Abstract Thu093: Comparative Single-Cell Atlas of the Vertebrate Cardiac Conduction System
Bibliographic record
Abstract
The development and function of cardiac conduction system (CCS) components are governed by specialized and unique gene expression programs. Although this transcriptional heterogeneity has been studied in mice, how these molecular profiles compare to those in humans remains unclear. Additionally, transcriptional changes during CCS maturation are not well understood. Here, we examine the conservation and divergence of CCS gene programs across species and development. To achieve this, CCS cells were isolated and analyzed using published single-cell/nucleus RNA sequencing and spatial transcriptomic data from mouse (embryonic/postnatal) and human (fetal/adult) hearts. As expected, species-conserved markers of broad CCS zones included pacemaker ion channels in the nodal regions and fast-conducting ion channels in the ventricular conduction system, as well as many genes newly implicated in the CCS. Additionally, we found species-conserved markers specific to individual CCS components, such as GNAO1 and CDH11 in the sinoatrial node; RSPO3 and BMP2 in the atrioventricular node; FBN2 in the His bundle; and IRX1 and IRX2 in Purkinje fibers. Our analyses also identified species- and stage-specific markers, reflecting evolutionary divergence and developmental changes in the CCS. These included functional genes such as ion channels, as well as signaling molecules and transcription factors that may regulate CCS development and maturation. Further examination of rat and zebrafish sinoatrial and atrioventricular nodes revealed a core set of vertebrate-conserved markers, as well as those conserved within mammals or rodents only. We then reconstructed gene regulatory networks and identified conserved transcriptional mechanisms that establish CCS heterogeneity. Moreover, we examined associations of common and rare genetic variants of conserved CCS genes with conduction-related traits. This analysis identified significant associations of 55 conserved CCS genes with arrhythmias and electrophysiological measures, suggesting functional and translational relevance. To enhance data accessibility, we launched an interactive web application (ccsatlas.com) that visualizes CCS gene expression across species and development. Our study provides a systematic comparative analysis of CCS transcriptional heterogeneity, identifying conserved gene programs relevant to human physiology and elucidating the molecular basis for species- and stage-dependent differences in CCS function.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".