Zebrafish homologs of genes within 16p11.2, a genomic region associated with brain disorders, are active during brain development, and include two deletion dosage sensor genes
TLDR
The first major finding is that the 16p11.2 region comprises a highly active set of genes, which could present a large genetic target and might explain why multiple brain function, and other, phenotypes are associated with this interval.Abstract:
Summary 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 9dosage sensors9), 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.read more
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Association between Microdeletion and Microduplication at 16p11.2 and Autism
Lauren A. Weiss,Yiping Shen,Joshua M. Korn,Joshua M. Korn,Dan E. Arking,David T. Miller,Ragnheidur Fossdal,Evald Saemundsen,Hreinn Stefansson,Todd Green,Todd Green,Orah S. Platt,Douglas M. Ruderfer,Douglas M. Ruderfer,Christopher A. Walsh,David Altshuler,David Altshuler,Aravinda Chakravarti,Aravinda Chakravarti,Rudolph E. Tanzi,Kari Stefansson,Susan L. Santangelo,James F. Gusella,James F. Gusella,Pamela Sklar,Pamela Sklar,Bai-Lin Wu,Mark J. Daly,Mark J. Daly +28 more
TL;DR: A novel, recurrent microdeletion and a reciprocal microduplication that carry substantial susceptibility to autism and appear to account for approximately 1% of cases are identified.
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