A new genetic model organism for primate-specific cardiac function and disease
Abstract/Contents
- Abstract
- Due to differences in cardiac structure and function, it has become increasingly clear that many aspects of cardiovascular anatomy, physiology, biochemistry, and disease are not well modeled in mice. This has spurred a search for new model organisms with the practical advantages of mice but that more closely mimic human biology and disease. This study examines mouse lemur (Microcebus species) -- the world's smallest, most prolific, and among the most abundant non-human primates -- and the cheapest and easiest to maintain, as such a model. Little is known of lemur cardiovascular physiology, cell types, or pathology. This thesis describes the characterization of normal cardiac anatomy and histology, and baseline values for heart rate, cholesterol/lipids, and cardiac waveform by electrocardiography (ECG). It also describes the development of a single cell RNA-sequencing and analysis pipeline for Microcebus murinus that provided genome-wide expression profiles of thousands of cardiac cells. Computational clustering of these transcriptomic profiles, and analysis of cluster-specific expression patterns of mouse lemur orthologues of canonical markers of human and mouse cardiac cell types, identified all major and many minor cardiac cell types in mouse lemur, including several exceedingly rare cell types. To begin to identify cardiac diseases in mouse lemur, a portable 3-lead ECG monitoring device was used to screen ~300 laboratory Microcebus murinus mouse lemurs and ~100 wild Microcebus rufus and a new species of mouse lemurs in Ranomafana National Park in Madagascar. This identified 20 naturally-occurring ECG variants in 170 affected lab and wild animals, with all identified variants resembling known human ECG variants including 8 major cardiac arrhythmias and pathologies plus 7 additional potentially pathological variants. The screen uncovered the first cases of heart disease in lemurs. One is atrial fibrillation, the most common arrhythmia in humans. Another is mouse lemur sick sinus syndrome (SSS), with episodic bradycardia resembling human SSS, whose familial forms arise from mutations in cardiac ion channel genes HCN4 or SCN5A. Both of these mouse lemur pathologic arrythmias show familial clustering, consistent with a genetic origin. The family pedigrees can now be used to determine the inheritance pattern of these diseases, map the underlying disease genes, and sequence the disease loci to identify the causative mutation. The results establish the mouse lemur as the first systematic, high-throughput primate genetic model for cardiovascular physiology and disease, and reveal human-like cardiac cell types and diseases. The approach uncovered naturally-occurring cardiac diseases that have not been found in mice. Furthermore, the strategy outlined here serves as a paradigm for identifying and studying physiological and behavioral traits and diseases beyond the cardiovascular system in this new primate genetic model organism
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2020; ©2020 |
| Publication date | 2020; 2020 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Chang, Stephen, (Cardiologist) |
|---|---|
| Degree supervisor | Harbury, Pehr |
| Degree supervisor | Krasnow, Mark, 1956- |
| Thesis advisor | Harbury, Pehr |
| Thesis advisor | Krasnow, Mark, 1956- |
| Thesis advisor | Quertermous, Thomas |
| Thesis advisor | Wu, Joseph Ching-Ming, 1971- |
| Degree committee member | Quertermous, Thomas |
| Degree committee member | Wu, Joseph Ching-Ming, 1971- |
| Associated with | Stanford University, Department of Biochemistry |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Stephen Chang |
|---|---|
| Note | Submitted to the Department of Biochemistry |
| Thesis | Thesis Ph.D. Stanford University 2020 |
| Location | electronic resource |
Access conditions
- Copyright
- © 2020 by Stephen Chang
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
Also listed in
Loading usage metrics...