Mitochondrial genomic variation drives differential nuclear gene expression in discrete regions of Drosophila gene and protein interaction networks

Abstract

Background Mitochondria perform many key roles in their eukaryotic hosts, from integrating signaling pathways through to modulating whole organism phenotypes. The > 1 billion years of nuclear and mitochondrial gene co-evolution has necessitated coordinated expression of gene products from both genomes that maintain mitochondrial, and more generally, eukaryotic cellular function. How mitochondrial DNA (mtDNA) variation modifies host fitness has proved a challenging question but has profound implications for evolutionary and medical genetics. In Drosophila, we have previously shown that recently diverged mtDNA haplotypes within-species can have more impact on organismal phenotypes than older, deeply diverged haplotypes from different species. Here, we tested the effects of mtDNA haplotype variation on gene expression in Drosophila under standardized conditions. Using the Drosophila Genetic Reference Panel (DGRP), we constructed a panel of mitonuclear genotypes that consists of factorial variation in nuclear and mtDNA genomes, with mtDNAs originating in D. melanogaster (2x haplotypes) and D. simulans (2x haplotypes). Results We show that mtDNA haplotype variation unequivocally alters nuclear gene expression in both females and males, and mitonuclear interactions are pervasive modifying factors for gene expression. There was appreciable overlap between the sexes for mtDNA-sensitive genes, and considerable transcriptional variation attributed to particular mtDNA contrasts. These genes are generally found in low-connectivity gene co-expression networks, occur in gene clusters along chromosomes, are often flanked by non-coding RNA, and are under-represented among housekeeping genes. Finally, we identify the giant ( gt ) transcription factor motif as a putative regulatory sequence associated with mtDNA-sensitive genes. Conclusions There are predictive conditions for nuclear genes that are influenced by mtDNA variation. Electronic supplementary material The online version of this article (10.1186/s12864-019-6061-y) contains supplementary material, which is available to authorized users.

Mitochondrial genotype alters the impact of rapamycin on the transcriptional response to nutrients in Drosophila

“…The genes in cluster 5 were significantly enriched for motifs associated with 28 different transcription factors (Supplementary Table S6 B), none of which were found in the analysis of the cluster 1 gene set. Two of the most highly enriched transcription factors for cluster 5 were Dref (DNA replication-related element factor) which has been shown to function in response to mTOR activity and gt (giant) which, through previous work from our lab, has been associated with mitonuclear genotype sensitive gene expression [ 43 , 44 ]. Together, Dref and gt were associated with 185 of the 258 genes in the enriched KEGG pathways for cluster 5 (Fig.…”

“…The transcription factor gt was previously detected in work from our laboratory as a mitonuclear genotype sensitive transcription factor [ 44 ]. It is notable that, while this previous study was also conducted to compare the effects of mitonuclear genetic interactions, it was done so using different mitonuclear genotypes than our current study.…”

Mitochondrial-nuclear coadaptation revealed through mtDNA replacements in Saccharomyces cerevisiae

“…This study highlights that mapping efforts will need to consider that coadapted mitonuclear loci are likely strain and niche specific. Most analysis of yeast mtDNAs have focused on coding sequences [ 51 , 52 , 73 ]. We did not find associations between mitochondrial coding SNPs and growth phenotypes in environments revealing coadapted mitonuclear genotypes.…”

Mitochondrial-nuclear coadaptation revealed through mtDNA replacements in Saccharomyces cerevisiae

“…Identifying the exact loci underlying mitonuclear interactions is an obvious future goal. This study highlights that mapping efforts will need to consider that coadapted mitonuclear loci are likely strain and niche speci c. Most analysis of yeast mtDNAs have focused on coding sequences [51,52,74]. We did not nd associations between mitochondrial coding SNPs and growth phenotypes in environments revealing coadapted mitonuclear genotypes.…”