Project 2 (Rapid Gene Discovery) has as its major goal the discovery of the gene(s) whose structure and/or expression are disrupted by individual balanced chromosome aberrations associated with developmental abnormalities of the nervous system, including neurological, behavioral and neuroendocrine phenotypes. In addition, Project 2 will assist investigators from Projects 1 and 3 in applying these strategies to subjects with phenotypes in other systems. Molecular biological methods will be employed in a sequence-based strategy to identify the precise genomic positions of breakpoints on chromosomes involved in apparently balanced aberrations and to determine the sequence of the breakpoints and consequent structure of the rearrangements. In the initial phase of the renewal period, we will implement Solexa-based paired-end sequencing of linking fragments to identify the site of the breakpoint without the need for initial FISH mapping. The potential functional consequences of each chromosomal rearrangement will then be examined. Direct gene disruption, either of annotated genes or suspected transcripts, and the potential generation of fusion proteins will be confirmed by analyses of DMA sequence, RNA expression and protein expression. Surrounding genes potentially subject to a position effect will be prioritized by bioinformatic analysis and analyzed at the RNA level for disrupted expression. Bioinformatic approaches will also be taken to identify potential non-coding RNAs and non-coding conserved sequences that could be affected by the chromosomal rearrangement. Finally, candidate genes/sequences will be validated by examining the loci in collections of patients who express similar phenotypes but who do not display chromosomal disruption. Candidate genie and non-genie sequences will be directly sequenced to determine whether individual sequence variants with function-disrupting potential are identified in patients but are" not present on control chromosomes. While itself focusing on driving the characterization of genes causing neurological, behavioral and neuroendocrine phenotypes, Project 2 will also act as a resource for completing these steps in the case characterization for subjects studied by Projects 1 and 3, which will focus on other body systems.

Public Health Relevance

The Developmental Genome Anatomy Project studies a group of patients underserved by the health care system: those with congenital abnormalities due to chromosome rearrangements. Our mission is to discover genes of importance in human development that are disrupted by these chromosomal rearrangements genes that are difficult to identify by more traditional human genetic strategies, thereby opening investigation of the disorders that they cause.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM061354-10
Application #
8460908
Study Section
Special Emphasis Panel (ZRG1-GGG-G)
Project Start
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
10
Fiscal Year
2013
Total Cost
$528,556
Indirect Cost
$134,647
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Wang, Jian; Yu, Tingting; Wang, Zhigang et al. (2016) A New Subtype of Multiple Synostoses Syndrome Is Caused by a Mutation in GDF6 That Decreases Its Sensitivity to Noggin and Enhances Its Potency as a BMP Signal. J Bone Miner Res 31:882-9
Chen, Xiaoli; An, Yu; Gao, Yonghui et al. (2016) Rare Deleterious PARD3 Variants in the aPKC-Binding Region are Implicated in the Pathogenesis of Human Cranial Neural Tube Defects via Disrupting Apical Tight Junction Formation. Hum Mutat :
Tai, Derek J C; Ragavendran, Ashok; Manavalan, Poornima et al. (2016) Engineering microdeletions and microduplications by targeting segmental duplications with CRISPR. Nat Neurosci 19:517-22
Ordulu, Zehra; Kammin, Tammy; Brand, Harrison et al. (2016) Structural Chromosomal Rearrangements Require Nucleotide-Level Resolution: Lessons from Next-Generation Sequencing in Prenatal Diagnosis. Am J Hum Genet 99:1015-1033
Mukherjee, Kusumika; Ishii, Kana; Pillalamarri, Vamsee et al. (2016) Actin capping protein CAPZB regulates cell morphology, differentiation, and neural crest migration in craniofacial morphogenesis†. Hum Mol Genet 25:1255-70
Brand, Harrison; Collins, Ryan L; Hanscom, Carrie et al. (2015) Paired-Duplication Signatures Mark Cryptic Inversions and Other Complex Structural Variation. Am J Hum Genet 97:170-6
Quintero-Rivera, Fabiola; Xi, Qiongchao J; Keppler-Noreuil, Kim M et al. (2015) MATR3 disruption in human and mouse associated with bicuspid aortic valve, aortic coarctation and patent ductus arteriosus. Hum Mol Genet 24:2375-89
Macera, M J; Sobrino, A; Levy, B et al. (2015) Prenatal diagnosis of chromothripsis, with nine breaks characterized by karyotyping, FISH, microarray and whole-genome sequencing. Prenat Diagn 35:299-301
Migliavacca, Eugenia; Golzio, Christelle; Männik, Katrin et al. (2015) A Potential Contributory Role for Ciliary Dysfunction in the 16p11.2 600 kb BP4-BP5 Pathology. Am J Hum Genet 96:784-96
Choi, Jin-Ho; Balasubramanian, Ravikumar; Lee, Phil H et al. (2015) Expanding the Spectrum of Founder Mutations Causing Isolated Gonadotropin-Releasing Hormone Deficiency. J Clin Endocrinol Metab 100:E1378-85

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