Natural Genetic Variation Screen in Drosophila Identifies Wnt Signaling, Mitochondrial Metabolism, and Redox Homeostasis Genes as Modifiers of Apoptosis

G3 (Bethesda). 2019 Dec 3;9(12):3995-4005. doi: 10.1534/g3.119.400722.


Apoptosis is the primary cause of degeneration in a number of neuronal, muscular, and metabolic disorders. These diseases are subject to a great deal of phenotypic heterogeneity in patient populations, primarily due to differences in genetic variation between individuals. This creates a barrier to effective diagnosis and treatment. Understanding how genetic variation influences apoptosis could lead to the development of new therapeutics and better personalized treatment approaches. In this study, we examine the impact of the natural genetic variation in the Drosophila Genetic Reference Panel (DGRP) on two models of apoptosis-induced retinal degeneration: overexpression of p53 or reaper (rpr). We identify a number of known apoptotic, neural, and developmental genes as candidate modifiers of degeneration. We also use Gene Set Enrichment Analysis (GSEA) to identify pathways that harbor genetic variation that impact these apoptosis models, including Wnt signaling, mitochondrial metabolism, and redox homeostasis. Finally, we demonstrate that many of these candidates have a functional effect on apoptosis and degeneration. These studies provide a number of avenues for modifying genes and pathways of apoptosis-related disease.

Keywords: Drosophila; apoptosis; genetic variation; modifier genes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics*
  • Drosophila / genetics*
  • Drosophila Proteins / genetics
  • Eye / anatomy & histology
  • Gene Regulatory Networks
  • Genetic Variation*
  • Genome-Wide Association Study
  • Homeostasis / genetics*
  • Mitochondria / metabolism*
  • Organ Size / genetics
  • Oxidation-Reduction
  • Tumor Suppressor Protein p53 / genetics
  • Wnt Signaling Pathway / genetics*


  • Drosophila Proteins
  • Tumor Suppressor Protein p53