The multi-tissue landscape of somatic mtdna mutations indicates tissue specific accumulation and removal in aging
- University of Washington, United States
Abstract
Accumulation of somatic mutations in the mitochondrial genome (mtDNA) has long been proposed as a possible mechanism of mitochondrial and tissue dysfunction that occurs during aging. A thorough characterization of age-associated mtDNA somatic mutations has been hampered by the limited ability to detect low frequency mutations. Here, we used Duplex Sequencing on eight tissues of an aged mouse cohort to detect >89,000 independent somatic mtDNA mutations and show significant tissue-specific increases during aging across all tissues examined which did not correlate with mitochondrial content and tissue function. G→A/C→T substitutions, indicative of replication errors and/or cytidine deamination, were the predominant mutation type across all tissues and increased with age, whereas G→T/C→A substitutions, indicative of oxidative damage, were the second most common mutation type, but did not increase with age regardless of tissue. We also show that clonal expansions of mtDNA mutations with age is tissue and mutation type dependent. Unexpectedly, mutations associated with oxidative damage rarely formed clones in any tissue and were significantly reduced in the hearts and kidneys of aged mice treated at late age with Elamipretide or nicotinamide mononucleotide. Thus, the lack of accumulation of oxidative damage-linked mutations with age suggests a life-long dynamic clearance of either the oxidative lesions or mtDNA genomes harboring oxidative damage.
Data availability
The Duplex-Seq-Pipeline is written in Python and R, but has dependencies written in other languages. The DuplexSeq-Pipeline software has been tested to run on Linux, Windows WSL1, Windows WSL2 and Apple OSX. The software can be obtained at https://github.com/KennedyLab-UW/Duplex-Seq-Pipeline. Raw mouse sequencing data used in this study are available at SRA accension PRJNA727407. The data from Arbeithuber et al. are available at SRA accension PRJNA563921. The final post-processed data, including variant call files, depth information, data summaries, and mutation frequencies, as well as the scripts to perform reproducible production of statistics and figure generation (with the exception of Figure 5C-E) are available at https://github.com/Kennedy-Lab-UW/Sanchez_Contreras_etal_2022.
Article and author information
Author details
Monica Sanchez-Contreras
Kristine A Tsantilas
Peter S Rabinovitch
Funding
National Institute on Aging (P01AG001751)
- David J Marcinek
- Peter S Rabinovitch
National Institute on Aging (K01AG062757)
- Mariya T Sweetwyne
National Institute of Diabetes and Digestive and Kidney Diseases (R21DK128540)
- Monica Sanchez-Contreras
- Mariya T Sweetwyne
Congressionally Directed Medical Research Programs (W81XWH-16-1-0579)
- Scott R Kennedy
National Human Genome Research Institute (R21HG011229)
- Scott R Kennedy
National Cancer Institute (R21CA259780)
- Scott R Kennedy
National Institute on Aging (T32AG000057)
- Kristine A Tsantilas
- Jeremy A Whitson
National Institute on Aging (T32AG066574)
- Kristine A Tsantilas
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- William Copeland, National Institute of Environmental Health Sciences, United States
Ethics
Animal experimentation: This study was performed in accordance to the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to an approved institutional animal care and use committee (IACUC) protocol (2174-23) at the University of Washington.
Version history
- Preprint posted: September 1, 2022 (view preprint)
- Received: September 11, 2022
- Accepted: February 15, 2023
- Accepted Manuscript published: February 17, 2023 (version 1)
- Version of Record published: April 4, 2023 (version 2)
Copyright
© 2023, Sanchez-Contreras et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 2,476
- views
-
- 310
- downloads
-
- 16
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
The multi-tissue landscape of somatic mtdna mutations indicates tissue specific accumulation and removal in aging
eLife 12:e83395.
https://doi.org/10.7554/eLife.83395
Further reading
-
- Computational and Systems Biology
- Genetics and Genomics
Gene expression is known to be affected by interactions between local genetic variation and DNA accessibility, with the latter organized into three-dimensional chromatin structures. Analyses of these interactions have previously been limited, obscuring their regulatory context, and the extent to which they occur throughout the genome. Here, we undertake a genome-scale analysis of these interactions in a genetically diverse population to systematically identify global genetic–epigenetic interaction, and reveal constraints imposed by chromatin structure. We establish the extent and structure of genotype-by-epigenotype interaction using embryonic stem cells derived from Diversity Outbred mice. This mouse population segregates millions of variants from eight inbred founders, enabling precision genetic mapping with extensive genotypic and phenotypic diversity. With 176 samples profiled for genotype, gene expression, and open chromatin, we used regression modeling to infer genetic–epigenetic interactions on a genome-wide scale. Our results demonstrate that statistical interactions between genetic variants and chromatin accessibility are common throughout the genome. We found that these interactions occur within the local area of the affected gene, and that this locality corresponds to topologically associated domains (TADs). The likelihood of interaction was most strongly defined by the three-dimensional (3D) domain structure rather than linear DNA sequence. We show that stable 3D genome structure is an effective tool to guide searches for regulatory elements and, conversely, that regulatory elements in genetically diverse populations provide a means to infer 3D genome structure. We confirmed this finding with CTCF ChIP-seq that revealed strain-specific binding in the inbred founder mice. In stem cells, open chromatin participating in the most significant regression models demonstrated an enrichment for developmental genes and the TAD-forming CTCF-binding complex, providing an opportunity for statistical inference of shifting TAD boundaries operating during early development. These findings provide evidence that genetic and epigenetic factors operate within the context of 3D chromatin structure.
-
- Genetics and Genomics
- Neuroscience
Single-cell RNA sequencing reveals the extent to which marmosets carry genetically distinct cells from their siblings.
