The Spectrum of Mitochondrial Mutation Differs across Species

Mitochondrial DNA mutation rates have now been measured in several model organisms. The patterns of mutation are strikingly different among species and point to modulation of mutation-selection balance in the evolution of nucleotide composition

Mitochondrial Dysfunction and Infection Generate Immunity–Fecundity Tradeoffs in \u3ci\u3eDrosophila\u3c/i\u3e

Physiological responses to short-term environmental stressors, such as infection, can have long-term consequences for fitness, particularly if the responses are inappropriate or nutrient resources are limited. Genetic variation affecting energy acquisition, storage, and usage can limit cellular energy availability and may influence resourceallocation tradeoffs even when environmental nutrients are plentiful. Here, we utilized Drosophila mitochondrial– nuclear genotypes to test whether disrupted mitochondrial function interferes with nutrient-sensing pathways, and whether this disruption has consequences for tradeoffs between immunity and fecundity. We found that an energetically-compromised genotype was relatively resistant to rapamycin—a drug that targets nutrient-sensing pathways and mimics resource limitation. Dietary resource limitation decreased survival of energetically-compromised flies. Furthermore, survival of infection with a natural pathogen was decreased in this genotype, and females of this genotype experienced immunity–fecundity tradeoffs that were not evident in genotypic controls with normal energy metabolism. Together, these results suggest that this genotype may have little excess energetic capacity and fewer cellular nutrients, even when environmental nutrients are not limiting. Genetic variation in energy metabolism may therefore act to limit the resources available for allocation to life-history traits in ways that generate tradeoffs even when environmental resources are not limiting

Functional and evolutionary analysis of host Synaptogyrin-2 in porcine circovirus type 2 susceptibility

Mammalian evolution has been influenced by viruses for millions of years, leaving signatures of adaptive evolution within genes encoding for viral interacting proteins. Synaptogyrin- 2 (SYNGR2) is a transmembrane protein implicated in promoting bacterial and viral infections. A genome-wide association study of pigs experimentally infected with porcine circovirus type 2b (PCV2b) uncovered a missense mutation (SYNGR2 p.Arg63Cys) associated with viral load. In this study, CRISPR/Cas9-mediated gene editing of the porcine kidney 15 (PK15, wtSYNGR2+p.63Arg) cell line generated clones homozygous for the favorable SYNGR2 p.63Cys allele (emSYNGR2+p.63Cys). Infection of edited clones resulted in decreased PCV2 replication compared to wildtype PK15 (P\u3c0.05), with consistent effects across genetically distinct PCV2b and PCV2d isolates. Sequence analyses of wild and domestic pigs (n\u3e700) revealed the favorable SYNGR2 p.63Cys allele is unique to domestic pigs and more predominant in European than Asian breeds. A haplotype defined by the SYNGR2 p.63Cys allele was likely derived from an ancestral haplotype nearly fixed within European (0.977) but absent from Asian wild boar. We hypothesize that the SYNGR2 p.63Cys allele arose post-domestication in ancestral European swine. Decreased genetic diversity in homozygotes for the SYNGR2 p.63Cys allele compared to SYNGR2 p.63Arg, corroborates a rapid increase in frequency of SYGNR2 p.63Cys via positive selection. Signatures of adaptive evolution across mammalian species were also identified within SYNGR2 intraluminal loop domains, coinciding with the location of SYNGR2 p.Arg63Cys. Therefore, SYNGR2 may reflect a novel component of the host-virus evolutionary arms race across mammals with SYNGR2 p.Arg63Cys representing a species-specific example of putative adaptive evolution

Energy demand and the context-dependent effects of genetic interactions underlying metabolism

Genetic effects are often context dependent, with the same genotype differentially affecting phenotypes across environments, life stages, and sexes.We used an environmental manipulation designed to increase energy demand during development to investigate energy demand as a general physiological explanation for context-dependent effects of mutations, particularly for those mutations that affect metabolism. We found that increasing the photoperiod during which Drosophila larvae are active during development phenocopies a temperature-dependent developmental delay in a mitochondrial-nuclear genotype with disrupted metabolism. This result indicates that the context-dependent fitness effects of this genotype are not specific to the effects of temperature and may generally result from variation in energy demand. The effects of this genotype also differ across life stages and between the sexes. The mitochondrial-nuclear genetic interaction disrupts metabolic rate in growing larvae, but not in adults, and compromises female, but not male, reproductive fitness. These patterns are consistent with a model where context-dependent genotype-phenotype relationships may generally arise from differences in energy demand experienced by individuals across environments, life stages, and sexes

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

The Mitochondrial Contribution to Animal Performance, Adaptation, and Life-History Variation

We thank the National Science Foundation (grant IOS1738378 to W.R.H. and K.S.), SICB’s division of Comparative Physiology and Biochemistry and Comparative Endocrinology, the Company of Biologists, the Society of Experimental Biology, and the Canadian Society of Zoology for funding the symposium.  Peer reviewedPostprin

Figure 6 Data

Figure 6 Fecundity Data: Each row represents the offspring by sex from an individual female. Column: Box—the box that the vial was placed into in the incubator; infectdate—date that individuals were infected; day—day of female egg lay; mito—mitochondrial genotype; nuc—nuclear genotype; sex—sex; treatment— infected (B) or control (P); rep—individuals taken from same replicate vial; number—replicate female number; sextotal—number of males or female offspring eclosed; vialtotal—total number of offspring produced per day; Vfail—denotation of failure to produce any offsprin

Supplementary Figure 4 Data

Supplementary Figure 4 Data: Each row is an individual timepoint. Columns: mito—mitochondrial genotype; nuc—nuclear genotype; rep—replicate; treatment— infected (B) or control (P); sex—sex; Date—setup date; OD—optical density of bacteria used for infection; ID—individuals within vial; start—start time of survival measurement; end—end time of survival measurement; death—0 is alive, 1 is dead; UniqueID—unique identifier of individual; vial—vial i