Genetic architecture of natural variations of cardiac perfomances in flies

Abstract

Drosophila, the simplest model system with a beating heart, has tremendous advantages for the identification and validation of genetic factors affecting heart development, function and aging. Our project aims to analyse the genetic architecture of the natural variation of heart function in Drosophila and to identify its main characteristics. In particular, we want to take advantage of this model system to disentangle the complex relationship between genetic and environmental factors influencing these complex traits. Cardiac performances were analysed in the Drosophila Genetic Reference Panel (DGRP), and Genome Wide Association Studies (GWAS) were conducted to identify variants associated to several cardiac traits (rate, rhythm, cardiac output, fractional shortening, etc). The compendium of variants and associated genes identified were studied using approaches based on the analysis of gene and protein interaction networks. Genetic and protein networks analyses pointed towards several signalling pathways involved, that were further validated in vivo by targeted gene knockdown. Phenotypic variance among genetically identical individuals was also analysed and associated variants were compared to those affecting variations of phenotypic mean, revealing that distinct though overlapping gene networks were affected. In addition, our results show that more than 90% of variants are located within non-coding regions, and we characterized and validated some aspects of the transcriptional regulatory network affected. We provide a comprehensive characterization of population scale diversity of cardiac traits and of their genetic basis. Our work may provide a framework to interpret similar data from highers eukaryotes, including humans.