Journal
NATURE
Volume 611, Issue 7934, Pages 105-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41586-022-05288-7
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Funding
- National Institute for Health Research of England (NIHR)
- UK Medical Research Council (MRC)
- Medical Research Council Mitochondrial Biology Unit [MC_UU_00015/9]
- Medical Research Council (MRC) International Centre for Genomic Medicine in Neuromuscular Disease [MR/S005021/1]
- Leverhulme Trust [RPG-2018-408]
- MRC [MR/S035699/1]
- Alzheimer's Society Project Grant [AS-PG-18b-022]
- National Institute for Health Research (NIHR) Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust
- University of Cambridge
- MRC strategic award
- International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) [MR/S005021/1]
- National Institute for Health Research
- Wellcome Trust
- Medical Research Council
- Cancer Research UK
- Department of Health and Social Care
- NHS England
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The transfer of mitochondrial DNA into the nucleus contributes to a complex landscape of nuclear-mitochondrial segments (NUMTs). Almost all individuals have multiple NUMTs, including rare ones that are present in less than 0.1% of the population. Most NUMTs inserted into the nuclear genome after humans diverged from apes. Once inserted, the sequences are no longer under mitochondrial evolutionary constraints and have different mutational signatures compared to mitochondrial DNA.
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 speciation(1-3). Here we analyse whole-genome sequences from 66,083 people-including 12,509 people with cancer-and demonstrate the on going 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 10(4) births and once in every 10(3) 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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