Tao W, Bianchini G, Schifani E
… +4 more, Kay C, Grasso DA, Donoghue PCJ, Pisani D
Mol Biol Evol
· 2026 Apr · PMID 41793117
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Ants, Formicidae, are a group of small social insects that inhabit nearly all terrestrial environments. Three competing hypotheses of ant relationships have been proposed, differing in the placement of Martialinae, a sub...Ants, Formicidae, are a group of small social insects that inhabit nearly all terrestrial environments. Three competing hypotheses of ant relationships have been proposed, differing in the placement of Martialinae, a subfamily of cryptic, endogean ants. We used BUSCO genes to investigate the signals in individual and concatenated gene datasets. We found that gene trees support all three hypotheses. After concatenation, the three signals persist but their relative strength is model-dependent. The CAT-posterior mean site frequencies approach (which our model adequacy tests show best explains the across-site compositional heterogeneity of the data) finds Martialinae as the sister of all ants but Leptanillinae. We tested the effect of across-lineage compositional heterogeneity using data-recoding and excluding highly heterogeneous taxa. These tests did not lead to the emergence of significant support for alternative tree topologies. However, we identified strong gene- and site-discordance in the data and evidence that signals representing incongruent evolutionary processes exist in ant genomes supporting all three hypotheses. Incomplete lineage sorting and/or introgression seem to have significantly affected early ant evolution, which might make it impossible to establish whether Leptanillinae, Leptanillinae plus Martialinae, or Martialinae represents the sister of all the other ants.
Shipova AA, Belousova IA, Yakimova ME
… +6 more, Kirichenko NI, Ageev AA, Cusson M, Lukhtanov VA, Ershov NI, Martemyanov VV
Mol Biol Evol
· 2026 Mar · PMID 41779147
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Most lepidopteran species have a WZ/ZZ sex chromosome system, suggesting a common origin. However, the exceptional variability of W chromosomes supports their multiple independent origins. Here, we investigated the genom...Most lepidopteran species have a WZ/ZZ sex chromosome system, suggesting a common origin. However, the exceptional variability of W chromosomes supports their multiple independent origins. Here, we investigated the genome of the recently formed species, Dendrolimus sibiricus, which is one of the most devastating pests of the boreal forests in Northern Asia. We found that its karyotype consists of 30 pairs of chromosomes and follows the WZ/ZZ sex chromosome system. We produced a chromosome-scale assembly of its female genome and identified the sequences of both sex chromosomes. With the exception of the W chromosome, the D. sibiricus genome displays a very high degree of synteny with genomes of other Dendrolimus representatives. The non-conserved W chromosome is composed entirely of recently acquired sequences, mainly young genomic repeats and a few unique loci derived from subtelomeric regions of the same species' Z chromosome as well as from the genome of the endosymbiotic Wolbachia bacterium. It shares no common ancestral sequences with the W chromosomes of two related species, Dendrolimus tabulaeformis and Lasiocampa quercus. They, in turn, display a similar organization relative to the W of D. sibiricus, including Z-derived loci. The W of D. tabulaeformis also contained multiple fragments of the mitochondrial genome, as seen in classical B chromosomes. We conclude that W chromosomes arose from their Z counterparts recently and independently in these three species. We propose that this mechanism may be a common feature of lepidopteran evolution, counteracting the inevitable degeneration of a non-recombining chromosome through its repeated, complete turnover.
Mol Biol Evol
· 2026 Feb · PMID 41761781
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Lateral gene transfer (LGT) is widespread in eukaryotes, including in animals and plants where it can fuel adaptive evolution and innovation. However, the factors that influence the integration and long-term retention of...Lateral gene transfer (LGT) is widespread in eukaryotes, including in animals and plants where it can fuel adaptive evolution and innovation. However, the factors that influence the integration and long-term retention of transferred genes remain poorly understood. The pangenome of the grass Alloteropsis has a high turnover of laterally acquired genes, and here we combine expression, methylation, and genomic data to identify factors promoting their long-term persistence. Most transferred genes appear to be degenerating, showing lower expression levels and/or greater sequence truncation compared to their vertically inherited homologs. These degenerating genes also show significantly higher levels of DNA methylation, potentially indicating transcriptional silencing. The likelihood of a transferred gene being retained will be influenced by how easily it can be expressed in the recipient genome. In Alloteropsis, putatively functional laterally acquired genes had expression levels significantly more similar to their donor ortholog than to their vertically inherited homolog. Transferred genes carry cis-regulatory elements encoded on the fragment of DNA that moves between species, likely facilitating their expression in the new genomic context. Evolutionary novelty may also increase the likelihood that selection retains a transferred gene. However, only a significant difference in expression level, not sequence divergence, between donor orthologs and vertically inherited homologs is associated with successful lateral gene transfer. Overall, our results show that most transferred genes degrade over time. However, those capable of regulating their own expression are more likely to persist and contribute to long-term evolutionary innovation.
Turner JH, Kuster RD, Staton ME
… +1 more, Moulton JK
Mol Biol Evol
· 2026 Mar · PMID 41755752
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Phylogenomics pipelines are designed to reconstruct evolutionary relationships among groups of organisms. Existing pipelines are dependent upon reference gene sets for which target copies may be retrieved through read-ma...Phylogenomics pipelines are designed to reconstruct evolutionary relationships among groups of organisms. Existing pipelines are dependent upon reference gene sets for which target copies may be retrieved through read-mapping. This read-mapping approach is limited by the availability of reference orthologs closely related to target taxa, which reduces its utility for nonmodel organisms. We introduce OrthoGarden, an automated and containerized de novo assembly-based phylogenomics pipeline aimed to recover accurate and reproducible phylogenies from any combination of short reads and assemblies with particular emphasis on nonmodel taxa. OrthoGarden is tested using 3 datasets of varying size, scope, and taxonomic identity and benchmarked against other phylogenomics pipelines for accuracy. When closely related reference orthologs are available, OrthoGarden produces phylogenies with comparable accuracy to existing pipelines; however, studies limited to distantly related reference orthologs yield increased accuracy using OrthoGarden relative to other mapping approaches. OrthoGarden produces highly accurate phylogenies across a wide range of taxa. Automated phylogenetic reconstruction using genes recovered through all-vs-all orthology inference among selected taxa allows for phylogenomic analysis without requiring in-group reference orthologs. Datasets using nonmodel taxa especially benefit from OrthoGarden's efficacy in the absence of a closely related reference group. Its consistent accuracy, automated usage of computational resources, and ability to utilize both short reads and assemblies make OrthoGarden a community-focused pipeline for both model and nonmodel phylogenomics. OrthoGarden is publicly available at github.com/jacksonhturner/orthogarden.
Mol Biol Evol
· 2026 Mar · PMID 41755717
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This note introduces HaploThread, a user-friendly desktop software with a graphical user interface designed for constructing and visualizing haplotype networks. Developed in C++ using the Qt library, HaploThread integrat...This note introduces HaploThread, a user-friendly desktop software with a graphical user interface designed for constructing and visualizing haplotype networks. Developed in C++ using the Qt library, HaploThread integrates network visualization with multiple multithreaded haplotype construction algorithms-including McAN and fastHaN (which incorporates MSN, MJN, and TCS)-through a modular plugin architecture. It provides an intuitive workflow for building and visualizing haplotype networks from large-scale datasets, while also supporting functional extensions via plugins to facilitate the analysis of genetic variation and evolutionary relationships. HaploThread is released as open-source software under the GNU General Public License. Its source code and precompiled executables for Windows and macOS are freely available at https://ngdc.cncb.ac.cn/biocode/tool/BT007948 and https://github.com/git-xubo/HaploThread.
Mol Biol Evol
· 2026 Mar · PMID 41744256
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X chromosome inactivation (XCI) partially balances gene dosage between sexes; yet, many genes are expressed from the inactive X (Xi) to a variable degree. In this study, we investigate whether variation in Xi expression...X chromosome inactivation (XCI) partially balances gene dosage between sexes; yet, many genes are expressed from the inactive X (Xi) to a variable degree. In this study, we investigate whether variation in Xi expression among genes predicts transcriptional and phenotypic consequences of X-linked variation. We find that Xi expression levels are a strong linear predictor of female-male expression differences, suggesting that other compensatory or regulatory mechanisms play a more minor role in sex differences in X-linked gene expression. Among females, we identify traits-including BMI, estradiol, and testosterone levels-for which higher Xi expression correlates with the strength of evidence for either additive or dominance effects on the trait. We hypothesize that an underappreciated mechanism could generate dominance effects of X-linked variants on a trait-specifically when the variant influences skew in X inactivation. This work establishes Xi expression as important for understanding transcriptional sex differences and physiological variation among females.
Gu TT, Zhai TY, Jiang Y
… +9 more, Qi BT, Yang F, Zhang ZX, Yu R, Omotosho O, Morenikeji O, Zhang HR, Hu JY, Yu L
Mol Biol Evol
· 2026 Mar · PMID 41744181
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The white-bellied pangolin (Phataginus tricuspis) serves as a critical biogeographic indicator for understanding faunal diversification in African rainforests and is a priority for conservation due to its status as the m...The white-bellied pangolin (Phataginus tricuspis) serves as a critical biogeographic indicator for understanding faunal diversification in African rainforests and is a priority for conservation due to its status as the most heavily trafficked and endangered mammal. However, the species' evolutionary history and the genetic consequences of population decline remain unclear. In this study, we conducted comprehensive phylogeographic and conservation genomic studies of 209 whole genomes, including 100 newly sequenced genomes, and 215 mitogenomes covering all geographic ranges. Our findings reveal four whole-genome genetic lineages and six mitochondrial genetic lineages, uncovering mito-nuclear discordance driven by deep mitochondrial divergence and the replacement of some mitochondrial lineages by nuclear lineages. We suggest that Pleistocene refugia and river barriers are hypothesized to have contributed to the pattern of genetic differentiation and biogeographic diversification. Demographic history reconstruction indicates that, historically, the population size dynamics were likely correlated with glacial-interglacial cycles. However, the recent sharp decline in population size can be attributed to overexploitation driven by international trade. The genetic consequence analyses and evolutionary potential simulation reveal that the Nigeria and West Africa lineages exhibit lower levels of genetic diversity, higher levels of inbreeding and genetic load, and lower survival status and future evolutionary potential, than the other lineages, indicating the need for urgent attention and priority conservation action. Our results provide novel insights into the evolutionary history and conservation priorities for white-bellied pangolins and offer a valuable phylogeographic and conservation framework for guiding conservation efforts to safeguard African rainforest biodiversity.
Ward MJ, Ellsworth SA, King EG
… +9 more, Ng'oma E, Nystrom GS, Lawrence KC, Maquet-Diafouka L, Oliver A, Margres MJ, Parkinson CL, Hughes KA, Rokyta DR
Mol Biol Evol
· 2026 Mar · PMID 41739857
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All species evolve under selective pressures that emerge from their interactions, often antagonistic, with other species. Phenotypes mediating species interactions manifest as the combined products of the genomes of inte...All species evolve under selective pressures that emerge from their interactions, often antagonistic, with other species. Phenotypes mediating species interactions manifest as the combined products of the genomes of interacting species; understanding the evolutionary processes acting in one lineage therefore cannot be attained without bridging the genomes of interacting species. Venoms have arisen independently more than 100 times in animals and serve diverse roles in species interactions, including predation and defense. Each venom is evolutionarily entwined with reciprocal phenotypes, such as venom resistance, in often diverse recipient species. Despite extensive work on venoms, the full genetic basis for resistance to whole venoms is largely unknown. Using the venom of the Florida blue centipede (Scolopendra viridis) comprised of 35 toxins and Drosophila melanogaster as model prey, we investigated the genetics of venom resistance for a naive prey through experimental evolution and genetic-mapping approaches. We identified 12 consensus genes across techniques associated with venom resistance, yet individual experiments suggested a genome-wide basis for resistance involving hundreds to thousands of genes, despite the relative simplicity of the venom of S. viridis. We found no evidence for fitness trade-offs associated with the evolution of resistance and revealed a stark contrast in the nature of venom resistance between prey sexes. The disparity in resistance genetics between prey sexes as well as the relative genetic complexity of venom versus resistance may ultimately give venomous predators a coevolutionary advantage over their prey.
Mol Biol Evol
· 2026 Mar · PMID 41739546
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The fundamental principle that selection acts on a gene's function often assumes implicitly that this function is fixed and intrinsic. However, empirical evidence from pangenomics, synthetic biology, and GWAS consistentl...The fundamental principle that selection acts on a gene's function often assumes implicitly that this function is fixed and intrinsic. However, empirical evidence from pangenomics, synthetic biology, and GWAS consistently demonstrates that organismal function is highly context-dependent, varying across genomic backgrounds and cellular states, even for core genes. Drawing a conceptual parallel with modern large language models (LLMs), I propose that genomes, like LLMs, do not encode fixed functions but rather "probability distributions" over functional and phenotypic outcomes. This framework draws a conceptual analogy between epistasis and transformer-style "attention mechanisms," suggesting that genomic context weights the influence of distant genetic elements. I also introduce the concept of "genomic perplexity"-an information-theoretic measure of the statistical unexpectedness and incompatibility of a genetic element within its host context. I demonstrate how perplexity serves as a quantifiable metric for the well-known fitness cost associated with interspecies gene flow (eg horizontal gene transfer (HGT) and introgression), where a new gene represents a high-perplexity token. This perspective formalizes long-standing observations of genomic fit and provides a testable framework for predicting the integration potential of accessory genes and directing future research in synthetic biology and evolutionary modeling.
Zhu T, Sato Y, Fukunaga T
… +3 more, Miya M, Iwasaki W, Yoshizawa S
Mol Biol Evol
· 2026 Mar · PMID 41707113
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Environmental DNA (eDNA) metabarcoding has become a powerful tool for assessing fish biodiversity in aquatic ecosystems. However, accurate species-level identification remains challenging due to incomplete and contaminat...Environmental DNA (eDNA) metabarcoding has become a powerful tool for assessing fish biodiversity in aquatic ecosystems. However, accurate species-level identification remains challenging due to incomplete and contaminated reference databases, as well as ambiguous taxa sharing identical barcode sequences. Here, we present MitoNGS, a next-generation platform that succeeds the widely used MiFish pipeline, designed for high-resolution analysis of fish metabarcoding data. MitoNGS addresses these challenges by incorporating more comprehensive references including non-fish species and detailed annotations of heterospecific regions. Additionally, it introduces the "species complex" strategy in conjunction with environmental habitat and geographic occurrence data to resolve ambiguous taxa. Furthermore, MitoNGS expands the functionalities of the legacy MiFish pipeline. It can analyze data from any mitochondrial markers and from Nanopore sequencing platforms. MitoNGS demonstrated excellent performance on our testing datasets from diverse locations, markers, and sequencing platforms. MitoNGS offers a user-friendly, web-based solution for fish detection, biodiversity monitoring, conservation research, and bioresource management. MitoNGS is freely available via https://mitofish.aori.u-tokyo.ac.jp/mito-ngs.
Mol Biol Evol
· 2026 Mar · PMID 41703705
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Molecular clocks are a fundamental technique in evolutionary biology for establishing the timing and tempo of organismal divergence. However, currently available molecular clock methods, which often rely on simple homoge...Molecular clocks are a fundamental technique in evolutionary biology for establishing the timing and tempo of organismal divergence. However, currently available molecular clock methods, which often rely on simple homogeneous substitution models, can produce inaccurate time estimates, particularly for deep-time or rapidly evolving lineages where substitution heterogeneity and saturation are common. Hereby, we introduce phyloHessian (https://github.com/evolbeginner/phyloHessianWrapper), a Julia-based software to enable the use of complex mixture substitution models in molecular dating. phyloHessian computes the phylogenetic Hessian matrix and integrates it into PAML-MCMCtree's approximate likelihood framework to conduct dating analyses. Simulations mimicking phylogenies at different timescales demonstrate that complex mixture substitution models significantly enhance the accuracy of divergence time and substitution rate estimates in deep-time phylogenies. This pattern remains consistent across a wide range of uncertainties associated with molecular clock analysis. Additionally, mixture models display greater robustness to model and calibration specifications compared to their homogeneous counterparts. Empirical analysis of ancient symbiont lineages Microsporidia and Rickettsiales with different substitution models shows that mixture models, compared to homogeneous models, yield accelerated substitution rates and in some cases significantly different divergence times, leading to a revised understanding of their host association origins. Our findings underscore the importance of incorporating complex mixture substitution models for constructing reliable evolutionary timelines and elucidating the evolutionary history of deep-time or fast-evolving lineages.
Grover-Thomas F, van Dorp L, Balloux F
… +2 more, Andrés AM, Camus MF
Mol Biol Evol
· 2026 May · PMID 41701624
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Mitochondria are essential for cellular energy production and biosynthesis, thermogenesis, and cell signaling, and thus help coordinate physiological responses to changing environments. Humans (Homo sapiens) have adapted...Mitochondria are essential for cellular energy production and biosynthesis, thermogenesis, and cell signaling, and thus help coordinate physiological responses to changing environments. Humans (Homo sapiens) have adapted to cope with a wide range of climatic conditions, however the role of the mitochondrial genome (mtDNA) in mediating this process remains poorly understood. Here, we curated a dataset of 19,570 publicly available full human mitochondrial genomes, an approximate 40-fold increase on earlier studies, paired with modern climate and reconstructed paleoclimate variables. Using a Generalized Linear Model approach, we identify 18 independent candidate variants significantly associated with climatic conditions, suggesting local adaptation in human mitochondrial genomes. Candidate variants are distributed across multiple loci in regulatory, tRNA, rRNA and protein-coding regions-including prominently in ND2 and ND4 complex I subunits. Specific variants are predicted to impact mtDNA transcription, ribosome or protein structure, and multiple have been associated with disease pathologies. We further show that candidate variant genotype distributions are each best modeled by different paleo-bioclimatic variables, consistent with environmental stressors linked to our measured variables exerting subtly distinct selective effects. These stressors may reflect dietary changes or different thermogenic demands at lower temperatures. Our results provide genetic evidence to support the accumulating body of work from functional studies that mitochondria can modulate adaptation to diverse environments. This work underscores the importance of mtDNA in evolutionary biology and its relevance for understanding both disease and physiological variation in global populations.
Fontan A, Lannes R, Fingerhut JM
… +2 more, Flynn JM, Yamashita YM
Mol Biol Evol
· 2026 Mar · PMID 41693153
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The Y chromosome evolves rapidly, often differing dramatically even between closely related species. While such divergence has long been suspected to contribute to hybrid male sterility, leading to reproductive isolation...The Y chromosome evolves rapidly, often differing dramatically even between closely related species. While such divergence has long been suspected to contribute to hybrid male sterility, leading to reproductive isolation and thus speciation, the underlying mechanisms remain elusive. Here, we identify a molecular basis linking Y chromosome divergence to reproductive isolation in Drosophila. We show that male hybrids between D. simulans and D. mauritiana fail to properly express key Y-linked fertility genes. These genes contain unusually large introns, exceeding megabases and show substantial sequence divergence between species. In the hybrids, these gigantic introns are misprocessed, resulting in widespread splicing defects, including aberrant "back-splicing" events that join later exons to earlier ones. Our findings suggest that sequence divergence within introns can disrupt essential gene expression through defective splicing, providing a mechanistic link between rapid Y chromosome evolution and hybrid sterility. This work highlights the underappreciated role of intronic divergence in speciation.
Mackenzie ES, Sendra KM, Baslé A
… +3 more, Mazgaj R, Kehl-Fie TE, Waldron KJ
Mol Biol Evol
· 2026 Mar · PMID 41684149
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Changes in protein properties and functions are central to the evolution of life. Metalloproteins can evolve by changing their preference from one metal cofactor to another. Recently, we demonstrated that the widely dist...Changes in protein properties and functions are central to the evolution of life. Metalloproteins can evolve by changing their preference from one metal cofactor to another. Recently, we demonstrated that the widely distributed iron- or manganese-dependent superoxide dismutase (SodFM) family has undergone numerous metal-preference changes, including during evolutionary adaptation of pathogenic bacteria to altered metal availability within the host. Yet the underlying properties of metal-binding sites that control metalloenzyme metal preference are unclear, and thus, we lack an understanding of how enzymatic metal preference can be reshaped by evolution. Here, we used spectral features of bound iron or manganese, whose intensities reflect their oxidation state, to assess how their redox properties are tuned during SodFM evolution. We systematically analyzed the metal oxidation state across diverse SodFMs from multiple phylogenetic groups with different catalytic metal preferences, including those known to have undergone evolutionary metal-preference switching. We observed a striking relationship between resting oxidation state and catalytic metal preferences. Mutagenesis of second-sphere residues previously identified as determining metal preference revealed that they modulate metal-dependent activity and cofactor oxidation state in tandem, demonstrating these properties are linked. Together, these data argue that the differing SodFM metal preferences observed across the tree of life evolved through tuning of their redox properties by the secondary coordination sphere. This study gives insight into the process by which a metalloenzyme originally optimized for one metal cofactor can evolve a new metal preference, under suitable selection pressure, through re-optimization of its active site for catalytic reactivity of the new metal cofactor.
Mol Biol Evol
· 2026 Feb · PMID 41668465
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Identifying recurrent changes in biological sequences is important to multiple aspects of biological research-from understanding the molecular basis of convergent phenotypes, to pinpointing the causative sequence changes...Identifying recurrent changes in biological sequences is important to multiple aspects of biological research-from understanding the molecular basis of convergent phenotypes, to pinpointing the causative sequence changes that give rise to antibiotic resistance and disease. Here, we present RECUR, a method for identifying recurrent amino acid substitutions from multiple sequence alignments that is fast, easy to use, and scalable to thousands of sequences. We demonstrate that RECUR's recurrence detection achieves 100% accuracy on simulated data with known evolutionary histories. We further show that RECUR is robust to realistic levels of tree inference error. Finally, we apply RECUR to a large set of surface glycoprotein (S) protein sequences from SARS-CoV-2. This analysis identified widespread recurrent evolution throughout the protein with significant enrichment in the exposed receptor-binding S1 subunit and at the interface with the human angiotensin-converting enzyme 2 (hACE2). In contrast, recurrent substitutions were depleted at the trimeric interface of the S protein. In silico modelling showed that recurrent substitutions had no directional effect on stability at either interface, but effects at the hACE2 interface were significantly more variable. Multiple substitutions with large destabilizing effects on hACE2 binding have been linked to immune escape, while others represented reversions back to the reference sequence, suggesting that recurrent evolution at this interface reflects opposing selective pressures balancing receptor binding with immune evasion. A standalone implementation of the algorithm is available under the GPLv3 license at https://github.com/OrthoFinder/RECUR.
Torres-Gonzalez E, Arbeithuber B, Stoler N
… +7 more, Cremona MA, Shebl O, Ebner T, Tiemann-Boege I, Diaz FJ, Chiaromonte F, Makova KD
Mol Biol Evol
· 2026 Mar · PMID 41664480
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Mitochondrial function can be affected by mutations in mitochondrial DNA (mtDNA). However, detecting de novo mutations in mtDNA has been challenging due to its high copy number, particularly in germline cells, and the lo...Mitochondrial function can be affected by mutations in mitochondrial DNA (mtDNA). However, detecting de novo mutations in mtDNA has been challenging due to its high copy number, particularly in germline cells, and the low accuracy of conventional next-generation sequencing technologies. Using highly accurate duplex sequencing, we study the frequency of de novo insertion and deletion (indel) mtDNA mutations across multiple age groups in somatic and germline tissues of three mammalian species-mouse, macaque, and human. We demonstrate that, similar to de novo nucleotide substitutions, indels accumulate rapidly with age in somatic tissues with high energetic demand (brain and skeletal muscle) or high proliferation (liver). However, in oocytes, indels accumulate slower with age than nucleotide substitutions (or do not accumulate at all). The increases in indel frequency with age are driven mostly by deletions. Short tandem repeats are highly enriched for indels, implicating DNA replication slippage as a major driver of indel formation in mtDNA. For some species and tissues, indels are depleted at protein-coding sequences; however, indels that are multiples of 3 bp are not overrepresented. Ours is the most detailed study of de novo small indels in mtDNA to date. It provides parameters for models of mtDNA evolution, informs molecular mechanisms for a multitude of human genetic diseases, and illuminates the accumulation of indel mutations with age. Such accumulation may have functional consequences, as it affects reproduction later in life and drives the decline of mitochondrial function during aging.