We are proposing a Community Zebrafish Resource for Modeling GWAS Biology that will exploit existing expertise within our institutions in zebrafish genetics, bioinformatics, zebrafish assay development, genetic modeling and mechanistic studies. These studies will lay the foundation for exploration of the gene networks underlying common human disease phenotypes, and establish high-throughput biology in the zebrafish as a platform to complement GWAS across a broad range of traits. Importantly, this approach is readily adapted to drug response phenotypes and novel traits as they emerge.
The Specific Aims are;
Aim 1 -Initial feasibility assessment and assay development a) Bioinformatics-An initial evaluation of the traits to assess the feasibility of modeling in the zebrafish combined with bioinformatic identification of true orthologs, reagent design and where possible in silico prioritization of candidates. In addition we will specifically explore the relationships between candidate causal SNPs (identified from 1000 genomes data [26, 27]) and the latest tissue-specific ENCODE maps to define the transcription factor networks that may be impacted by the common variants [28, 29]. b) Assay design-We will build representative and quantitative assays for the phenotypes of interest, and anchor these to existing human genotypes and phenotypes using known manipulations of known Mendelian genes regulating the phenotype.
Aim 2 -Systematic evaluation of candidate genes and non-coding variants across multiple loci-Once the phenotypic assays have been validated, we will test in the zebrafish each of the candidate genes and regulatory sequences (where the orthologs can be identified) for their effects alone and in combination on the primary trait [30]. Quantitative assessments will be generated for loss of function and gain of function alleles, using existing mutants, morpholinos and transient or stable transgenesis. We propose to study approximately 15-20 GWAS loci per year.
Aim 3 -Establishing zebrafish models for downstream discovery-Once we have established the causal genes underlying each GWAS locus, we will develop stable loss of function (using TALEN or zinc finger nuclease technology) or gain of function alleles for each gene [31 -33]. In addition, where relevant we will generate stable reporter strains for subsequent genetic or chemical screens. These lines will be made freely available to the community to accelerate the translation of completed and ongoing GWAS.

Public Health Relevance

Modern human genetic studies generate new markers of disease much more rapidly than biologists can study the underlying mechanisms. We propose to generate a community resource to allow investigators to use new high-throughput techniques in the zebrafish to explore the mechanisms of their recent genetic results. This resource will identify the genes causing major common human diseases and will generate animal models to allow additional studies of disease mechanism or potentially drug discovery.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
Resource-Related Research Projects (R24)
Project #
5R24OD017870-02
Application #
8840336
Study Section
Special Emphasis Panel (ZOD1)
Program Officer
Contreras, Miguel A
Project Start
2014-05-01
Project End
2018-02-28
Budget Start
2015-03-01
Budget End
2016-02-29
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
Vo, Linda T; Kinney, Melissa A; Liu, Xin et al. (2018) Regulation of embryonic haematopoietic multipotency by EZH1. Nature 553:506-510
Colombo, Sophie; de Sena-Tomás, Carmen; George, Vanessa et al. (2018) Nkx genes establish second heart field cardiomyocyte progenitors at the arterial pole and pattern the venous pole through Isl1 repression. Development 145:
Natarajan, Niranjana; Abbas, Yamen; Bryant, Donald M et al. (2018) Complement Receptor C5aR1 Plays an Evolutionarily Conserved Role in Successful Cardiac Regeneration. Circulation 137:2152-2165
Cox, Andrew G; Tsomides, Allison; Yimlamai, Dean et al. (2018) Yap regulates glucose utilization and sustains nucleotide synthesis to enable organ growth. EMBO J 37:
Cesana, Marcella; Guo, Michael H; Cacchiarelli, Davide et al. (2018) A CLK3-HMGA2 Alternative Splicing Axis Impacts Human Hematopoietic Stem Cell Molecular Identity throughout Development. Cell Stem Cell 22:575-588.e7
Crawford, Nicholas G; Kelly, Derek E; Hansen, Matthew E B et al. (2017) Loci associated with skin pigmentation identified in African populations. Science 358:
Aday, Aaron W; MacRae, Calum A (2017) Genomic Medicine in Cardiovascular Fellowship Training. Circulation 136:345-346
MacRae, Calum A; Seidman, Christine E (2017) Closing the Genotype-Phenotype Loop for Precision Medicine. Circulation 136:1492-1494
Khajavi, Mehrdad; Zhou, Yi; Birsner, Amy E et al. (2017) Identification of Padi2 as a novel angiogenesis-regulating gene by genome association studies in mice. PLoS Genet 13:e1006848
Choudhuri, Avik; Fast, Eva M; Zon, Leonard I (2017) Using Zebrafish to Study Pathways that Regulate Hematopoietic Stem Cell Self-Renewal and Migration. Stem Cell Reports 8:1465-1471

Showing the most recent 10 out of 33 publications