Insights into clonal haematopoiesis from 8,342 mosaic chromosomal alterations
The selective pressures that shape clonal evolution in healthy individuals are largely unknown. Here we investigate 8,342 mosaic chromosomal alterations, from 50 kb to 249 Mb long, that we uncovered in blood-derived DNA from 151,202 UK Biobank participants using phase-based computational techniques...
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| Veröffentlicht in: | Nature (London) 2018-07, Vol.559 (7714), p.350-355 |
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| creator | Loh, Po-Ru Genovese, Giulio Handsaker, Robert E. Finucane, Hilary K. Reshef, Yakir A. Palamara, Pier Francesco Birmann, Brenda M. Talkowski, Michael E. Bakhoum, Samuel F. McCarroll, Steven A. Price, Alkes L. |
| description | The selective pressures that shape clonal evolution in healthy individuals are largely unknown. Here we investigate 8,342 mosaic chromosomal alterations, from 50 kb to 249 Mb long, that we uncovered in blood-derived DNA from 151,202 UK Biobank participants using phase-based computational techniques (estimated false discovery rate, 6–9%). We found six loci at which inherited variants associated strongly with the acquisition of deletions or loss of heterozygosity in
cis
. At three such loci (
MPL
,
TM2D3
–
TARSL2
, and
FRA10B
), we identified a likely causal variant that acted with high penetrance (5–50%). Inherited alleles at one locus appeared to affect the probability of somatic mutation, and at three other loci to be objects of positive or negative clonal selection. Several specific mosaic chromosomal alterations were strongly associated with future haematological malignancies. Our results reveal a multitude of paths towards clonal expansions with a wide range of effects on human health.
Analysis of genotyping data for more than 150,000 individuals from the UK Biobank using long-range phase information sheds light on mechanisms of clonal haematopoiesis. |
| doi_str_mv | 10.1038/s41586-018-0321-x |
| format | Article |
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cis
. At three such loci (
MPL
,
TM2D3
–
TARSL2
, and
FRA10B
), we identified a likely causal variant that acted with high penetrance (5–50%). Inherited alleles at one locus appeared to affect the probability of somatic mutation, and at three other loci to be objects of positive or negative clonal selection. Several specific mosaic chromosomal alterations were strongly associated with future haematological malignancies. Our results reveal a multitude of paths towards clonal expansions with a wide range of effects on human health.
Analysis of genotyping data for more than 150,000 individuals from the UK Biobank using long-range phase information sheds light on mechanisms of clonal haematopoiesis.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/s41586-018-0321-x</identifier><identifier>PMID: 29995854</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>45/43 ; 631/114/2415 ; 631/208/205 ; 631/208/737 ; Adult ; Age ; Aged ; Alleles ; Analysis ; Biological Specimen Banks ; Blood ; Blood cancer ; Cell aging ; Chromosome Aberrations ; Chromosome Breakage ; Chromosome Fragile Sites - genetics ; Chromosomes ; Chromosomes, Human, Pair 10 - genetics ; Clonal selection ; Clone Cells - cytology ; Clone Cells - metabolism ; Computer applications ; Deoxyribonucleic acid ; DNA ; Evolution ; Female ; Genetic aspects ; Genomes ; Growth ; Haplotypes ; Health ; Hematologic Neoplasms - genetics ; Hematologic Neoplasms - mortality ; Hematology ; Hematopoiesis - genetics ; Hematopoietic stem cells ; Heterozygosity ; Humanities and Social Sciences ; Humans ; Leukemia ; Loci ; Loss of heterozygosity ; Male ; Middle Aged ; Mosaicism ; multidisciplinary ; Mutation ; Penetrance ; Science ; Science (multidisciplinary) ; Statistical analysis ; Tumors ; United Kingdom</subject><ispartof>Nature (London), 2018-07, Vol.559 (7714), p.350-355</ispartof><rights>Macmillan Publishers Ltd., part of Springer Nature 2018</rights><rights>COPYRIGHT 2018 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jul 19, 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c541t-68236115fdc97d616b2154bbd9fa9ff04a2d05000d5073f7c13354e25b21e77f3</citedby><cites>FETCH-LOGICAL-c541t-68236115fdc97d616b2154bbd9fa9ff04a2d05000d5073f7c13354e25b21e77f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41586-018-0321-x$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41586-018-0321-x$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29995854$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Loh, Po-Ru</creatorcontrib><creatorcontrib>Genovese, Giulio</creatorcontrib><creatorcontrib>Handsaker, Robert E.</creatorcontrib><creatorcontrib>Finucane, Hilary K.</creatorcontrib><creatorcontrib>Reshef, Yakir A.</creatorcontrib><creatorcontrib>Palamara, Pier Francesco</creatorcontrib><creatorcontrib>Birmann, Brenda M.</creatorcontrib><creatorcontrib>Talkowski, Michael E.</creatorcontrib><creatorcontrib>Bakhoum, Samuel F.</creatorcontrib><creatorcontrib>McCarroll, Steven A.</creatorcontrib><creatorcontrib>Price, Alkes L.</creatorcontrib><title>Insights into clonal haematopoiesis from 8,342 mosaic chromosomal alterations</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><description>The selective pressures that shape clonal evolution in healthy individuals are largely unknown. Here we investigate 8,342 mosaic chromosomal alterations, from 50 kb to 249 Mb long, that we uncovered in blood-derived DNA from 151,202 UK Biobank participants using phase-based computational techniques (estimated false discovery rate, 6–9%). We found six loci at which inherited variants associated strongly with the acquisition of deletions or loss of heterozygosity in
cis
. At three such loci (
MPL
,
TM2D3
–
TARSL2
, and
FRA10B
), we identified a likely causal variant that acted with high penetrance (5–50%). Inherited alleles at one locus appeared to affect the probability of somatic mutation, and at three other loci to be objects of positive or negative clonal selection. Several specific mosaic chromosomal alterations were strongly associated with future haematological malignancies. Our results reveal a multitude of paths towards clonal expansions with a wide range of effects on human health.
Analysis of genotyping data for more than 150,000 individuals from the UK Biobank using long-range phase information sheds light on mechanisms of clonal haematopoiesis.</description><subject>45/43</subject><subject>631/114/2415</subject><subject>631/208/205</subject><subject>631/208/737</subject><subject>Adult</subject><subject>Age</subject><subject>Aged</subject><subject>Alleles</subject><subject>Analysis</subject><subject>Biological Specimen Banks</subject><subject>Blood</subject><subject>Blood cancer</subject><subject>Cell aging</subject><subject>Chromosome Aberrations</subject><subject>Chromosome Breakage</subject><subject>Chromosome Fragile Sites - genetics</subject><subject>Chromosomes</subject><subject>Chromosomes, Human, Pair 10 - genetics</subject><subject>Clonal selection</subject><subject>Clone Cells - cytology</subject><subject>Clone Cells - metabolism</subject><subject>Computer applications</subject><subject>Deoxyribonucleic 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alterations</atitle><jtitle>Nature (London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2018-07</date><risdate>2018</risdate><volume>559</volume><issue>7714</issue><spage>350</spage><epage>355</epage><pages>350-355</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><abstract>The selective pressures that shape clonal evolution in healthy individuals are largely unknown. Here we investigate 8,342 mosaic chromosomal alterations, from 50 kb to 249 Mb long, that we uncovered in blood-derived DNA from 151,202 UK Biobank participants using phase-based computational techniques (estimated false discovery rate, 6–9%). We found six loci at which inherited variants associated strongly with the acquisition of deletions or loss of heterozygosity in
cis
. At three such loci (
MPL
,
TM2D3
–
TARSL2
, and
FRA10B
), we identified a likely causal variant that acted with high penetrance (5–50%). Inherited alleles at one locus appeared to affect the probability of somatic mutation, and at three other loci to be objects of positive or negative clonal selection. Several specific mosaic chromosomal alterations were strongly associated with future haematological malignancies. Our results reveal a multitude of paths towards clonal expansions with a wide range of effects on human health.
Analysis of genotyping data for more than 150,000 individuals from the UK Biobank using long-range phase information sheds light on mechanisms of clonal haematopoiesis.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>29995854</pmid><doi>10.1038/s41586-018-0321-x</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0028-0836 |
| ispartof | Nature (London), 2018-07, Vol.559 (7714), p.350-355 |
| issn | 0028-0836 1476-4687 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2068911283 |
| source | MEDLINE; Springer Nature - Complete Springer Journals; Nature Journals Online |
| subjects | 45/43 631/114/2415 631/208/205 631/208/737 Adult Age Aged Alleles Analysis Biological Specimen Banks Blood Blood cancer Cell aging Chromosome Aberrations Chromosome Breakage Chromosome Fragile Sites - genetics Chromosomes Chromosomes, Human, Pair 10 - genetics Clonal selection Clone Cells - cytology Clone Cells - metabolism Computer applications Deoxyribonucleic acid DNA Evolution Female Genetic aspects Genomes Growth Haplotypes Health Hematologic Neoplasms - genetics Hematologic Neoplasms - mortality Hematology Hematopoiesis - genetics Hematopoietic stem cells Heterozygosity Humanities and Social Sciences Humans Leukemia Loci Loss of heterozygosity Male Middle Aged Mosaicism multidisciplinary Mutation Penetrance Science Science (multidisciplinary) Statistical analysis Tumors United Kingdom |
| title | Insights into clonal haematopoiesis from 8,342 mosaic chromosomal alterations |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-14T20%3A16%3A37IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Insights%20into%20clonal%20haematopoiesis%20from%208,342%20mosaic%20chromosomal%20alterations&rft.jtitle=Nature%20(London)&rft.au=Loh,%20Po-Ru&rft.date=2018-07&rft.volume=559&rft.issue=7714&rft.spage=350&rft.epage=355&rft.pages=350-355&rft.issn=0028-0836&rft.eissn=1476-4687&rft_id=info:doi/10.1038/s41586-018-0321-x&rft_dat=%3Cgale_proqu%3EA572710421%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2081646731&rft_id=info:pmid/29995854&rft_galeid=A572710421&rfr_iscdi=true |