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1. Single-sperm sequencing reveals the accelerated mitochondrial mutation rate in male Daphnia pulex (Crustacea, Cladocera)

   https://doi.org/10.1098/rspb.2017.1548  

   Xu, Sen; Van Tran, Kenny; Neupane, Swatantra; Snyman, Marelize; Huynh, Trung Viet; Sung, Way (September 2017, Proceedings of the Royal Society B: Biological Sciences)

   null (Ed.)

   Mutation rate in the nuclear genome differs between sexes, with males contributing more mutations than females to their offspring. The male-biased mutation rates in the nuclear genome is most likely to be driven by a higher number of cell divisions in spermatogenesis than in oogenesis, generating more opportunities for DNA replication errors. However, it remains unknown whether male-biased mutation rates are present in mitochondrial DNA (mtDNA). Although mtDNA is maternally inherited and male mtDNA mutation typically does not contribute to genetic variation in offspring, male mtDNA mutations are critical for male reproductive health. In this study, we measured male mtDNA mutation rate using publicly available whole-genome sequences of single sperm of the freshwater microcrustacean Daphnia pulex . Using a stringent mutation detection pipeline, we found that the male mtDNA mutation rate is 3.32 × 10 −6 per site per generation. All the detected mutations are heteroplasmic base substitutions, with 57% of mutations converting G/C to A/T nucleotides. Consistent with the male-biased mutation in the nuclear genome, the male mtDNA mutation rate in D. pulex is approximately 20 times higher than the female rate per generation. We propose that the elevated mutation rate per generation in male mtDNA is consistent with an increased number of cell divisions during male gametogenesis. 

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2. Impact of the POLRMT inhibitor IMT1B on mitochondrial genome copy number in Caenorhabditis elegans

   https://doi.org/10.5061/dryad.dfn2z35cf  

   Kakudji, Eve; Lewis, Samantha (February 2025, Dryad)

   POLRMT is the dedicated mitochondrial RNA polymerase in metazoans and is essential for priming mitochondrial DNA (mtDNA) synthesis. Aberrant POLRMT causes mitochondrial dysfunction and has previously been linked to human metabolic disease. The small molecule IMT1B is an allosteric inhibitor of POLRMT, and its use in diverse model organisms is informative about various aspects of mtDNA synthesis and transcription. Previously, this drug has been shown to be effective in perturbing mtDNA gene expression in human cells and mice. Moreover, a leucine to phenylalanine substitution at position 813 of human POLRMT is predicted to disrupt interaction with the drug. However, the effect of the F813L mutation on the efficacy of POLRMT inhibition (POLRMTi) has not been rigorously tested. Here, we determined by multiple sequence alignment and phylogenetic analysis that this mutation in POLRMT is common among invertebrates, including the model nematode Caenorhabditis elegans. AlphaFold analyses of metazoan POLRMT folding suggest that the F813L substitution alters the physicochemical features of the IMT1B binding pocket. Finally, we find that IMT1B treatment of larval Caenorhabditis elegans has little impact on mtDNA copy number, suggesting that POLRMTi via IMT1B may not be effective in this model organism. 

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3. Mitochondrial mutations in Caenorhabditis elegans show signatures of oxidative damage and an AT-bias

   https://doi.org/10.1093/genetics/iyab116  

   Waneka, Gus; Svendsen, Joshua M; Havird, Justin C; Sloan, Daniel B (August 2021, Genetics)

   Surtees, J A (Ed.)

   Abstract Rapid mutation rates are typical of mitochondrial genomes (mtDNAs) in animals, but it is not clear why. The difficulty of obtaining measurements of mtDNA mutation that are not biased by natural selection has stymied efforts to distinguish between competing hypotheses about the causes of high mtDNA mutation rates. Several studies which have measured mtDNA mutations in nematodes have yielded small datasets with conflicting conclusions about the relative abundance of different substitution classes (i.e., the mutation spectrum). We therefore leveraged Duplex Sequencing, a high-fidelity DNA sequencing technique, to characterize de novo mtDNA mutations in Caenorhabditis elegans. This approach detected nearly an order of magnitude more mtDNA mutations than documented in any previous nematode mutation study. Despite an existing extreme AT bias in the C. elegans mtDNA (75.6% AT), we found that a significant majority of mutations increase genomic AT content. Compared to some prior studies in nematodes and other animals, the mutation spectrum reported here contains an abundance of CG→AT transversions, supporting the hypothesis that oxidative damage may be a driver of mtDNA mutations in nematodes. Furthermore, we found an excess of G→T and C→T changes on the coding DNA strand relative to the template strand, consistent with increased exposure to oxidative damage. Analysis of the distribution of mutations across the mtDNA revealed significant variation among protein-coding genes and as well as among neighboring nucleotides. This high-resolution view of mitochondrial mutations in C. elegans highlights the value of this system for understanding relationships among oxidative damage, replication error, and mtDNA mutation. 

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4. Mitochondrial Recombination Reveals Mito-Mito Epistasis in Yeast

   https://doi.org/genetics.117.300660  

   Wolters, John F; Charron, Guillaume; Gaspary, Alec; Landry, Christian R; Fiumera, Anthony C; Fiumera, Heather L (April 2018, Genetics)

   enetic variation in mitochondrial DNA (mtDNA) provides adaptive potential although the underlying genetic architecture of fitness components within mtDNAs is not known. To dissect functional variation within mtDNAs, we first identified naturally occurring mtDNAs that conferred high or low fitness in Saccharomyces cerevisiae by comparing growth in strains containing identical nuclear genotypes but different mtDNAs. During respiratory growth under temperature and oxidative stress conditions, mitotype effects were largely independent of nuclear genotypes even in the presence of mitonuclear interactions. Recombinant mtDNAs were generated to determine fitness components within high and low fitness mtDNAs. Based on phenotypic distributions of isogenic strains containing recombinant mtDNAs, we found that multiple loci contributed to mitotype fitness differences. These mitochondrial loci interacted in epistatic, non-additive ways in certain environmental conditions. Mito-mito epistasis (i.e. non-additive interactions between mitochondrial loci) influenced fitness in progeny from 4 different crosses, suggesting that mito-mito epistasis is a widespread phenomenon in yeast and other systems with recombining mtDNAs. Furthermore, we found that interruption of coadapted mito-mito interactions produced recombinant mtDNAs with lower fitness. Our results demonstrate that mito-mito epistasis results in functional variation through mitochondrial recombination in fungi, providing modes for adaptive evolution and the generation of mito-mito incompatibilities. 

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5. A large deletion at the cortex locus eliminates butterfly wing patterning

   https://doi.org/10.1093/g3journal/jkac021  

   Hanly, Joseph J.; Livraghi, Luca; Heryanto, Christa; McMillan, W. Owen; Jiggins, Chris D.; Gilbert, Lawrence E.; Martin, Arnaud; Oliver, ed., B. (January 2022, G3 Genes|Genomes|Genetics)

   Abstract As the genetic basis of natural and domesticated variation has been described in recent years, a number of hotspot genes have been repeatedly identified as the targets of selection, Heliconius butterflies display a spectacular diversity of pattern variants in the wild and the genetic basis of these patterns has been well-described. Here, we sought to identify the mechanism behind an unusual pattern variant that is instead found in captivity, the ivory mutant, in which all scales on both the wings and body become white or yellow. Using a combination of autozygosity mapping and coverage analysis from 37 captive individuals, we identify a 78-kb deletion at the cortex wing patterning locus, a gene which has been associated with wing pattern evolution in H. melpomene and 10 divergent lepidopteran species. This deletion is undetected among 458 wild Heliconius genomes samples, and its dosage explains both homozygous and heterozygous ivory phenotypes found in captivity. The deletion spans a large 5′ region of the cortex gene that includes a facultative 5′UTR exon detected in larval wing disk transcriptomes. CRISPR mutagenesis of this exon replicates the wing phenotypes from coding knock-outs of cortex, consistent with a functional role of ivory-deleted elements in establishing scale color fate. Population demographics reveal that the stock giving rise to the ivory mutant has a mixed origin from across the wild range of H. melpomene, and supports a scenario where the ivory mutation occurred after the introduction of cortex haplotypes from Ecuador. Homozygotes for the ivory deletion are inviable while heterozygotes are the targets of artificial selection, joining 40 other examples of allelic variants that provide heterozygous advantage in animal populations under artificial selection by fanciers and breeders. Finally, our results highlight the promise of autozygosity and association mapping for identifying the genetic basis of aberrant mutations in captive insect populations. 

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