From evolutionary bystander to master manipulator: the emerging roles for the mitochondrial genome as a modulator of nuclear gene expression

Horan, Martin; Gemmell, Neil J.; Wolff, Jonci N.

doi:10.1038/ejhg.2013.75

Cited by 27 publications

(20 citation statements)

References 34 publications

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“…In other species, mito-nuclear interactions have pleiotropic effects [11, 22] and affect genome wide mRNA expression patterns [94, 95]. Thus, although lacking data to specifically address the evolutionary genetics that maintain selectively different mito-nuclear interactions, we suggest that temporal environmental variation affects mito-nuclear polymorphisms that have pleiotropic effects.…”

Section: Resultsmentioning

confidence: 90%

Evolved genetic and phenotypic differences due to mitochondrial-nuclear interactions

et al. 2017

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The oxidative phosphorylation (OxPhos) pathway is responsible for most aerobic ATP production and is the only pathway with both nuclear and mitochondrial encoded proteins. The importance of the interactions between these two genomes has recently received more attention because of their potential evolutionary effects and how they may affect human health and disease. In many different organisms, healthy nuclear and mitochondrial genome hybrids between species or among distant populations within a species affect fitness and OxPhos functions. However, what is less understood is whether these interactions impact individuals within a single natural population. The significance of this impact depends on the strength of selection for mito-nuclear interactions. We examined whether mito-nuclear interactions alter allele frequencies for ~11,000 nuclear SNPs within a single, natural Fundulus heteroclitus population containing two divergent mitochondrial haplotypes (mt-haplotypes). Between the two mt-haplotypes, there are significant nuclear allele frequency differences for 349 SNPs with a p-value of 1% (236 with 10% FDR). Unlike the rest of the genome, these 349 outlier SNPs form two groups associated with each mt-haplotype, with a minority of individuals having mixed ancestry. We use this mixed ancestry in combination with mt-haplotype as a polygenic factor to explain a significant fraction of the individual OxPhos variation. These data suggest that mito-nuclear interactions affect cardiac OxPhos function. The 349 outlier SNPs occur in genes involved in regulating metabolic processes but are not directly associated with the 79 nuclear OxPhos proteins. Therefore, we postulate that the evolution of mito-nuclear interactions affects OxPhos function by acting upstream of OxPhos.

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Section: Resultsmentioning

confidence: 90%

Evolved genetic and phenotypic differences due to mitochondrial-nuclear interactions

et al. 2017

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“…The two genomes are well suited for studying the evolution of epistasis because proteins encoded by mitochondrial genes require direct interactions with nuclear gene products to form the oxidative phosphorylation (OXPHOS) pathway, the major generator of ATP in the cell. Moreover, it has been shown that regulatory elements in the mitochondrial genome can affect the nuclear gene expression beyond their role in the OXPHOS metabolic pathway (Horan et al 2013). Hence, considering the fundamental role that mitochondrion plays in metabolism, and consequently in all upstream life history traits through its coordinated expression with nuclear genes, it is conceivable that any disruption of the coevolved mitonuclear gene combinations should invoke deleterious fitness consequences.…”

Section: Introductionmentioning

confidence: 99%

Intergenomic Interactions in Hybrids Between Short-Lived and Long-Lived Lines of a Seed Beetle: Analyses of Life History Traits

et al. 2015

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Products and regulatory motifs of the mitochondrial and nuclear genomes interact closely to enable efficient cellular energy production within mitochondria. Although recent evidences support the prediction that during evolutionary time combinations of these interactions are optimized by selection acting on important life history traits, relatively few studies have directly tested it. The goal of this study was to test the role of mitonuclear interactions in shaping preadult and adult life history traits under age-specific selection in the seed beetle (Acanthoscelides obtectus). In order to disentangle the effects of mitochondria, nuclei and their interaction in the evolutionary response to the long-term laboratory selection for early (E) and late (L) reproduction, we used mitonuclear introgression lines in which E and L mitochondrial genomes were expressed in both E and L nuclear background. We found that mitonuclear genotypes carrying disrupted pair of nuclear and mitochondrial genomes mainly affected preadult life history traits-egg-to-adult viability and developmental time. Neither mitochondria nor their interaction with nuclear genomes had effects on realized fecundity of mated females and longevity of virgin beetles. However, when involved in reproductive activities females and males with disrupted genotypes mostly exhibited reduced longevity. Furthermore, since reproduced males exhibited greater longevity cost than females, our results are in accordance with the mother's curse hypothesis. Being that for the most life history traits we detected smaller additive mitochondrial genetic effects compared with epistatic mitonuclear effects, we concluded that mitonuclear interactions might be the target of age-specific selection.

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“…Similarly, de-novo mutations in mtDNA genes (heteroplasmy) may become pathogenic in individuals with predisposing mutations in NEMP genes. Alternatively, with the emerging roles for the mitochondrial genome in nuclear gene expression [35,36], polymorphisms affecting the interplay between nuclear and mitochondrial genes may increase the risk for HIV progression through attenuation or exhaustion of protective cellular mechanisms co-regulated by the two genomes such as apoptosis. Whereas neither refinement of the phenotypes nor consideration of alternative clinical end points is an option in the REACH study, the observed association of set-point VL with mtDNA haplogroups sharing common root with those implicated in AIDS progression in Caucasians may reflect sharing of specific nuclear genetic factors underlying unmeasured subphenotypes.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA variation and virologic and immunological HIV outcomes in African Americans

Aissani¹,

Shrestha²,

Wiener³

et al. 2014

Aids

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Objective To evaluate the impact of mitochondrial DNA (mtDNA) haplogroups on virologic and immunological outcomes of HIV infection. Design HAART-naive African American adolescent participants to the Reaching for Excellence in Adolescent Care and Health study. Methods The mtDNA haplogroups were inferred from sequenced mtDNA hypervariable regions HV1 and HV2 and their predictive value on HIV outcomes were evaluated in linear mixed models, controlled for human leukocyte antigen (HLA)-B27, HLA-B57 and HLA-B35-Px alleles and other covariates. Results We report data showing that the mtDNA L2 lineage, a group composed of L2a, L2b and L2e mtDNA haplogroups in the studied population, is significantly associated (beta=−0.08; Bonferroni-adjusted P=0.004) with decline of CD4+ T cells (median loss of 8 ± 1 cells per month) in HAART-naive HIV-infected individuals of African American descent (n=133). No significant association (P<0.05) with set-point viral load was observed with any of the tested mtDNA haplogroups. The present data concur with previous findings in the AIDS Clinical Trials Group study 384, implicating the L2 lineage with slower CD4+ T-cell recovery after antiretroviral therapy in African Americans. Conclusions Whereas the L2 lineage showed an association with unfavorable immunological outcomes of HIV infection, its phylogenetic divergence from J and U5a, two lineages associated with accelerated HIV progression in European Americans, raises the possibility that interactions with common nucleus-encoded variants drive HIV progression. Disentangling the effects of mitochondrial and nuclear gene variants on the outcomes of HIV infection is an important step to be taken toward a better understanding of HIV/AIDS pathogenesis and pharmacogenomics.

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From evolutionary bystander to master manipulator: the emerging roles for the mitochondrial genome as a modulator of nuclear gene expression

Cited by 27 publications

References 34 publications

Evolved genetic and phenotypic differences due to mitochondrial-nuclear interactions

Evolved genetic and phenotypic differences due to mitochondrial-nuclear interactions

Intergenomic Interactions in Hybrids Between Short-Lived and Long-Lived Lines of a Seed Beetle: Analyses of Life History Traits

Mitochondrial DNA variation and virologic and immunological HIV outcomes in African Americans

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