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.
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.
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 measures comprised of morphological and densitometric traits from a large number sites in 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. Analyzing phenotypic patterns may increase productivity in genetic screens, and could facilitate the study of genetic variants associated with smaller effect sizes, such as those that underlie complex diseases. Using a high-throughput automated synchrotron-based tomographic microscopy system, Mader et al. [7] quantified 22 different measurements in the mouse femur. In zebrafish, Pardo-Martin et al. [8] used automated sample handling and optical projection tomography to acquire high-dimensional phenotypic profiles (~200 measurements) in the craniofacial cartilage of early larvae, representing one of the most ambitious approachesto perform large-scale phenotyping in the skeleton to date. Yet, even in this analysis, traits were derived from only 9 skeletal elements. Further, this method is not readily extendable to bones outside of the craniofacial skeleton, or to adults. Finally, while both the mouse and zebrafish spine are amenable to whole-body microCT imaging [9, 10], indepth phenotyping is usually limited to a few vertebral bodies [11]. In this context, methods to perform in-depth phenotyping in a large number of bones represents a unique class of problems that has not been adequately addressed.
Individuals with a history of epilepsy are at higher risk for bone fractures compared to the general population. Although clinical studies support an association between low bone mineral density (BMD) and anti-seizure medications, little is known on whether a history of seizures is linked to altered bone health. Therefore, in this study we tested the hypothesis that bone mass, morphology, and bone mineralization are altered by seizures in genetically epileptic animals and in animals subjected to an episode of status epilepticus. In this study, we used NS-Pten conditional knockout mice (a well-studied genetic model of epilepsy). We used microCT analysis to measure BMD, morphology, and mineralization in NS-Pten (wildtype) and NS-Pten (knockout) mice at 4 and 8weeks, as well as adult Kv4.2 and Kv4.2 mice. We measured BMD, bone morphology, and mineralization in adult NS-Pten mice that received status epilepticus through kainic acid (20mg/kg intraperitoneal). Further, we measured locomotion for NS-Pten and NS-Pten mice at 4 and 6weeks. We found that NS-Pten mice exhibited low BMD in the tibial metaphysis and midshaft compared to non-epileptic mice. Morphologically, NS-Pten mice exhibited decreased trabecular volume fraction, and endocortical expansion in both the metaphyeal and diaphyseal compartments. In the midshaft, NS-Pten mice exhibited reduced tissue mineral density, indicating impaired mineralization in addition to morphological deficits. NS-Pten mice exhibited hyperactivity in open field testing, suggesting low bone mass in NS-Pten mice was not attributable to hypoactivity. Differences in BMD were not observed following kainate-induced seizures or in the Kv4.2 model of seizure susceptibility. Our findings suggest that deletion of Pten in the brain results in impaired bone mass and mineralization, which may contribute to weaker bones and thereby a higher fracture risk.
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