High throughput in vivo functional validation of candidate congenital heart disease genes in Drosophila

Elife. 2017 Jan 20:6:e22617. doi: 10.7554/eLife.22617.

Abstract

Genomic sequencing has implicated large numbers of genes and de novo mutations as potential disease risk factors. A high throughput in vivo model system is needed to validate gene associations with pathology. We developed a Drosophila-based functional system to screen candidate disease genes identified from Congenital Heart Disease (CHD) patients. 134 genes were tested in the Drosophila heart using RNAi-based gene silencing. Quantitative analyses of multiple cardiac phenotypes demonstrated essential structural, functional, and developmental roles for more than 70 genes, including a subgroup encoding histone H3K4 modifying proteins. We also demonstrated the use of Drosophila to evaluate cardiac phenotypes resulting from specific, patient-derived alleles of candidate disease genes. We describe the first high throughput in vivo validation system to screen candidate disease genes identified from patients. This approach has the potential to facilitate development of precision medicine approaches for CHD and other diseases associated with genetic factors.

Keywords: D. melanogaster; Drosophila; congenital heart disease; developmental biology; heart development; histone modification; human biology; in vivo validation; medicine; stem cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Disease Models, Animal
  • Drosophila
  • Drosophila Proteins / genetics*
  • Gene Silencing
  • Genetic Testing*
  • Heart Diseases / congenital*
  • Heart Diseases / genetics*
  • High-Throughput Screening Assays
  • Humans
  • RNA Interference

Substances

  • Drosophila Proteins