Dataset Information

Novel cardiovascular gene functions revealed via systematic phenotype prediction in zebrafish.

ABSTRACT: 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.

SUBMITTER: Musso G

PROVIDER: S-EPMC3865760 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Novel cardiovascular gene functions revealed via systematic phenotype prediction in zebrafish.

Musso Gabriel G Tasan Murat M Mosimann Christian C Beaver John E JE Plovie Eva E Carr Logan A LA Chua Hon Nian HN Dunham Julie J Zuberi Khalid K Rodriguez Harold H Morris Quaid Q Zon Leonard L Roth Frederick P FP MacRae Calum A CA

Development (Cambridge, England) 20140101 1

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 fu ...[more]

PMID: 24346703

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Project description:BACKGROUND:Cardiovascular disease (CVD) risk is elevated in HIV-infected individuals, with contributions from both traditional and nontraditional risk factors. The accuracy of established CVD risk prediction functions in HIV is uncertain. We sought to assess the performance of 3 established CVD risk prediction functions in a longitudinal cohort of HIV-infected men. METHODS:The FHS (Framingham Heart Study) functions for hard coronary heart disease (FHS CHD) and atherosclerotic CVD (FHS ASCVD) and the American College of Cardiology/American Heart Association ASCVD function were applied to the Partners HIV cohort. Risk scores were calculated between January 1, 2006, and December 31, 2008. Outcomes included CHD (myocardial infarction or coronary death) for the FHS CHD function and ASCVD (myocardial infarction, stroke, or coronary death) for the FHS ASCVD and American College of Cardiology/American Heart Association ASCVD functions. We investigated the accuracy of CVD risk prediction for each function when applied to the HIV cohort using comparison of Cox regression coefficients, discrimination, and calibration. RESULTS:The HIV cohort was comprised of 1272 men followed for a median of 4.4 years. There were 78 (6.1%) ASCVD events; the 5-year incidence rate was 16.4 per 1000 person-years. Discrimination was moderate to poor as indicated by the low c statistic (0.68 for FHS CHD, 0.65 for American College of Cardiology/American Heart Association ASCVD, and 0.67 for FHS ASCVD). Observed CVD risk exceeded the predicted risk for each of the functions in most deciles of predicted risk. Calibration, or goodness of fit of the models, was consistently poor, with significant χ2P values for all functions. Recalibration did not significantly improve model fit. CONCLUSIONS:Cardiovascular risk prediction functions developed for use in the general population are inaccurate in HIV infection and systematically underestimate risk in a cohort of HIV-infected men. Development of tailored CVD risk prediction functions incorporating traditional CVD risk factors and HIV-specific factors is likely to result in more accurate risk estimation to guide preventative CVD care.

Dataset Information

Novel cardiovascular gene functions revealed via systematic phenotype prediction in zebrafish.

Publications

Novel cardiovascular gene functions revealed via systematic phenotype prediction in zebrafish.

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