microCT-based phenomics in the zebrafish skeleton reveals virtues of deep phenotyping in a distributed organ system
- University of Washington, United States
- Ghent University, Belgium
- Boston College, United States
- University of Virginia, United States
Abstract
Phenomics, which ideally involves in-depth phenotyping at the whole-organism scale, may enhance our functional understanding of genetic variation. Here, we demonstrate methods to profile hundreds of phenotypic measures comprised of morphological and densitometric traits at a large number of sites within the axial skeleton of adult zebrafish. We show the potential for vertebral patterns to confer heightened sensitivity, with similar specificity, in discriminating mutant populations compared to analyzing individual vertebrae in isolation. We identify phenotypes associated with human brittle bone disease and thyroid stimulating hormone receptor hyperactivity. Finally, we develop allometric models and show their potential to aid in the discrimination of mutant phenotypes masked by alterations in growth. Our studies demonstrate virtues of deep phenotyping in a spatially distributed organ system. Analyzing phenotypic patterns may increase productivity in genetic screens, and facilitate the study of genetic variants associated with smaller effect sizes, such as those that underlie complex diseases.
Data availability
-
Data from: microCT-Based Skeletal Phenomics in Zebrafish Reveals Virtues of Deep Phenotyping in a Single Organ SystemAvailable at Dryad Digital Repository under a CC0 Public Domain Dedication.
Article and author information
Author details
Funding
University of Washington (A88052)
- Ronald Y Kwon
National Institutes of Health (AR066061)
- Ronald Y Kwon
Belgian Science Policy Office Interuniversity Attraction Poles Program (IAP P7/43-BeMGI)
- Paul Coucke
National Institutes of Health (GM105874)
- Sarah K McMenamin
National Institutes of Health (HD091634)
- Sarah K McMenamin
National Institutes of Health (GM11233)
- David M Parichy
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All studies were performed on an approved protocol (#4306-01) in accordance with the University of Washington Institutional Animal Care and Use Committee (IACUC).
Copyright
© 2017, Hur et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 2,994
- views
-
- 390
- downloads
-
- 60
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
microCT-based phenomics in the zebrafish skeleton reveals virtues of deep phenotyping in a distributed organ system
eLife 6:e26014.
https://doi.org/10.7554/eLife.26014
Further reading
-
- Computational and Systems Biology
- Evolutionary Biology
As pathogens spread in a population of hosts, immunity is built up, and the pool of susceptible individuals are depleted. This generates selective pressure, to which many human RNA viruses, such as influenza virus or SARS-CoV-2, respond with rapid antigenic evolution and frequent emergence of immune evasive variants. However, the host’s immune systems adapt, and older immune responses wane, such that escape variants only enjoy a growth advantage for a limited time. If variant growth dynamics and reshaping of host-immunity operate on comparable time scales, viral adaptation is determined by eco-evolutionary interactions that are not captured by models of rapid evolution in a fixed environment. Here, we use a Susceptible/Infected model to describe the interaction between an evolving viral population in a dynamic but immunologically diverse host population. We show that depending on strain cross-immunity, heterogeneity of the host population, and durability of immune responses, escape variants initially grow exponentially, but lose their growth advantage before reaching high frequencies. Their subsequent dynamics follows an anomalous random walk determined by future escape variants and results in variant trajectories that are unpredictable. This model can explain the apparent contradiction between the clearly adaptive nature of antigenic evolution and the quasi-neutral dynamics of high-frequency variants observed for influenza viruses.
-
- Computational and Systems Biology
- Medicine
Sudden death after myocardial infarction (MI) is associated with electrophysiological heterogeneities and ionic current remodelling. Low ejection fraction (EF) is used in risk stratification, but its mechanistic links with pro-arrhythmic heterogeneities are unknown. We aim to provide mechanistic explanations of clinical phenotypes in acute and chronic MI, from ionic current remodelling to ECG and EF, using human electromechanical modelling and simulation to augment experimental and clinical investigations. A human ventricular electromechanical modelling and simulation framework is constructed and validated with rich experimental and clinical datasets, incorporating varying degrees of ionic current remodelling as reported in literature. In acute MI, T-wave inversion and Brugada phenocopy were explained by conduction abnormality and local action potential prolongation in the border zone. In chronic MI, upright tall T-waves highlight large repolarisation dispersion between the border and remote zones, which promoted ectopic propagation at fast pacing. Post-MI EF at resting heart rate was not sensitive to the extent of repolarisation heterogeneity and the risk of repolarisation abnormalities at fast pacing. T-wave and QT abnormalities are better indicators of repolarisation heterogeneities than EF in post-MI.
