Cardiac mass and cardiomyocyte size are governed by different genetic loci on either autosomes or chromosome Y in recombinant inbred mice

Llamas, Bastien; Bélanger, Sonia; Picard, Sylvie; Deschepper, Christian F.

doi:10.1152/physiolgenomics.00072.2007

Cited by 18 publications

(27 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…See web site for date of publication (http://physiolgenomics.physiology.org).of blood pressure regulation are similar to the QTL effects estimated by Llamas et al (2). The observation of a transgressive QTL tells us something about the system.…”

supporting

confidence: 73%

“…When the perturbations in a systems biology experiment are genetic variants, we refer to the approach as systems genetics. Llamas et al (2), in this issue of Physiological Genomics, provide us with a simple but compelling demonstration of systems genetics in practice.…”

mentioning

confidence: 99%

“…Experiments that simultaneously perturb multiple factors can be much more efficient than approaches that perturb one factor at a time, but they still require a reasonable sample size to achieve effective results. Despite the success exemplified by Llamas et al (2), existing RI mouse strain panels are too small to tackle the complex systems of genetic and physiological regulation that underlie most common disease phenotypes. In addition, existing RI panels capture only a fraction of the genetic diversity that exists in mice and there are substantial blind spots due to shared ancestry among strains (4).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Recombinant inbred strain panels: a tool for systems genetics

Churchill

2007

Physiological Genomics

View full text Add to dashboard Cite

SYSTEMS BIOLOGY IS "the study of the interactions between the components of biological systems and how these interactions give rise to the function and behavior of that system" (ref. Wikipedia). Ideally the practice of systems biology is a cyclical process that alternates between stages of mathematical modeling and experimentation. A model is a quantitative description of the system. By solving the model, the "forward problem," we can make predictions about the behavior of the system that can be verified experimentally. Based on the outcome of the experiment, the model may be refined and the cycle begins again. In essence, systems biology is an approach to solving an "inverse problem": given observations of a system in response to perturbations we attempt to deduce or infer the functional properties of the system. Inverse problem are notoriously hard to solve, and the key to success is to choose a set of perturbations that provides good discrimination among alternative models. When the perturbations in a systems biology experiment are genetic variants, we refer to the approach as systems genetics. Llamas et al. (2), in this issue of Physiological Genomics, provide us with a simple but compelling demonstration of systems genetics in practice.For sake of illustration, consider a simplified model of the "system" of blood pressure regulation. In our initial model, blood pressure (BP) is the product of cardiac output (CO) and peripheral resistance (PR). Thus BP ϭ CO * PR. We know that genetic factors affect blood pressure and would like to extend the simple model by adding genetic effects on cardiac output, peripheral resistance, or both. We are able to measure blood pressure and cardiac output but cannot measure both on the same animal. Direct measurements of peripheral resistance are not available to us. Fortunately we have access to a panel of recombinant inbred (RI) mouse strains with a wide range of blood pressures. We measure blood pressure and cardiac output on different, but genetically identical, animals and study the relationships of the measured traits at the level of the strain means. Moreover, the RI panel has been densely genotyped and extensively phenotyped by other researchers, opening the possibility of extending our "system" to include other measured traits. We can also map the genetic loci [quantitative trait loci (QTL)] associated with blood pressure, at no extra cost.Suppose that we have mapped two QTL. Both are associated with blood pressure but only one QTL (Q1) has an effect on cardiac output. According to our model, the other QTL must act on blood pressure through the peripheral resistance pathway. The model is illustrated graphically in Fig. 1. The estimated allelic effects provide quantitative parameters with which one can make predictions. The effect of a "B" genotype at Q1 is to reduce cardiac output by a factor of 0.9 relative to the "A" genotype, with a corresponding decrease in blood pressure. The "B" genotype at Q2, acting through its effect on peripheral resistance, increases blood ...

show abstract

supporting

confidence: 73%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Recombinant inbred strain panels: a tool for systems genetics

Churchill

2007

Physiological Genomics

View full text Add to dashboard Cite

show abstract

“…Since overall cardiac size can vary between males and females [26], we used only male mice with maximal LV dilation, as determined by echocardiograph, for representative whole mount sections for each cohort. Hearts were bi-valved with a razor blade, processed, embedded in paraffin, and stained with Masson's trichome (MT) and Hematoxylin and Eosin (H&E).…”

Section: Preparation and Selection Of Whole-mount Heart Sectionsmentioning

confidence: 99%

Cardiac-Targeted Transgenic Mutant Mitochondrial Enzymes: mtDNA Defects, Antiretroviral Toxicity and Cardiomyopathy

et al. 2008

View full text Add to dashboard Cite

Mitochondrial (mt) DNA biogenesis is critical to cardiac contractility. DNA polymerase gamma (Pol gamma) replicates mtDNA, whereas thymidine kinase 2 (TK2) monophosphorylates pyrimidines intramitochondrially. Point mutations in POLG and TK2 result in clinical diseases associated with mtDNA depletion and organ dysfunction. Pyrimidine analogs (NRTIs) inhibit Pol gamma and mtDNA replication. Cardiac "dominant negative" murine transgenes (TGs; Pol gamma Y955C, and TK2 H121N or I212N) defined the role of each in the heart. mtDNA abundance, histopathological features, histochemistry, mitochondrial protein abundance, morphometry, and echocardiography were determined for TGs in "2 x 2" studies with or without pyrimidine analogs. Cardiac mtDNA abundance decreased in Y955C TGs ( approximately 50%) but increased in H121N and I212N TGs (20-70%). Succinate dehydrogenase (SDH) increased in hearts of all mutants. Ultrastructural changes occurred in Y955C and H121N TGs. Histopathology demonstrated hypertrophy in H121N, LV dilation in I212N, and both hypertrophy and dilation in Y955C TGs. Antiretrovirals increased LV mass ( approximately 50%) for all three TGs which combined with dilation indicates cardiomyopathy. Taken together, these studies demonstrate three manifestations of cardiac dysfunction that depend on the nature of the specific mutation and antiretroviral treatment. Mutations in genes for mtDNA biogenesis increase risk for defective mtDNA replication, leading to LV hypertrophy.

show abstract

“…These will be of particular interest in the AXB/BXA mouse RI strain panel, which has a single QTL for LVM in both male and female mice in a region syntenic with the rat LVM QTL described in our study. 10,87 It is also notable that in this mouse panel, LVM QTLs are independent of cardiac myocyte cross-sectional area, length, or volume. 87 Given these data and the fact that half of all cells in the heart are nonmyocytes 88 and our finding that an Ogn controls LVM, we should examine in more detail the role(s) of cells other than cardiac myocytes in the regulation of LVM.…”

Section: Examples Of Eqtl and Qtt Studiesmentioning

confidence: 82%