Nuclear-embedded mitochondrial DNA sequences in 66,083 human genomes
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 w...
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| Veröffentlicht in: | Nature (London) 2022-11, Vol.611 (7934), p.105-114 |
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| creator | Wei, Wei Schon, Katherine R. Elgar, Greg Orioli, Andrea Tanguy, Melanie Giess, Adam Tischkowitz, Marc Caulfield, Mark J. Chinnery, Patrick F. |
| description | 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 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 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.
A study examining DNA transfer from mitochondria to the nucleus using whole-genome sequences from 66,083 people shows that this is an ongoing dynamic process in normal cells with distinct roles in different types of cancer. |
| doi_str_mv | 10.1038/s41586-022-05288-7 |
| format | Article |
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1
–
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 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.
A study examining DNA transfer from mitochondria to the nucleus using whole-genome sequences from 66,083 people shows that this is an ongoing dynamic process in normal cells with distinct roles in different types of cancer.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/s41586-022-05288-7</identifier><identifier>PMID: 36198798</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>45/23 ; 631/208/212 ; 631/443/319/333 ; 631/67/69 ; 692/420/2489/144 ; Cancer ; Cell Nucleus - genetics ; Cell Nucleus - metabolism ; Chromosomes ; Confidence intervals ; Deoxyribonucleic acid ; DNA ; DNA biosynthesis ; DNA Breaks, Double-Stranded ; DNA methylation ; DNA Repair ; DNA, Mitochondrial - genetics ; DNA, Mitochondrial - metabolism ; Double-strand break repair ; Families & family life ; Gene sequencing ; Genome, Human - genetics ; Genomes ; Genomics ; Germ-Line Mutation ; Humanities and Social Sciences ; Humans ; Insertion ; Liposarcoma ; Liposarcoma, Myxoid - genetics ; Mann-Whitney U test ; Mitochondria - genetics ; Mitochondrial DNA ; multidisciplinary ; Mutation ; Neoplasms - genetics ; Nuclei (cytology) ; Nucleotide sequence ; Organelles ; Phylogeny ; Replication origins ; Science ; Science (multidisciplinary) ; Sequence Analysis, DNA ; Tumors ; Zinc finger proteins</subject><ispartof>Nature (London), 2022-11, Vol.611 (7934), p.105-114</ispartof><rights>The Author(s) 2022</rights><rights>2022. The Author(s).</rights><rights>Copyright Nature Publishing Group Nov 3, 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c540t-f499b1e14b8d3c06f41a68b702ae2c804288bff1d35268364ddae6c71ee77b613</citedby><cites>FETCH-LOGICAL-c540t-f499b1e14b8d3c06f41a68b702ae2c804288bff1d35268364ddae6c71ee77b613</cites><orcidid>0000-0002-7065-6617 ; 0000-0001-8054-8954 ; 0000-0001-7323-1596 ; 0000-0002-7880-0628 ; 0000-0001-9295-3594</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41586-022-05288-7$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41586-022-05288-7$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36198798$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wei, Wei</creatorcontrib><creatorcontrib>Schon, Katherine R.</creatorcontrib><creatorcontrib>Elgar, Greg</creatorcontrib><creatorcontrib>Orioli, Andrea</creatorcontrib><creatorcontrib>Tanguy, Melanie</creatorcontrib><creatorcontrib>Giess, Adam</creatorcontrib><creatorcontrib>Tischkowitz, Marc</creatorcontrib><creatorcontrib>Caulfield, Mark J.</creatorcontrib><creatorcontrib>Chinnery, Patrick F.</creatorcontrib><title>Nuclear-embedded mitochondrial DNA sequences in 66,083 human genomes</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><description>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 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 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.
A study examining DNA transfer from mitochondria to the nucleus using whole-genome sequences from 66,083 people shows that this is an ongoing dynamic process in normal cells with distinct roles in different types of cancer.</description><subject>45/23</subject><subject>631/208/212</subject><subject>631/443/319/333</subject><subject>631/67/69</subject><subject>692/420/2489/144</subject><subject>Cancer</subject><subject>Cell Nucleus - genetics</subject><subject>Cell Nucleus - metabolism</subject><subject>Chromosomes</subject><subject>Confidence intervals</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA biosynthesis</subject><subject>DNA Breaks, Double-Stranded</subject><subject>DNA methylation</subject><subject>DNA Repair</subject><subject>DNA, Mitochondrial - genetics</subject><subject>DNA, Mitochondrial - metabolism</subject><subject>Double-strand break repair</subject><subject>Families & family life</subject><subject>Gene sequencing</subject><subject>Genome, Human - genetics</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Germ-Line Mutation</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Insertion</subject><subject>Liposarcoma</subject><subject>Liposarcoma, Myxoid - genetics</subject><subject>Mann-Whitney U test</subject><subject>Mitochondria - genetics</subject><subject>Mitochondrial DNA</subject><subject>multidisciplinary</subject><subject>Mutation</subject><subject>Neoplasms - genetics</subject><subject>Nuclei (cytology)</subject><subject>Nucleotide sequence</subject><subject>Organelles</subject><subject>Phylogeny</subject><subject>Replication origins</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Sequence Analysis, DNA</subject><subject>Tumors</subject><subject>Zinc finger 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mitochondrial DNA sequences in 66,083 human genomes</title><author>Wei, Wei ; Schon, Katherine R. ; Elgar, Greg ; Orioli, Andrea ; Tanguy, Melanie ; Giess, Adam ; Tischkowitz, Marc ; Caulfield, Mark J. ; Chinnery, Patrick F.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c540t-f499b1e14b8d3c06f41a68b702ae2c804288bff1d35268364ddae6c71ee77b613</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>45/23</topic><topic>631/208/212</topic><topic>631/443/319/333</topic><topic>631/67/69</topic><topic>692/420/2489/144</topic><topic>Cancer</topic><topic>Cell Nucleus - genetics</topic><topic>Cell Nucleus - metabolism</topic><topic>Chromosomes</topic><topic>Confidence intervals</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA biosynthesis</topic><topic>DNA Breaks, Double-Stranded</topic><topic>DNA methylation</topic><topic>DNA Repair</topic><topic>DNA, 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(London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2022-11-03</date><risdate>2022</risdate><volume>611</volume><issue>7934</issue><spage>105</spage><epage>114</epage><pages>105-114</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><abstract>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 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 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.
A study examining DNA transfer from mitochondria to the nucleus using whole-genome sequences from 66,083 people shows that this is an ongoing dynamic process in normal cells with distinct roles in different types of cancer.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>36198798</pmid><doi>10.1038/s41586-022-05288-7</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0002-7065-6617</orcidid><orcidid>https://orcid.org/0000-0001-8054-8954</orcidid><orcidid>https://orcid.org/0000-0001-7323-1596</orcidid><orcidid>https://orcid.org/0000-0002-7880-0628</orcidid><orcidid>https://orcid.org/0000-0001-9295-3594</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Nature (London), 2022-11, Vol.611 (7934), p.105-114 |
| issn | 0028-0836 1476-4687 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9630118 |
| source | MEDLINE; Springer Nature - Complete Springer Journals; Nature Journals Online |
| subjects | 45/23 631/208/212 631/443/319/333 631/67/69 692/420/2489/144 Cancer Cell Nucleus - genetics Cell Nucleus - metabolism Chromosomes Confidence intervals Deoxyribonucleic acid DNA DNA biosynthesis DNA Breaks, Double-Stranded DNA methylation DNA Repair DNA, Mitochondrial - genetics DNA, Mitochondrial - metabolism Double-strand break repair Families & family life Gene sequencing Genome, Human - genetics Genomes Genomics Germ-Line Mutation Humanities and Social Sciences Humans Insertion Liposarcoma Liposarcoma, Myxoid - genetics Mann-Whitney U test Mitochondria - genetics Mitochondrial DNA multidisciplinary Mutation Neoplasms - genetics Nuclei (cytology) Nucleotide sequence Organelles Phylogeny Replication origins Science Science (multidisciplinary) Sequence Analysis, DNA Tumors Zinc finger proteins |
| title | Nuclear-embedded mitochondrial DNA sequences in 66,083 human genomes |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-21T14%3A29%3A12IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Nuclear-embedded%20mitochondrial%20DNA%20sequences%20in%2066,083%20human%20genomes&rft.jtitle=Nature%20(London)&rft.au=Wei,%20Wei&rft.date=2022-11-03&rft.volume=611&rft.issue=7934&rft.spage=105&rft.epage=114&rft.pages=105-114&rft.issn=0028-0836&rft.eissn=1476-4687&rft_id=info:doi/10.1038/s41586-022-05288-7&rft_dat=%3Cproquest_pubme%3E2731821881%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2731821881&rft_id=info:pmid/36198798&rfr_iscdi=true |