Mammalian Mitochondrial DNA Accumulates Insertions and Deletions with Age in Energetically Demanding Tissues
Jan 29, 2026·
E Torres-González, B Arbeithuber, N Stoler, MA Cremona, O Shebl, T Ebner, I Tiemann-Boege, F Diaz, F Chiaromonte, KD Makova
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Abstract
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.
Type
Publication
Molecular Biology and Evolution
Authors
Ph.D. student
Before starting his PhD in the Makova lab, Edmundo worked on regional human variation as an undergraduate in Puerto Rico and on translational cancer genomics as a postdoc in NIH. As part of this thesis work, he focuses on mitochondrial genomics that cover its evolution, and
relation to complex phenotypes.
Authors
Postdoctoral scholar
In Prof. Makova’s lab Barbara was interested in the accurate measurement of rare mutations. Her project was focused on the inheritance of mitochondrial DNA; particularly, analysis of de novo mutations in the germ line, as well as the inheritance of low-level variants.
Authors
Ph.D. student
My focus is on variation in mitochondrial DNA. I develop methods
and software tools to analyze mitochondrial sequencing data, as
well as data from other non-diploid systems like viral populations,
cancer, and somatic variation.
Authors
Visiting Research Professor
Marzia develops statistical techniques for the analysis of large, high-dimensional and complex data – in particular functional data. An important aspect of her research is its collaborative and multidisciplinary nature. Indeed, much of her work is at the interface between statistics and computational biology, and her main application area is in the “Omics” sciences.
Authors
Francesca is a statistician developing methods for the analysis of large, high-dimensional and complex data, and applying such methods in contemporary “Omics” sciences and other scientific fields – including Meteorology and Economics.
Authors
Professor
Kateryna is interested in genomics, evolution, and human genetics.
Her lab studies mutations using both computational and experimental
approaches. Additional topics of interest include sex chromosome
evolution and genomics of childhood obesity.