Mitonuclear Interactions Mediate Transcriptional Responses to Hypoxia in Drosophila.

Among the major challenges in quantitative genetics and personalized medicine is to understand how gene × gene interactions (G × G: epistasis) and gene × environment interactions (G × E) underlie phenotypic variation. Here, we use the intimate relationship between mitochondria and oxygen availability to dissect the roles of nuclear DNA (nDNA) variation, mitochondrial DNA (mtDNA) variation, hypoxia, and their interactions on gene expression in Drosophila melanogaster. Mitochondria provide an important evolutionary and medical context for understanding G × G and G × E given their central role in integrating cellular signals. We hypothesized that hypoxia would alter mitonuclear communication and gene expression patterns. We show that first order nDNA, mtDNA, and hypoxia effects vary between the sexes, along with mitonuclear epistasis and G × G × E effects. Females were generally more sensitive to genetic and environmental perturbation. While dozens to hundreds of genes are altered by hypoxia in individual genotypes, we found very little overlap among mitonuclear genotypes for genes that were significantly differentially expressed as a consequence of hypoxia; excluding the gene hairy. Oxidative phosphorylation genes were among the most influenced by hypoxia and mtDNA, and exposure to hypoxia increased the signature of mtDNA effects, suggesting retrograde signaling between mtDNA and nDNA. We identified nDNA-encoded genes in the electron transport chain (succinate dehydrogenase) that exhibit female-specific mtDNA effects. Our findings have important implications for personalized medicine, the sex-specific nature of mitonuclear communication, and gene × gene coevolution under variable or changing environments.

Mitochondrial-Nuclear Interactions Mediate Sex-Specific Transcriptional Profiles in Drosophila.

The assembly and function of mitochondria require coordinated expression from two distinct genomes, the mitochondrial DNA (mtDNA) and nuclear DNA (nDNA). Mutations in either genome can be a source of phenotypic variation, yet their coexpression has been largely overlooked as a source of variation, particularly in the emerging paradigm of mitochondrial replacement therapy. Here we tested how the transcriptome responds to mtDNA and nDNA variation, along with mitonuclear interactions (mtDNA × nDNA) in Drosophila melanogaster We used two mtDNA haplotypes that differ in a substantial number of single nucleotide polymorphisms, with >100 amino acid differences. We placed each haplotype on each of two D. melanogaster nuclear backgrounds and tested for transcription differences in both sexes. We found that large numbers of transcripts were differentially expressed between nuclear backgrounds, and that mtDNA type altered the expression of nDNA genes, suggesting a retrograde, trans effect of mitochondrial genotype. Females were generally more sensitive to genetic perturbation than males, and males demonstrated an asymmetrical effect of mtDNA in each nuclear background; mtDNA effects were nuclear-background specific. mtDNA-sensitive genes were not enriched in male- or female-limited expression space in either sex. Using a variety of differential expression analyses, we show the responses to mitonuclear covariation to be substantially different between the sexes, yet the mtDNA genes were consistently differentially expressed across nuclear backgrounds and sexes. Our results provide evidence that the main mtDNA effects can be consistent across nuclear backgrounds, but the interactions between mtDNA and nDNA can lead to sex-specific global transcript responses.

Myeloma Cell Dynamics in Response to Treatment Supports a Model of Hierarchical Differentiation and Clonal Evolution.

PURPOSE: Since the pioneering work of Salmon and Durie, quantitative measures of tumor burden in multiple myeloma have been used to make clinical predictions and model tumor growth. However, such quantitative analyses have not yet been performed on large datasets from trials using modern chemotherapy regimens. EXPERIMENTAL DESIGN: We analyzed a large set of tumor response data from three randomized controlled trials of bortezomib-based chemotherapy regimens (total sample size n = 1,469 patients) to establish and validate a novel mathematical model of multiple myeloma cell dynamics. RESULTS: Treatment dynamics in newly diagnosed patients were most consistent with a model postulating two tumor cell subpopulations, "progenitor cells" and "differentiated cells." Differential treatment responses were observed with significant tumoricidal effects on differentiated cells and less clear effects on progenitor cells. We validated this model using a second trial of newly diagnosed patients and a third trial of refractory patients. When applying our model to data of relapsed patients, we found that a hybrid model incorporating both a differentiation hierarchy and clonal evolution best explains the response patterns. CONCLUSIONS: The clinical data, together with mathematical modeling, suggest that bortezomib-based therapy exerts a selection pressure on myeloma cells that can shape the disease phenotype, thereby generating further inter-patient variability. This model may be a useful tool for improving our understanding of disease biology and the response to chemotherapy regimens. Clin Cancer Res; 22(16); 4206-14. ©2016 AACR.