Deletion or duplication of one copy of the human 16p11.2 interval is tightly associated with impaired brain function, including autism spectrum disorders (ASD), intellectual disability disorder (IDD), and other phenotypes, indicating the importance of gene dosage in this copy number variant region (CNV). The core of this CNV includes 25 genes, however, the number of genes that contribute to these phenotypes is not known. Further, genes whose functional levels change with deletion or duplication (termed 'dosage sensors'), which may associate the CNV with pathologies, have not been identified. Using the zebrafish as a tool, a set of 16p11.2 homologs was identified, primarily on chromosomes 3 and 12. Use of eleven phenotypic assays, spanning the first five days of development, demonstrates that this set of genes is highly active, such that 21 out of 22 homologs tested show loss of function phenotypes. Most genes are required for nervous system development − impacting brain morphology, eye development, axonal density or organization, and motor response. In general, human genes can substitute for the fish homolog, demonstrating orthology, and consistent with conserved molecular pathways. In a screen for 16p11.2 genes whose function is sensitive to hemizygosity, the aldolase a (aldoa) and kinesin family member 22 (kif22) genes were identified as giving clear phenotypes when RNA levels are reduced by ~50%, suggesting that these genes are deletion dosage sensors. This study leads to two major findings. The first is that the 16p11.2 region comprises a highly active set of genes, which may present a large genetic target, and may explain why multiple brain function and other phenotypes are associated with this interval. The second major finding is that there are (at least) two genes with deletion dosage sensor properties amongst the 16p11.2 set, which may link this CNV to brain disorders including ASD and IDD.
- Received March 28, 2012.
- Accepted April 25, 2012.
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