harbor Laboratory in New York. These studies suggest that, among the hundreds or even thousands of genes associated with autism, there could be a relatively small number of final common pathways affected. However, we know very little about whether these transcriptional signatures are similar or different among different tissues.

Talkowski and his group plan to rapidly build a 16p11.2 tissue expression atlas in mouse models harboring deletion and duplication of 7qf3. They hope to determine the gene expression changes associated with the CNV in multiple different tissues, assess similarities and differences among the networks perturbed in each tissue, and study the effect of the CNV on alternative splicing, which can vary widely between tissues. At its conclusion, this pilot study aims to define the tissue-specific molecular mechanisms altered by 16p11.2 CNVs, and provide all raw and processed data to SFARI for general use by investigators aiming to perform tissue-specific analyses in patients.