Mitonuclear epistasis, genotype‐by‐environment interactions, and personalized genomics of complex traits in Drosophila

Abstract

Mitochondrial function requires the coordinated expression of dozens of gene products from the mitochondrial genome and hundreds from the nuclear genomes. The systems that emerge from these interactions convert the food we eat and the oxygen we breathe into energy for life, while regulating a wide range of other cellular processes. These facts beg the question of whether the gene‐by‐gene interactions (G x G) that enable mitochondrial function are distinct from the gene‐by‐environment interactions (G x E) that fuel mitochondrial activity. We examine this question using a Drosophila model of mitonuclear interactions in which experimental combinations of mtDNA and nuclear chromosomes generate pairs of mitonuclear genotypes to test for epistatic interactions (G x G). These mitonuclear genotypes are then exposed to altered dietary or oxygen environments to test for G x E interactions. We use development time to assess dietary effects, and genome wide RNAseq analyses to assess hypoxic effects on transcription, which can be partitioned in to mito, nuclear, and environmental (G x G x E) contributions to these complex traits. We find that mitonuclear epistasis is universal, and that dietary and hypoxic treatments alter the epistatic interactions. We further show that the transcriptional response to alternative mitonuclear interactions has significant overlap with the transcriptional response to alternative oxygen environments. Gene coexpression analyses suggest that these shared genes are more central in networks of gene interactions, implying some functional overlap between epistasis and genotype by environment interactions. These results are discussed in the context of evolutionary fitness, the genetic basis of complex traits, and the challenge of achieving precision in personalized medicine. © 2018 The Authors. IUBMB Life published by Wiley Periodicals, Inc. on behalf of International Union of Biochemistry and Molecular Biology, 70(12):1275–1288, 2018

Mitochondrial-nuclear coadaptation revealed through mtDNA replacements in Saccharomyces cerevisiae

“…Perhaps the major challenge in identifying coevolved mitonuclear genotypes is the environmentally-sensitive nature of phenotypes that result from mitonuclear interactions. For instance, differences in diet and oxygen availability altered mitonuclear interactions in Drosophila [15,41]. These three-way mtDNA × nDNA × environment interactions may explain why replacing mtDNAs within a species can lead to more pronounced effects than that of between species [13] and why it can be challenging to conclusively document mitonuclear coadaptation [36].…”

Mitochondrial-nuclear coadaptation revealed through mtDNA replacements in Saccharomyces cerevisiae

“…Perhaps the major challenge in identifying coevolved mitonuclear genotypes is the environmentally-sensitive nature of phenotypes that result from mitonuclear interactions. For instance, differences in diet and oxygen availability greatly altered mitonuclear interactions in Drosophila [15,41]. These three-way mtDNA × nDNA × environment interactions may explain why replacing mtDNAs within a species can lead to more pronounced effects than that of between species [13] and why it can be challenging to conclusively document mitonuclear coadaptation [36].…”

Peer Review #3 of "The cuticle inward barrier in Drosophila melanogaster is shaped by mitochondrial and nuclear genotypes and a sex-specific effect of diet (v0.1)"

“…The seeming independence of the inward barrier function from mito-nuclear interaction possibly represents a particular case. Indeed, mitonuclear interactions have been demonstrated to affect a wide range of biological processes such as developmental time, sex-specific transcription, hypoxia and longevity (Dowling et al, 2010;Mossman et al, 2016aMossman et al, ,b, 2017Rand et al, 2006;Rand et al, 2018). We will need to expand the number of different geographical populations of D. melanogaster or refine the quantification of our dye-penetration assay in our analyses to uncover whether any subtle mito-nuclear effects on cuticle barrier function exist.…”