Are some mutations more equal than others?

Cote-L'Heureux, Auden; Maithania, Yogesh N K; Franco, Melissa; Khrapko, Konstantin

doi:10.7554/elife.87194

Cited by 5 publications

(2 citation statements)

References 9 publications

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“…These findings recapitulate prior studies conducted by Arbeithuber et al 35 and Sanchez-Contreras et al 37 . Several hypotheses have been proposed to explain this phenomenon ranging from potential molecular mechanisms that recognize and remove ROS damage through ageing 37 to the existence of mitochondrial subpopulations that dictate the replication of specific, mutation-limited mtDNA molecules 52 , 53 . Further work is needed to identify the ultimate mechanisms that result in such non-clocklike signatures.…”

Section: Discussionmentioning

confidence: 99%

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

Serrano,

Hirose,

Valentine

et al. 2024

Nat Ecol Evol

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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 mitochondrial genome in different tissues throughout ageing. We used ultrasensitive duplex sequencing to profile ~2.5 million mitochondrial genomes across five mitochondrial haplotypes and three tissues in young and aged mice, cataloguing ~1.2 million mitochondrial somatic and ultralow-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 with 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.

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Section: Discussionmentioning

confidence: 99%

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

Serrano,

Hirose,

Valentine

et al. 2024

Nat Ecol Evol

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“…Respiring or “working” molecules perform OXOHOS activity, while “replicating” molecules are responsible for renewing the mtDNA pool. This way, replicating molecules are protected from oxidative stress and avoid the accumulation of mutations with age [ 31 ]. However, as discussed earlier, the low number of adult individuals makes it difficult to properly evaluate this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the diversity of barn owl’s mitochondrial genome reveals high copy number variations in the control region

Serrano,

Goudet,

Cumer

2024

PLoS ONE

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Mitochondria are known to play an essential role in the cell. These organelles contain their own DNA, which is divided in a coding and non-coding region (NCR). While much of the NCR’s function is unknown, tandem repeats have been observed in several vertebrates, with extreme intra-individual, intraspecific and interspecific variation. Taking advantage of a new complete reference for the mitochondrial genome of the Afro-European Barn Owl (Tyto alba), as well as 172 whole genome-resequencing; we (i) describe the reference mitochondrial genome with a special focus on the repeats in the NCR, (ii) quantify the variation in number of copies between individuals, and (iii) explore the possible factors associated with the variation in the number of repetitions. The reference mitochondrial genome revealed a long (256bp) and a short (80bp) tandem repeat in the NCR region. The re-sequenced genomes showed a great variation in number of copies between individuals, with 4 to 38 copies of the Long and 6 to 135 copies of the short repeat. Among the factors associated with this variation between individuals, the tissue used for extraction was the most significant. The exact mechanisms of the formations of these repeats are still to be discovered and understanding them will help explain the maintenance of the polymorphism in the number of copies, as well as their interactions with the metabolism, the aging and health of the individuals.

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Genomic Mosaicism of the Brain: Origin, Impact, and Utility

Graham,

Schlachetzki,

Yang

et al. 2023

Neurosci. Bull.

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Genomic mosaicism describes the phenomenon where some but not all cells within a tissue harbor unique genetic mutations. Traditionally, research focused on the impact of genomic mosaicism on clinical phenotype—motivated by its involvement in cancers and overgrowth syndromes. More recently, we increasingly shifted towards the plethora of neutral mosaic variants that can act as recorders of cellular lineage and environmental exposures. Here, we summarize the current state of the field of genomic mosaicism research with a special emphasis on our current understanding of this phenomenon in brain development and homeostasis. Although the field of genomic mosaicism has a rich history, technological advances in the last decade have changed our approaches and greatly improved our knowledge. We will provide current definitions and an overview of contemporary detection approaches for genomic mosaicism. Finally, we will discuss the impact and utility of genomic mosaicism.

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Are some mutations more equal than others?

Abstract: A large-scale study of mutations in mitochondrial DNA has revealed a subset that do not accumulate with age.

Cited by 5 publications

References 9 publications

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

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

Characterization of the diversity of barn owl’s mitochondrial genome reveals high copy number variations in the control region

Genomic Mosaicism of the Brain: Origin, Impact, and Utility

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