M. Florencia Camus

Mitochondria, Maternal Inheritance, and Male Aging

The maternal transmission of mitochondrial genomes invokes a sex-specific selective sieve, whereby mutations in mitochondrial DNA can only respond to selection acting directly on females. In theory, this enables male-harming mutations to accumulate in mitochondrial genomes when these same mutations are neutral, beneficial, or only slightly deleterious in their effects on females. Ultimately, this evolutionary process could result in the evolution of male-specific mitochondrial mutation loads; an idea previously termed Mothers Curse. Here, we present evidence that the effects of this process are broader than hitherto realized, and that it has resulted in mutation loads affecting patterns of aging in male, but not female Drosophila melanogaster. Furthermore, our results indicate that the mitochondrial mutation loads affecting male aging generally comprise numerous mutations over multiple sites. Our findings thus suggest that males are subject to dramatic consequences that result from the maternal transmission of mitochondrial genomes. They implicate the diminutive mitochondrial genome as a hotspot for mutations that affect sex-specific patterns of aging, thus promoting the idea that a sex-specific selective sieve in mitochondrial genome evolution is a contributing factor to sexual dimorphism in aging, commonly observed across species.

Complete mitochondrial genome sequences of thirteen globally sourced strains of fruit fly (Drosophila melanogaster) form a powerful model for mitochondrial research

Abstract The complete mitogenomes of 13 strains of the fruit fly Drosophila melanogaster were sequenced. Haplotypes varied between 19 532 and 19 537 bp in length, and followed standard dipteran mitogenome content and organization. We detected a total of 354 variable sites between all thirteen haplotypes, while single pairs of haplotypes were separated by an average of 123 variable sites. The sequenced fly strains form a powerful model for mitochondrial research, when it comes to elucidating the links between the mitochondrial genotype and the phenotype.

Experimental Support That Natural Selection Has Shaped the Latitudinal Distribution of Mitochondrial Haplotypes in Australian Drosophila melanogaster

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.

Coadaptation of mitochondrial and nuclear genes, and the cost of mother's curse

Strict maternal inheritance renders the mitochondrial genome susceptible to accumulating mutations that harm males, but are otherwise benign or beneficial for females. This ‘mothers curse’ effect can degrade male survival and fertility if unopposed by counteracting evolutionary processes. Coadaptation between nuclear and mitochondrial genomes—with nuclear genes evolving to compensate for male-harming mitochondrial substitutions—may ultimately resolve mothers curse. However, males are still expected to incur a transient fitness cost during mito-nuclear coevolution, and it remains unclear how severe such costs should be. We present a population genetic analysis of mito-nuclear coadaptation to resolve mothers curse effects, and show that the magnitude of the ‘male mitochondrial load’—the negative impact of mitochondrial substitutions on male fitness components—may be large, even when genetic variation for compensatory evolution is abundant. We also find that the male load is surprisingly sensitive to population size: male fitness costs of mito-nuclear coevolution are particularly pronounced in both small and large populations, and minimized in populations of intermediate size. Our results reveal complex interactions between demography and genetic constraints during the resolution of mothers curse, suggesting potentially widespread species differences in susceptibility to mothers curse effects.

Sex and genotype effects on nutrient-dependent fitness landscapes in Drosophila melanogaster

The sexes perform different reproductive roles and have evolved sometimes strikingly different phenotypes. One focal point of adaptive divergence occurs in the context of diet and metabolism, and males and females of a range of species have been shown to require different nutrients to maximize their fitness. Biochemical analyses in Drosophila melanogaster have confirmed that dimorphism in dietary requirements is associated with molecular sex differences in metabolite titres. In addition, they also showed significant within-sex genetic variation in the metabolome. To date however, it is unknown whether this metabolic variation translates into differences in reproductive fitness. The answer to this question is crucial to establish whether genetic variation is selectively neutral or indicative of constraints on sex-specific physiological adaptation and optimization. Here we assay genetic variation in consumption and metabolic fitness effects by screening male and female fitness of thirty D. melanogaster genotypes across four protein-to-carbohydrate ratios. In addition to confirming sexual dimorphism in consumption and fitness, we find significant genetic variation in male and female dietary requirements. Importantly, these differences are not explained by feeding responses and probably reflect metabolic variation that, in turn, suggests the presence of genetic constraints on metabolic dimorphism.

Evolving Plastic Responses to External and Genetic Environments

Phenotypic plasticity can mitigate adaptive trade-offs in fluctuating environments but how plasticity arises is little known. New research documents this process in a bacterial system. We highlight remarkable parallels to the evolution of sexual dimorphism and argue that their approach can aid our understanding of adaptive conflicts between the sexes.

Mitochondrial genetic effects on reproductive success: signatures of positive intrasexual, but negative intersexual pleiotropy

Theory predicts that maternal inheritance of mitochondria will facilitate the accumulation of mtDNA mutations that are male biased, or even sexually antagonistic, in effect. While there are many reported cases of mtDNA mutations conferring cytoplasmic male sterility in plants, historically it was assumed such mutations would not persist in the streamlined mitochondrial genomes of bilaterian metazoans. Intriguingly, recent cases of mitochondrial variants exerting male biases in effect have come to light in bilaterians. These cases aside, it remains unknown whether the mitochondrial genetic variation affecting phenotypic expression, and in particular reproductive performance, in bilaterians is routinely composed of sex-biased or sex-specific variation. If selection consistently favours mtDNA variants that augment female fitness, but at cost to males, this could shape patterns of pleiotropy and lead to negative intersexual correlations across mtDNA haplotypes. Here, we show that genetic variation across naturally occurring mitochondrial haplotypes affects components of reproductive success in both sexes, in the fruit fly Drosophila melanogaster. We find that intrasexual correlations across mitochondrial haplotypes, for components of reproductive success, are generally positive, while intersexual correlations are negative. These results accord with theoretical predictions, suggesting that maternal inheritance has led to the fixation of numerous mutations of sexually antagonistic effect.

Mitonuclear epistasis and mitochondrial disease

Wang et al. (2015) report the joint effect of genetic variants in both the nuclear and mitochondrial DNA (mtDNA) on the occurrence of Kallmann syndrome in a large Han Chinese family. The nuclear variant (KAL1 c.146G > T, p.Cys49Phe) is not expected to cause changes to protein structure or function. Although the pathogenicity of the mitochondrial variant (tRNA, m.5800A > G) has been predicted (Bannwarth et al., 2013), there is no empirical evidence to support that prediction and it was not found to depress cellular oxidative phosphorylation (Wang et al., 2015). Their interpretation is that the two point mutations act synergistically, causing abnormal migration of gonadotropin-releasing hormone neurons, which is thought to be the underlying mechanism for this developmental disorder. Since mutations in both genomes are required for manifestation of the phenotype, their results challenge how mitochondrial disease may be defined. We suggest that this two-locus/genome model of mitochondrial disease phenotypes may apply more broadly than is currently appreciated. Although the action of genetic background or modifiers have been implicated in altering the penetrance of primary pathological mutations underlying mitochondrial disease, reviews of this evidence have focused on specific disease sub-types (Bénit et al., 2010). Here, a review of the published evidence from the medical literature suggest that mitonuclear epistatic interactions are widespread and make a significant contribution to the variability in disease penetrance, which is a widely reported feature of mitochondrial pathologies (Limongelli et al., 2004). We have identified 15 loci in mtDNA where the pathogenic effect (spanning a number of different mitochondrial diseases) is dependent upon the nuclear background, specific nuclear polymorphic sites, or expression levels of nuclear genes (Table 1). In most cases, the defect in the mtDNA can be modified by multiple different nuclear loci, although some ‘master modifiers’ appear capable of influencing multiple mtDNA mutations (e.g. VARS2, LARS2). A further 11 nuclear loci have been identified where mitochondrial haplotype (or variants) have modified the pathogenic phenotype, which includes type II diabetes, Parkinsons and Alzheimers disease as well as classical mitochondrial diseases. Only 6 of these loci co-localize to mitochondria. In one example, the deleterious effect of the m.5703G > A mutation in human cell lines disappeared after a period of time in culture (Hao et al., 1999). However, replacement of the nuclear background (using cybrids) reintroduced the deleterious phenotype. These data support a compensatory model of evolution within the nuclear genome in response to the presence of deleterious mutations within the mitochondrial genome. Together these studies highlight the potential role of mitonuclear epistasis in the expression and penetrance of human mitochondrial disease. We declare no competing interests. Funding has been provided to EHM by a Royal Society University Research Fellowship and the European Research Council (#280632). MFC was supported by the European Research Council under the Marie Skłodowska-Curie Actions (#708362).

Experimental evidence that thermal selection shapes mitochondrial genome evolution

Mitochondria are essential organelles, found within eukaryotic cells, which contain their own DNA. Mitochondrial DNA (mtDNA) has traditionally been used in population genetic and biogeographic studies as a maternally-inherited and evolutionary-neutral genetic marker. However, it is now clear that polymorphisms within the mtDNA sequence are routinely non-neutral, and furthermore several studies have suggested that such mtDNA polymorphisms are also sensitive to thermal selection. These observations led to the formulation of the “mitochondrial climatic adaptation” hypothesis, for which all published evidence to date is correlational. Here, we use laboratory-based experimental evolution in the fruit fly, Drosophila melanogaster, to test whether thermal selection can shift population frequencies of two mtDNA haplogroups whose natural frequencies exhibit clinal associations with latitude along the Australian east-coast. We present experimental evidence that the thermal regime in which the laboratory populations were maintained drove changes in haplogroup frequencies across generations. Our results strengthen the emerging view that intra-specific mtDNA variants are sensitive to selection, and suggest spatial distributions of mtDNA variants in natural populations of metazoans might reflect adaptation to climatic environments rather than within-population coalescence and diffusion of selectively-neutral haplotypes across populations.

Experimental evidence that thermal selection has shaped the latitudinal distribution of mitochondrial haplotypes in Australian fruit flies

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 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, than temperate counterparts. 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 counterparts 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 indicate that standing genetic variation in the mitochondrial genome can be shaped by thermal selection, and could therefore contribute to evolutionary adaptation under climatic stress.