Biparental inheritance of mitochondrial DNA revisited

Pagnamenta, Alistair T; Wei, Wei; Rahman, Shamima; Chinnery, Patrick F.

doi:10.1038/s41576-021-00380-6

Cited by 15 publications

(10 citation statements)

References 10 publications

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“…Recently, whole-genome sequencing (WGS) has identified ultra-rare NUMTs in humans 5 , implying that mtDNA-nuclear transfer is an ongoing process, but the rate of germline NUMT formation remains unknown. Novel mtDNA-nuclear incursions have important implications, as they can potentially disrupt protein-coding genes, causing disease [6][7][8][9] , and create artefacts resembling mixed populations of mtDNA 10,11 (pseudo-heteroplasmy). Inadvertently interpreting the NUMT sequence as a mtDNA variant could confound the diagnosis of mitochondrial diseases 12 and raise questions about the possible paternal inheritance of mtDNA 13 .…”

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confidence: 99%

Nuclear-embedded mitochondrial DNA sequences in 66,083 human genomes

Wei

Schon

Elgar

et al. 2022

Nature

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DNA transfer from cytoplasmic organelles to the cell nucleus is a legacy of the endosymbiotic event—the majority of nuclear-mitochondrial segments (NUMTs) are thought to be ancient, preceding human speciation1–3. Here we analyse whole-genome sequences from 66,083 people—including 12,509 people with cancer—and demonstrate the ongoing transfer of mitochondrial DNA into the nucleus, contributing to a complex NUMT landscape. More than 99% of individuals had at least one of 1,637 different NUMTs, with 1 in 8 individuals having an ultra-rare NUMT that is present in less than 0.1% of the population. More than 90% of the extant NUMTs that we evaluated inserted into the nuclear genome after humans diverged from apes. Once embedded, the sequences were no longer under the evolutionary constraint seen within the mitochondrion, and NUMT-specific mutations had a different mutational signature to mitochondrial DNA. De novo NUMTs were observed in the germline once in every 104 births and once in every 103 cancers. NUMTs preferentially involved non-coding mitochondrial DNA, linking transcription and replication to their origin, with nuclear insertion involving multiple mechanisms including double-strand break repair associated with PR domain zinc-finger protein 9 (PRDM9) binding. The frequency of tumour-specific NUMTs differed between cancers, including a probably causal insertion in a myxoid liposarcoma. We found evidence of selection against NUMTs on the basis of size and genomic location, shaping a highly heterogenous and dynamic human NUMT landscape.

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confidence: 99%

Nuclear-embedded mitochondrial DNA sequences in 66,083 human genomes

Wei

Schon

Elgar

et al. 2022

Nature

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“…At present, evidence for biparental inheritance of mtDNA remains sparse (Pagnamenta et al . 2021) with recent genomic studies moreover describing the role of NUMTs in previous parental leakage studies (e.g. Balciuniene & Balciunas, 2019).…”

Section: Discussionmentioning

confidence: 86%

“…Additionally, heteroplasmy or paternal leakage of mitochondria could counteract deleterious mutations (Gemmell et al 2004). At present, evidence for biparental inheritance of mtDNA remains sparse (Pagnamenta et al 2021) with recent genomic studies moreover describing the role of NUMTs in previous parental leakage studies (e.g. Balciuniene & Balciunas, 2019).…”

Section: Discussionmentioning

confidence: 99%

Mother’s curse on conservation: assessing the role of mtDNA in sex‐specific survival differences in ex‐situ breeding programs

Leeflang

Dongen

Helsen

2021

Animal Conservation

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For captive breeding to be an effective conservation tool, population fitness needs to be guaranteed according to the latest insights. Preserving genetic diversity has been a major pillar in conservation breeding, as it is a proxy for long-term population viability. Small differences on the DNA level can impact an individual's overall fitness and when situated on the mitochondrial genome might more specifically affect the process of aging and fertility. In general, mitochondrial DNA is transmitted via the mother. In the process of natural selection, variants beneficial for female fitness will be selected for whereas male-harming variants that are neutral or beneficial in females will never be selected against. This biased selective sieve results in the accumulation of male-harming mutations in the mitochondrial DNA, a process labelled "mother's curse". Regardless of the susceptibility of zoo populations to "mother's curse", mitochondrial-induced fitness effects have remained unstudied within captive breeding programs. While current conservation breeding strategies focus on retaining nuclear diversity, studies that specifically concentrate on aberrant extra-nuclear genetic processes might improve breeding practices. Here, we provide a framework and empirical evidence for the presence of mtDNA-induced sexspecific differences starting from readily available population information. We analyzed whether an individual's mitochondrial background partly affects survival in a sex-specific manner using studbook data from captive populations representing 16 species. Our results indicate male survival is affected in five maternal lineages on pre-and postnatal level. Additionally, we describe the overall beneficial effects some maternal lineages have over others in terms of survival. These results are of interest in the debate on the maintenance of healthy captive populations and how to further improve safeguarding their genetic diversity for both ex-situ and in-situ conservation.

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“…Once integrated, Numts are bi-parentally transmitted to future generations, like other types of genetic variation. While mostly benign, Numts have been implicated with cellular evolution and function (14,15), various cancers (16,17), and can confound studies of mitochondrial DNA heteroplasmy (18,19), maternal inheritance of mitochondria (6,(20)(21)(22)(23), and forensics (24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%

Somatic nuclear mitochondrial DNA insertions are prevalent in the human brain and accumulate over time in fibroblasts

Zhou

Karan

Gu³

et al. 2023

Preprint

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The transfer of mitochondrial DNA into the nuclear genomes of eukaryotes (Numts) has been linked to lifespan in some non-human species. We investigated their association with human aging in two ways. First, we quantified Numts in 1,187 post-mortem brain and blood samples. Human brains exhibited a 5.5-fold enrichment of somatic Numt insertions in the dorsolateral prefrontal cortex compared to the cerebellum, suggesting that they arose spontaneously during development or with aging. Moreover, more brain Numts was linked to earlier mortality. The brains of individuals with no cognitive impairment who died at younger ages carried approximately 2 more Numts per decade of life lost than those who lived longer. Second, we tested the dynamic transfer of Numts in a repeated-measures WGS study in a human fibroblast model that recapitulates several molecular features of human aging. These longitudinal experiments revealed a gradual accumulation of one Numt every ~9 days, independent of large-scale genomic instability. Targeted genetic and pharmacological perturbations of mitochondrial oxidative phosphorylation did not affect numtogenesis, whereas chronic glucocorticoid stress increased the Numts transfer rate by 39.8%. Combined, our data document spontaneous numtogenesis in aging human cells and demonstrate an association between brain cortical somatic Numts and human lifespan.

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Biparental inheritance of mitochondrial DNA revisited

Cited by 15 publications

References 10 publications

Nuclear-embedded mitochondrial DNA sequences in 66,083 human genomes

Nuclear-embedded mitochondrial DNA sequences in 66,083 human genomes

Mother’s curse on conservation: assessing the role of mtDNA in sex‐specific survival differences in ex‐situ breeding programs

Somatic nuclear mitochondrial DNA insertions are prevalent in the human brain and accumulate over time in fibroblasts

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