Gierten Jakob, Welz Bettina, Fitzgerald Tomas, Thumberger Thomas, Agarwal Rashi, Hummel Oliver, Leger Adrien, Weber Philipp, Naruse Kiyoshi, Hassel David, Hübner Norbert, Birney Ewan, Wittbrodt Joachim
Centre for Organismal Studies (COS), Heidelberg University, Heidelberg, Germany.
Department of Pediatric Cardiology, Heidelberg University Hospital, Heidelberg, Germany.
Nat Commun. 2025 Apr 30;16(1):4062. doi: 10.1038/s41467-025-59425-7.
The polygenic contribution to heart development and function along the health-disease continuum remains unresolved. To gain insight into the genetic basis of quantitative cardiac phenotypes, we utilize highly inbred Japanese rice fish models, Oryzias latipes, and Oryzias sakaizumii. Employing automated quantification of embryonic heart rates as core metric, we profiled phenotype variability across five inbred strains. We observed maximal phenotypic contrast between individuals of the HO5 and the HdrR strain. HO5 showed elevated heart rates associated with embryonic ventricular hypoplasia and impaired adult cardiac function. This contrast served as the basis for genome-wide mapping. In an F2 segregation population of 1192 HO5 x HdrR embryos, we mapped 59 loci (173 genes) associated with heart rate. Experimental validation of the top 12 candidate genes by gene editing revealed their causal and distinct impact on heart rate, development, ventricle size, and arrhythmia. Our study uncovers new diagnostic and therapeutic targets for developmental and electrophysiological cardiac diseases and provides a novel scalable approach to investigate the intricate genetic architecture of the vertebrate heart.
多基因对心脏发育及沿健康-疾病连续谱的功能的贡献仍未明确。为深入了解心脏定量表型的遗传基础，我们利用高度近交的日本稻田鱼模型，即青鳉和坂井青鳉。以胚胎心率的自动量化作为核心指标，我们对五个近交品系的表型变异性进行了分析。我们观察到HO5品系和HdrR品系个体之间存在最大的表型差异。HO5表现出心率升高，伴有胚胎心室发育不全和成年心脏功能受损。这种差异作为全基因组定位的基础。在由1192个HO5×HdrR胚胎组成的F2分离群体中，我们定位了59个与心率相关的位点（173个基因）。通过基因编辑对前12个候选基因进行实验验证，揭示了它们对心率、发育、心室大小和心律失常的因果及独特影响。我们的研究揭示了发育性和电生理性心脏病的新诊断和治疗靶点，并提供了一种新颖的可扩展方法来研究脊椎动物心脏复杂的遗传结构。
