Mitochondrial-nuclear epistasis affects fitness within species but does not contribute to fixed incompatibilities between species of \u3ci\u3eDrosophila\u3c/i\u3e

Efficient mitochondrial function requires physical interactions between the proteins encoded by the mitochondrial and nuclear genomes. Co-evolution between these genomes may result in the accumulation of incompatibilities between divergent lineages. We test whether mitochondrialnuclear incompatibilities have accumulated within the Drosophila melanogaster species subgroup by combining divergent mitochondrial and nuclear lineages and quantifying the effects on relative fitness. Precise placement of nine mtDNAs from D. melanogaster, D. simulans and D. mauritiana into two D. melanogaster nuclear genetic backgrounds reveals significant mitochondrial-nuclear epistasis affecting fitness in females. Combining the mitochondrial genomes with three different D. melanogaster X chromosomes reveals significant epistasis for male fitness between X-linked and mitochondrial variation. However, we find no evidence that the more than 500 fixed differences between the mitochondrial genomes of D. melanogaster and the D. simulans species complex are incompatible with the D. melanogaster nuclear genome. Rather, the interactions of largest effect occur between mitochondrial and nuclear polymorphisms that segregate within species of the D. melanogaster species subgroup. We propose that a low mitochondrial substitution rate, resulting from a low mutation rate and/or efficient purifying selection, precludes the accumulation of mitochondrial-nuclear incompatibilities among these Drosophila species

An Incompatibility between a Mitochondrial tRNA and Its Nuclear-Encoded tRNA Synthetase Compromises Development and Fitness in \u3ci\u3eDrosophila\u3c/i\u3e

Mitochondrial transcription, translation, and respiration require interactions between genes encoded in two distinct genomes, generating the potential for mutations in nuclear and mitochondrial genomes to interact epistatically and cause incompatibilities that decrease fitness. Mitochondrial-nuclear epistasis for fitness has been documented within and between populations and species of diverse taxa, but rarely has the genetic or mechanistic basis of these mitochondrial–nuclear interactions been elucidated, limiting our understanding of which genes harbor variants causing mitochondrial–nuclear disruption and of the pathways and processes that are impacted by mitochondrial–nuclear coevolution. Here we identify an amino acid polymorphism in the Drosophila melanogaster nuclear-encoded mitochondrial tyrosyl–tRNA synthetase that interacts epistatically with a polymorphism in the D. simulans mitochondrial-encoded tRNATyr to significantly delay development, compromise bristle formation, and decrease fecundity. The incompatible genotype specifically decreases the activities of oxidative phosphorylation complexes I, III, and IV that contain mitochondrial-encoded subunits. Combined with the identity of the interacting alleles, this pattern indicates that mitochondrial protein translation is affected by this interaction. Our findings suggest that interactions between mitochondrial tRNAs and their nuclear-encoded tRNA synthetases may be targets of compensatory molecular evolution. Human mitochondrial diseases are often genetically complex and variable in penetrance, and the mitochondrial–nuclear interaction we document provides a plausible mechanism to explain this complexity

An Incompatibility between a Mitochondrial tRNA and Its Nuclear-Encoded tRNA Synthetase Compromises Development and Fitness in \u3ci\u3eDrosophila\u3c/i\u3e

Mitochondrial transcription, translation, and respiration require interactions between genes encoded in two distinct genomes, generating the potential for mutations in nuclear and mitochondrial genomes to interact epistatically and cause incompatibilities that decrease fitness. Mitochondrial-nuclear epistasis for fitness has been documented within and between populations and species of diverse taxa, but rarely has the genetic or mechanistic basis of these mitochondrial–nuclear interactions been elucidated, limiting our understanding of which genes harbor variants causing mitochondrial–nuclear disruption and of the pathways and processes that are impacted by mitochondrial–nuclear coevolution. Here we identify an amino acid polymorphism in the Drosophila melanogaster nuclear-encoded mitochondrial tyrosyl–tRNA synthetase that interacts epistatically with a polymorphism in the D. simulans mitochondrial-encoded tRNATyr to significantly delay development, compromise bristle formation, and decrease fecundity. The incompatible genotype specifically decreases the activities of oxidative phosphorylation complexes I, III, and IV that contain mitochondrial-encoded subunits. Combined with the identity of the interacting alleles, this pattern indicates that mitochondrial protein translation is affected by this interaction. Our findings suggest that interactions between mitochondrial tRNAs and their nuclear-encoded tRNA synthetases may be targets of compensatory molecular evolution. Human mitochondrial diseases are often genetically complex and variable in penetrance, and the mitochondrial–nuclear interaction we document provides a plausible mechanism to explain this complexity

mitofitnessFinalCDM

Excel file with fitness scores from mitonuclear genotype

Data from: Mitochondrial–nuclear epistasis affects fitness within species but does not contribute to fixed incompatibilities between species of Drosophila

Efficient mitochondrial function requires physical interactions between the proteins encoded by the mitochondrial and nuclear genomes. Coevolution between these genomes may result in the accumulation of incompatibilities between divergent lineages. We test whether mitochondrial–nuclear incompatibilities have accumulated within the Drosophila melanogaster species subgroup by combining divergent mitochondrial and nuclear lineages and quantifying the effects on relative fitness. Precise placement of nine mtDNAs from D. melanogaster, D. simulans, and D. mauritiana into two D. melanogaster nuclear genetic backgrounds reveals significant mitochondrial–nuclear epistasis affecting fitness in females. Combining the mitochondrial genomes with three different D. melanogaster X chromosomes reveals significant epistasis for male fitness between X-linked and mitochondrial variation. However, we find no evidence that the more than 500 fixed differences between the mitochondrial genomes of D. melanogaster and the D. simulans species complex are incompatible with the D. melanogaster nuclear genome. Rather, the interactions of largest effect occur between mitochondrial and nuclear polymorphisms that segregate within species of the D. melanogaster species subgroup. We propose that a low mitochondrial substitution rate, resulting from a low mutation rate and/or efficient purifying selection, precludes the accumulation of mitochondrial–nuclear incompatibilities among these Drosophila species

An Incompatibility between a Mitochondrial tRNA and Its Nuclear-Encoded tRNA Synthetase Compromises Development and Fitness in Drosophila

Mitochondrial transcription, translation, and respiration require interactions between genes encoded in two distinct genomes, generating the potential for mutations in nuclear and mitochondrial genomes to interact epistatically and cause incompatibilities that decrease fitness. Mitochondrial-nuclear epistasis for fitness has been documented within and between populations and species of diverse taxa, but rarely has the genetic or mechanistic basis of these mitochondrial–nuclear interactions been elucidated, limiting our understanding of which genes harbor variants causing mitochondrial–nuclear disruption and of the pathways and processes that are impacted by mitochondrial–nuclear coevolution. Here we identify an amino acid polymorphism in the Drosophila melanogaster nuclear-encoded mitochondrial tyrosyl–tRNA synthetase that interacts epistatically with a polymorphism in the D. simulans mitochondrial-encoded tRNA Tyr to significantly delay development, compromise bristle formation, and decrease fecundity. The incompatible genotype specifically decreases the activities of oxidative phosphorylation complexes I, III, and IV that contain mitochondrial-encoded subunits. Combined with the identity of the interacting alleles, this pattern indicates that mitochondrial protein translation is affected by this interaction. Our findings suggest that interactions between mitochondrial tRNAs and their nuclear-encoded tRNA synthetases may be targets of compensatory molecular evolution. Human mitochondrial diseases are often geneticall

Divergent sites between the <i>D. simulans sm21</i> and <i>simw⁵⁰¹</i> mtDNAs.

1<p>Position using the <i>D. simulans</i> mitochondrial genome sequence AF200839.1 as a reference.</p>2<p>The sequence state in mtDNAs of the <i>D. melanogaster</i> species subgroup <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003238#pgen.1003238-Ballard1" target="_blank">[34]</a>. <i>D. mel</i> is <i>D. melanogaster</i> (NC_001709), <i>D. sec</i> is <i>D. sechellia</i> (NC_005780), and <i>D. mau</i> is the <i>D. mauritiana maII</i> haplotype (AF200830).</p

Effects of a mitochondrial–nuclear interaction on development.

<p>(A) Mitochondrial-nuclear interactions between the <i>D. simulans simw⁵⁰¹</i> mtDNA and the <i>D. melanogaster OreR</i> nuclear genome significantly extend egg-to-adult development time in both sexes (mtDNA×nuclear interaction: <i>P_ANOVA</i>≤0.0001, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003238#pgen.1003238.s004" target="_blank">Table S1</a>). The <i>D. simulans sm21</i> mtDNA is closely related to <i>simw⁵⁰¹</i>, but has no effect on development time relative to the <i>D. melanogaster ore</i> mtDNA. (B and C) Both larval development and metamorphosis are delayed in <i>(simw⁵⁰¹);OreR</i>. Crosses between mitochondrial-nuclear genotypes indicated that the <i>OreR</i> nuclear effect on development is similar in males and females, autosomal and largely recessive (<i>h</i> = 0.18, 0.19 and 0.23, for pupation time, and male and female eclosion times, respectively, where <i>h</i> = 0 is complete dominance of <i>AutW132</i> and <i>h</i> = 0.5 is additivity). Listed below the graphs are the (<i>mtDNA</i>);<i>sex chromosome</i>;<i>autosome</i> genotypes (<i>O</i> = <i>OreR</i>, <i>A</i> = <i>AutW132</i>). <i>O/A</i> and <i>A/O</i> heterozygotes indicate the offspring of reciprocal crosses and differ in the parent-of-origin of the autosomes (<i>maternal</i>/<i>paternal</i>). The difference in time from egg to pupation between (<i>simw⁵⁰¹</i>);<i>AutW132</i> and (<i>simw⁵⁰¹</i>);<i>OreR</i> is approximately 65 hours. The difference in time from egg to adult emergence between (<i>simw⁵⁰¹</i>);<i>AutW132</i> and (<i>simw⁵⁰¹</i>);<i>OreR</i> is 80 and 82 hours in males and females, respectively. The 65 hour delay in larval development and the additional 15–17 hour delay during metamorphosis between (<i>simw⁵⁰¹</i>);<i>AutW132</i> and (<i>simw⁵⁰¹</i>);<i>OreR</i> are both statistically significant (<i>P</i>_t-test<0.001).</p

Genetic mapping implicates an interaction between the mt-tRNA^Tyr and its nuclear-encoded mt-TyrRS.

<p>(A) Chromosome segregation mapping using dominant, visible markers on the second and third chromosomes (<i>Cy</i> and <i>Sb</i>, respectively) revealed that the developmental delay is caused by a largely recessive factor on the <i>OreR</i> second chromosome. Only flies homozygous for the <i>OreR</i> second chromosome (squares) have extended development time. (B) Meiotic mapping using visible markers on the second chromosome indicates that flies with the <i>simw⁵⁰¹</i> mtDNA that are homozygous for the <i>OreR</i> second chromosome (red) at the marker <i>speck</i> (<i>sp</i>) take significantly longer to develop than flies with the <i>simw⁵⁰¹</i> mtDNA that are heterozygous for <i>OreR</i> and the mapping chromosome allele at this marker (gray), resulting in a significant marker-trait association (LOD score). (C) Two overlapping chromosomal deficiencies (<i>BSC606</i> and <i>BSC856</i>) at the tip of Chromosome arm 2R fail to complement the <i>OreR</i> nuclear factor and significantly extend development time when combined with the <i>simw⁵⁰¹</i> mtDNA (<i>P_ANOVA</i><0.0001, both deficiencies). Two neighboring deficiencies (<i>BSC780</i> and <i>ED4061</i>) complement the nuclear factor and restore development time to that of controls. Gray bars represent mean development time of (<i>simw⁵⁰¹</i>);<i>OreR</i> individuals inheriting the deficiency chromosome and white bars are control siblings inheriting a compatible balancer chromosome. The effects of these deficiencies are independent of sex, require the <i>simw⁵⁰¹</i> mtDNA (<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003238#pgen.1003238.s002" target="_blank">Figure S2</a>), and implicate <i>Aatm</i>, the only gene contained in both <i>BSC606</i> and <i>BSC856</i> with annotated mitochondrial function.</p

Effects of a mitochondrial–nuclear interaction on adult fecundity and sensory structures.

<p>(A) The <i>simw⁵⁰¹</i> mtDNA decreases the total number of eggs females laid by 50% only in the <i>OreR</i> nuclear background (mtDNA×nuclear interaction: <i>F</i> = 9.772, <i>P</i> = 0.004, <i>N</i> = 6–11 females per genotype). There is a main effect of the nuclear genome on fecundity, presumably because <i>OreR</i> and <i>AutW132</i> are from different populations and differ at thousands of loci across their genomes. (B) A second experiment reveals the same significant mitochondrial-nuclear interaction (<i>P_ANOVA</i> = 0.001, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003238#pgen.1003238.s004" target="_blank">Table S1</a>) and also shows that the closely related <i>D. simulans</i> mtDNA <i>sm21</i> does not decrease fecundity in either nuclear background. (C) The <i>simw⁵⁰¹</i> mtDNA shortens adult mechanosensory bristles by 50% in the <i>OreR</i> nuclear background. (D) Measurement of the posterior scutellar bristles reveals a significant mitochondrial-nuclear interaction effect on bristle length (<i>P_ANOVA</i>≤0.001, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003238#pgen.1003238.s004" target="_blank">Table S1</a>). There was no sex-by-genotype interaction, and sexes are pooled in this plot. Some error bars are smaller than the symbols.</p