Natural genetic variation quantitatively regulates heart rate and dimension.

Area of Science:

• Genetics
• Cardiovascular Biology
• Developmental Biology

Background:

• The genetic underpinnings of heart development and function across health and disease states are not fully understood.
• Investigating quantitative cardiac phenotypes is crucial for understanding congenital and acquired heart conditions.

Purpose of the Study:

• To elucidate the genetic basis of quantitative cardiac phenotypes using fish models.
• To identify specific genes and loci that control heart rate and cardiac development.

Main Methods:

• Utilized highly inbred Japanese rice fish (Oryzias latipes and Oryzias sakaizumii) for genetic studies.
• Employed automated quantification of embryonic heart rates to assess phenotype variability across five inbred strains.
• Performed genome-wide mapping in an F2 segregation population (1192 embryos) derived from contrasting HO5 and HdrR strains.
• Validated candidate genes using gene editing techniques.

Main Results:

• Identified maximal phenotypic contrast in heart rate between HO5 (elevated rate, ventricular hypoplasia) and HdrR strains.
• Mapped 59 loci, encompassing 173 genes, associated with heart rate variation.
• Experimental validation confirmed causal roles for 12 top candidate genes in heart rate, development, ventricle size, and arrhythmia.

Conclusions:

• Uncovered novel diagnostic and therapeutic targets for developmental and electrophysiological cardiac diseases.
• Established a scalable approach for investigating the genetic architecture of vertebrate heart function.
• Highlighted the polygenic nature of cardiac traits and their implications for health and disease.