Mitochondrial haplotype and mito-nuclear matching drive somatic mutation and selection throughout aging.

Autor:	Serrano IM; Center for Computational Biology, University of California, Berkeley., Hirose M; Lübeck Institute of Experimental Dermatology, University of Lübeck., Valentine CC; TwinStrand Biosciences., Roesner S; TwinStrand Biosciences., Schmidt E; TwinStrand Biosciences., Pratt G; TwinStrand Biosciences., Williams L; TwinStrand Biosciences., Salk J; TwinStrand Biosciences., Ibrahim S; Department of Integrative Biology, University of California, Berkeley., Sudmant PH; Center for Computational Biology, University of California, Berkeley.; Department of Integrative Biology, University of California, Berkeley.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Oct 23. Date of Electronic Publication: 2023 Oct 23.
DOI:	10.1101/2023.03.06.531392
Abstrakt:	Mitochondrial genomes co-evolve with the nuclear genome over evolutionary timescales and are shaped by selection in the female germline. Here, we investigate how mismatching between nuclear and mitochondrial ancestry impacts the somatic evolution of the mt-genome in different tissues throughout aging. We used ultra-sensitive Duplex Sequencing to profile ~2.5 million mt-genomes across five mitochondrial haplotypes and three tissues in young and aged mice, cataloging ~1.2 million mitochondrial somatic and ultra low frequency inherited mutations, of which 81,097 are unique. We identify haplotype-specific mutational patterns and several mutational hotspots, including at the Light Strand Origin of Replication, which consistently exhibits the highest mutation frequency. We show that rodents exhibit a distinct mitochondrial somatic mutational spectrum compared to primates with a surfeit of reactive oxygen species-associated G>T/C>A mutations, and that somatic mutations in protein coding genes exhibit signatures of negative selection. Lastly, we identify an extensive enrichment in somatic reversion mutations that "re-align" mito-nuclear ancestry within an organism's lifespan. Together, our findings demonstrate that mitochondrial genomes are a dynamically evolving subcellular population shaped by somatic mutation and selection throughout organismal lifetimes. Competing Interests: Conflicts of Interests C.V., S. A., E.S., G.P., L.W., and J.S. declare they are equity holders of TwinStrand Biosciences, Inc. Additionally, C.V., E.S., and J.S. are current employees of TwinStrand Biosciences and C.V., E.S., L.W., and J.S. are inventors on one or more Duplex Sequencing-related patents.
Databáze:	MEDLINE
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