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Mitochondria are key to energy conversion in virtually all eukaryotes. Intriguingly, despite billions of years of evolution inside the eukaryote, mitochondria have retained their own small set of genes involved in the regulation of oxidative phosphorylation (OXPHOS) and protein translation. Although there was a long-standing assumption that the genetic variation found within the mitochondria would be selectively neutral, research over the past 3 decades has challenged this assumption. This research has provided novel insight into the genetic and evolutionary forces that shape mitochondrial evolution and broader implications for evolutionary ecological processes. Many of the seminal studies in this field, from the inception of the research field to current studies, have been conducted using Drosophila flies, thus establishing the species as a model system for studies in mitochondrial evolutionary biology. In this review, we comprehensively review these studies, from those focusing on genetic processes shaping evolution within the mitochondrial genome, to those examining the evolutionary implications of interactions between genes spanning mitochondrial and nuclear genomes, and to those investigating the dynamics of mitochondrial heteroplasmy. We synthesize the contribution of these studies to shaping our understanding of the evolutionary and ecological implications of mitochondrial genetic variation., Competing Interests: Conflicts of interest The author(s) declare no conflict of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Genetics Society of America.)

Mitochondrial sequence variants affect phenotypic function, often through interaction with the nuclear genome. These "mitonuclear" interactions have been linked both to evolutionary processes and human health. The study of these interactions has focused on mechanisms regulating communication between mitochondrial and nuclear proteins; the role of mitochondrial (mt) RNAs has received little attention. Here, we show that small mt-RNAs bind to the nuclear protein Argonaute 2, and that nuclear miRNAs bind to mt-mRNAs. We identify one small mt-RNA that binds to Argonaute 2 in human tissues whose expression and sequence remain unchanged across vertebrates. Although analyses of CLEAR-CLIP sequencing data sets of human and mouse did not reveal consistent interactions between small mt-RNAs and nuclear mRNAs, we found that MT-ND4 and MT-ATP6 mRNAs are bound by different nuclear miRNAs in humans and mice. Our work homes in on previously unknown interactions between nuclear and small mt-RNAs, which may play key roles in intergenomic communication., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Many traits correlate with body size. Studies that seek to uncover the ecological factors that drive evolutionary responses in traits typically examine these responses relative to associated changes in body size using multiple regression analysis. However, it is not well appreciated that in the presence of strongly correlated variables, the partial (i.e., relative) regression coefficients often change sign compared to the original coefficients. Such sign reversals are difficult to interpret in a biologically meaningful way, and could lead to erroneous evolutionary inferences if the true mechanism underlying the sign reversal differed from the proposed mechanism. Here, we use simulations to demonstrate that sign reversal occurs over a wide range of parameter values common in the biological sciences. Further, as a case-in-point, we review the literature on brain size evolution; a field that explores how ecological traits relate to the evolution of relative brain size (brain size relative to body size). We find that most studies show sign reversals and thus that the inferences of many studies in this field may be inconclusive. Finally, we propose some approaches to mitigating this issue., (© 2019 The Authors. Evolution Letters published by Wiley Periodicals, Inc. on behalf of Society for the Study of Evolution (SSE) and European Society for Evolutionary Biology (ESEB).)

Eukaryotes are the outcome of an ancient symbiosis and as such, eukaryotic cells fundamentally possess two genomes. As a consequence, gene products encoded by both nuclear and mitochondrial genomes must interact in an intimate and precise fashion to enable aerobic respiration in eukaryotes. This genomic architecture of eukaryotes is proposed to necessitate perpetual coevolution between the nuclear and mitochondrial genomes to maintain coadaptation, but the presence of two genomes also creates the opportunity for intracellular conflict. In the collection of papers that constitute this symposium volume, scientists working in diverse organismal systems spanning vast biological scales address emerging topics in integrative, comparative biology in light of mitonuclear interactions., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email: journals.permissions@oup.com.)

Maternal inheritance of mitochondrial DNA (mtDNA) renders selection blind to mutations whose effects are limited to males. Evolutionary theory predicts this will lead to the accumulation of a male-specific genetic load within the mitochondrial genomes of populations; that is, a pool of mutations that negatively affects male, but not female, fitness components. This principle has been termed the Mother's Curse hypothesis. While the hypothesis has received some empirical support, its relevance to natural populations of metazoans remains unclear, and these ambiguities are compounded by the lack of a clear predictive framework for studies attempting to test Mother's Curse. Here, we seek to redress this by outlining the core predictions of the hypothesis, as well as the key features of the experimental designs that are required to enable direct testing of the predictions. Our goal is to provide a roadmap for future research seeking to elucidate the evolutionary significance of the Mother's Curse hypothesis., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email: journals.permissions@oup.com.)

Several studies have linked mitochondrial genetic variation to phenotypic modifications; albeit the identity of the mitochondrial polymorphisms involved remains elusive. The search for these polymorphisms led to the discovery of small noncoding RNAs, which appear to be transcribed by the mitochondrial DNA ("small mitochondrial RNAs"). This contention is, however, controversial because the nuclear genome of most animals harbors mitochondrial pseudogenes (NUMTs) of identical sequence to regions of mtDNA, which could alternatively represent the source of these RNAs. To discern the likely contributions of the mitochondrial and nuclear genome to transcribing these small mitochondrial RNAs, we leverage data from six vertebrate species exhibiting markedly different levels of NUMT sequence. We explore whether abundances of small mitochondrial RNAs are associated with levels of NUMT sequence across species, or differences in tissue-specific mtDNA content within species. Evidence for the former would support the hypothesis these RNAs are primarily transcribed by NUMT sequence, whereas evidence for the latter would provide strong evidence for the counter hypothesis that these RNAs are transcribed directly by the mtDNA. No association exists between the abundance of small mitochondrial RNAs and NUMT levels across species. Moreover, a sizable proportion of transcripts map exclusively to the mtDNA sequence, even in species with highest NUMT levels. Conversely, tissue-specific abundances of small mitochondrial RNAs are strongly associated with the mtDNA content. These results support the hypothesis that small mitochondrial RNAs are primarily transcribed by the mitochondrial genome and that this capacity is conserved across Amniota and, most likely, across most metazoan lineages., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

The signature of sexual selection has been revealed through the study of differences in patterns of genome-wide gene expression, both between the sexes and between alternative reproductive morphs within a single sex. What remains unclear, however, is whether differences in gene expression patterns between individuals of a given sex consistently map to variation in individual quality. Such a pattern, particularly if found in males, would provide unambiguous evidence that the phenotypic response to sexual selection is shaped through sex-specific alterations to the transcriptome. To redress this knowledge gap, we explored whether patterns of sex-biased gene expression are associated with variation in male reproductive quality in Drosophila melanogaster. We measured two male reproductive phenotypes, and their association with sex-biased gene expression, across a selection of inbred lines from the Drosophila Genetic Reference Panel. Genotypes with higher expression of male-biased genes produced males exhibiting shorter latencies to copulation, and higher capacity to inseminate females. Conversely, female-biased genes tended to show negative associations with these male reproductive traits across genotypes. We uncovered similar patterns, by reanalyzing a published dataset from a second D. melanogaster population. Our results reveal the footprint of sexual selection in masculinising the male transcriptome., (© 2018 The Author(s). Evolution © 2018 The Society for the Study of Evolution.)

Cellular metabolism is regulated by enzyme complexes within the mitochondrion, the function of which are sensitive to the prevailing temperature. Such thermal sensitivity, coupled with the observation that population frequencies of mitochondrial haplotypes tend to associate with latitude, altitude, or climatic regions across species distributions, led to the hypothesis that thermal selection has played a role in shaping standing variation in the mitochondrial DNA (mtDNA) sequence. This hypothesis, however, remains controversial, and requires evidence that the distribution of haplotypes observed in nature corresponds with the capacity of these haplotypes to confer differences in thermal tolerance. Specifically, haplotypes predominating in tropical climates are predicted to encode increased tolerance to heat stress, but decreased tolerance to cold stress. We present direct evidence for these predictions, using mtDNA haplotypes sampled from the Australian distribution of Drosophila melanogaster. We show that the ability of flies to tolerate extreme thermal challenges is affected by sequence variation across mtDNA haplotypes, and that the thermal performance associated with each haplotype corresponds with its latitudinal prevalence. The haplotype that predominates at low (subtropical) latitudes confers greater resilience to heat stress, but lower resilience to cold stress, than haplotypes predominating at higher (temperate) latitudes. We explore molecular mechanisms that might underlie these responses, presenting evidence that the effects are in part regulated by SNPs that do not change the protein sequence. Our findings suggest that standing variation in the mitochondrial genome can be shaped by thermal selection, and could therefore contribute to evolutionary adaptation under climatic stress., (© The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Under maternal inheritance, mitochondrial genomes are prone to accumulate mutations that exhibit male-biased effects. Such mutations should, however, place selection on the nuclear genome for modifier adaptations that mitigate mitochondrial-incurred male harm. One gene region that might harbor such modifiers is the Y-chromosome, given the abundance of Y-linked variation for male fertility, and because Y-linked modifiers would not exert antagonistic effects in females because they would be found only in males. Recent studies in Drosophila revealed a set of nuclear genes whose expression is sensitive to allelic variation among mtDNA- and Y-haplotypes, suggesting these genes might be entwined in evolutionary conflict between mtDNA and Y. Here, we test whether genetic variation across mtDNA and Y haplotypes, sourced from three disjunct populations, interacts to affect male mating patterns and fertility across 10 days of early life in D. melanogaster. We also investigate whether coevolved mito-Y combinations outperform their evolutionarily novel counterparts, as predicted if the interacting Y-linked variance is comprised of modifier adaptations. Although we found no evidence that coevolved mito-Y combinations outperformed their novel counterparts, interactions between mtDNA and Y-chromosomes affected male mating patterns. These interactions were dependent on male age; thus male reproductive success was shaped by G × G × E interactions., (© 2015 The Author(s). Evolution © 2015 The Society for the Study of Evolution.)

The extent to which mitochondrial DNA (mtDNA) variation is involved in adaptive evolutionary change is currently being reevaluated. In particular, emerging evidence suggests that mtDNA genes coevolve with the nuclear genes with which they interact to form the energy producing enzyme complexes in the mitochondria. This suggests that intergenomic epistasis between mitochondrial and nuclear genes may affect whole-organism metabolic phenotypes. Here, we use crossed combinations of mitochondrial and nuclear lineages of the seed beetle Callosobruchus maculatus and assay metabolic rate under two different temperature regimes. Metabolic rate was affected by an interaction between the mitochondrial and nuclear lineages and the temperature regime. Sequence data suggests that mitochondrial genetic variation has a role in determining the outcome of this interaction. Our genetic dissection of metabolic rate reveals a high level of complexity, encompassing genetic interactions over two genomes, and genotype × genotype × environment interactions. The evolutionary implications of these results are twofold. First, because metabolic rate is at the root of life histories, our results provide insights into the complexity of life-history evolution in general, and thermal adaptation in particular. Second, our results suggest a mechanism that could contribute to the maintenance of nonneutral mtDNA polymorphism., (© 2010 The Author(s). Evolution© 2010 The Society for the Study of Evolution.)

Explanations for the evolution of polyandry often center on the idea that females garner genetic benefits for their offspring by mating multiply. Furthermore, postcopulatory processes are thought to be fundamental to enabling polyandrous females to screen for genetic quality. Much attention has focused on the potential for polyandrous females to accrue such benefits via a sexy- or good-sperm mechanism, whereby additive variation exists among males in sperm competitiveness. Likewise, attention has focused on an alternative model, in which offspring quality (in this context, the sperm competitiveness of sons) hinges on an interaction between parental haplotypes (genetic compatibility). Sperm competitiveness that is contingent on parental compatibility will exhibit nonadditive genetic variation. We tested these models in the Australian cricket, Teleogryllus oceanicus, using a design that allowed us to partition additive, nonadditive genetic, and parental variance for sperm competitiveness. We found an absence of additive and nonadditive genetic variance in this species, challenging the direct relevance of either model to the evolution of sperm competitiveness in particular, and polyandry in general. Instead, we found maternal effects that were possibly sex-linked or cytoplasmically linked. We also found effects of focal male age on sperm competitiveness, with small increments in age conferring more competitive sperm.

The symbiotic relationship between the mitochondrial and nuclear genomes coordinates metabolic energy production and is fundamental to life among eukaryotes. Consequently, there is potential for strong selection to shape interactions between these two genomes. Substantial research attention has focused on the possibility that within-population sequence polymorphism in mitochondrial DNA (mtDNA) is maintained by mitonuclear fitness interactions. Early theory predicted that selection will often eliminate mitochondrial polymorphisms. However, recent models demonstrate that intergenomic interactions can promote the maintenance of polymorphism, especially if the nuclear genes involved are linked to the X chromosome. Most empirical studies to date that have assessed cytonuclear fitness interactions have studied variation across populations and it is still unclear how general and strong such interactions are within populations. We experimentally tested for cytonuclear interactions within a laboratory population of Drosophila melanogaster using 25 randomly sampled cytoplasmic genomes, expressed in three different haploid nuclear genetic backgrounds, while eliminating confounding effects of intracellular bacteria (e.g., Wolbachia). We found sizable cytonuclear fitness interactions within this population and present limited evidence suggesting that these effects were sex specific. Moreover, the relative fitness of cytonuclear genotypes was environment specific. Sequencing of mtDNA (2752 bp) revealed polymorphism within the population, suggesting that the observed cytoplasmic genetic effects may be mitochondrial in origin.

The integration of the mitochondrial and nuclear genomes coordinates cellular energy production and is fundamental to life among eukaryotes. Therefore, there is potential for strong selection to shape the interactions between the two genomes. Several studies have now demonstrated that epistatic interactions between cytoplasmic and nuclear genes for fitness can occur both at a "within" and "across" population level. Genotype-by-environment interactions are common for traits that are encoded by nuclear genes, but the effects of environmental heterogeneity on traits that are partly encoded by cytoplasmic genes have received little attention despite the fact that there are reasons to believe that phenotypic effects of cytoplasmic genetic variation may often be environment specific. Consequently, the importance of environmental heterogeneity to the outcomes of cyto-nuclear fitness interactions and to the maintenance of mitochondrial polymorphism is unclear. Here, we assess the influence of temperature on cyto-nuclear effects on egg-to-adult development time in seed beetles (Callosobruchus maculatus). We employed an "across-population" design, sourcing beetles from five distinct populations and using backcrossing to create orthogonal combinations of distinct introgression lines, fixed for their cytoplasmic and nuclear lineages. We then assayed development times at two different temperatures and found sizeable cyto-nuclear effects in general, as well as temperature- and block-specific cyto-nuclear effects. These results demonstrate that environmental factors such as temperature do exert selection on cytoplasmic genes by favoring specific cyto-nuclear genetic combinations, and are consistent with the suggestion that complex genotype-by-environment interactions may promote the maintenance of polymorphism in mitochondrial genes.

It has been suggested that mitochondrial DNA (mtDNA) may play an important role in aging. Yet, few empirical studies have tested this hypothesis, partly because the degree of sequence polymorphism in mtDNA is assumed to be low. However, low sequence variation may not necessarily translate into low phenotypic variation. Here, we report an experiment that tests whether there is within-population variation in cytoplasmic genes for female longevity and senescence. To achieve this, we randomly selected 25 "mitochondrial founders" from a single, panmictic population of Drosophila melanogaster and used these founders to generate distinct "mt" lines in which we controlled for the nuclear background by successive backcrossing. Potential confounding effects of cytoplasmically transmitted bacteria were eliminated by tetracycline treatment. The mt lines were then assayed for differences in longevity, Gompertz intercept (frailty), and demographic rate of change in mortality with age (rate-of-senescence) in females. We found significant cytoplasmic effects on all three variables. This provides evidence that genetic variation in cytoplasmic genes, presumably mtDNA, contributes to variation in female mortality and aging.