Novel cardiovascular gene functions revealed via systematic phenotype prediction in zebrafish

Development (Cambridge) - Tập 141 Số 1 - Trang 224-235 - 2014
Gabriel Musso1,2, Murat Taşan3,4, Christian Mosimann5,6,7, John Beaver3, Eva Plovie1, Logan A. Carr5,6,7, Hon Nian Chua4, Julie Dunham4, Khalid Zuberi4, Harold Rodriguez4, Quaid Morris4, Leonard I. Zon5,6,7, Frederick P. Roth8,3,4,9, Calum A. MacRae1,2
1Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA
2Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
3Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
4Donnelly Centre and Departments of Molecular Genetics and Computer Science, University of Toronto, Toronto, ON M5S 3E1, Canada
5Division of Hematology/Oncology, Children's Hospital Boston, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA
6Howard Hughes Medical Institute, Boston, MA 02115, USA
7Stem Cell Program, Children's Hospital Boston, Boston, MA 02115, USA
8Center for Cancer Systems Biology, Dan-Farber Cancer Institute, Boston, MA 02115, USA
9Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto, ON, M5G 1X5, Canada

Tóm tắt

Comprehensive functional annotation of vertebrate genomes is fundamental to biological discovery. Reverse genetic screening has been highly useful for determination of gene function, but is untenable as a systematic approach in vertebrate model organisms given the number of surveyable genes and observable phenotypes. Unbiased prediction of gene-phenotype relationships offers a strategy to direct finite experimental resources towards likely phenotypes, thus maximizing de novo discovery of gene functions. Here we prioritized genes for phenotypic assay in zebrafish through machine learning, predicting the effect of loss of function of each of 15,106 zebrafish genes on 338 distinct embryonic anatomical processes. Focusing on cardiovascular phenotypes, the learning procedure predicted known knockdown and mutant phenotypes with high precision. In proof-of-concept studies we validated 16 high-confidence cardiac predictions using targeted morpholino knockdown and initial blinded phenotyping in embryonic zebrafish, confirming a significant enrichment for cardiac phenotypes as compared with morpholino controls. Subsequent detailed analyses of cardiac function confirmed these results, identifying novel physiological defects for 11 tested genes. Among these we identified tmem88a, a recently described attenuator of Wnt signaling, as a discrete regulator of the patterning of intercellular coupling in the zebrafish cardiac epithelium. Thus, we show that systematic prioritization in zebrafish can accelerate the pace of developmental gene function discovery.

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Development (Cambridge)

Tập 141 Số 1

224-235

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