Genetic drivers and cellular selection of female mosaic X chromosome loss.

Autor: Liu A; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland. liuaoxin@broadinstitute.org.; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. liuaoxin@broadinstitute.org.; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA. liuaoxin@broadinstitute.org.; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. liuaoxin@broadinstitute.org.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. liuaoxin@broadinstitute.org., Genovese G; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. giulio@broadinstitute.org.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. giulio@broadinstitute.org.; Department of Genetics, Harvard Medical School, Boston, MA, USA. giulio@broadinstitute.org., Zhao Y; MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK., Pirinen M; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.; Department of Public Health, University of Helsinki, Helsinki, Finland.; Department of Mathematics and Statistics, University of Helsinki, Helsinki, Finland., Zekavat SM; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.; Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA., Kentistou KA; MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK., Yang Z; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland., Yu K; Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA., Vlasschaert C; Department of Medicine, Queen's University, Kingston, Ontario, Canada., Liu X; Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan., Brown DW; Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.; Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute, Rockville, MD, USA., Hudjashov G; Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia., Gorman BR; Center for Data and Computational Sciences (C-DACS), VA Cooperative Studies Program, VA Boston Healthcare System, Boston, MA, USA.; Booz Allen Hamilton, McLean, VA, USA., Dennis J; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK., Zhou W; Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.; Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Momozawa Y; Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan., Pyarajan S; Center for Data and Computational Sciences (C-DACS), VA Cooperative Studies Program, VA Boston Healthcare System, Boston, MA, USA.; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Tuzov V; Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia., Pajuste FD; Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.; Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia., Aavikko M; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland., Sipilä TP; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland., Ghazal A; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland., Huang WY; Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA., Freedman ND; Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA., Song L; Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA., Gardner EJ; MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK., Sankaran VG; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Palotie A; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Ollila HM; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA., Tukiainen T; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland., Chanock SJ; Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA., Mägi R; Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia., Natarajan P; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA., Daly MJ; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Bick A; Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA., McCarroll SA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Genetics, Harvard Medical School, Boston, MA, USA., Terao C; Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.; Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan.; Department of Applied Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan., Loh PR; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. poruloh@broadinstitute.org.; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. poruloh@broadinstitute.org.; Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. poruloh@broadinstitute.org., Ganna A; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland. andrea.ganna@helsinki.fi.; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. andrea.ganna@helsinki.fi.; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. andrea.ganna@helsinki.fi.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. andrea.ganna@helsinki.fi., Perry JRB; MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK. john.perry@mrc-epid.cam.ac.uk., Machiela MJ; Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA. mitchell.machiela@nih.gov.
Jazyk: angličtina
Zdroj: Nature [Nature] 2024 Jul; Vol. 631 (8019), pp. 134-141. Date of Electronic Publication: 2024 Jun 12.
DOI: 10.1038/s41586-024-07533-7
Abstrakt: Mosaic loss of the X chromosome (mLOX) is the most common clonal somatic alteration in leukocytes of female individuals 1,2 , but little is known about its genetic determinants or phenotypic consequences. Here, to address this, we used data from 883,574 female participants across 8 biobanks; 12% of participants exhibited detectable mLOX in approximately 2% of leukocytes. Female participants with mLOX had an increased risk of myeloid and lymphoid leukaemias. Genetic analyses identified 56 common variants associated with mLOX, implicating genes with roles in chromosomal missegregation, cancer predisposition and autoimmune diseases. Exome-sequence analyses identified rare missense variants in FBXO10 that confer a twofold increased risk of mLOX. Only a small fraction of associations was shared with mosaic Y chromosome loss, suggesting that distinct biological processes drive formation and clonal expansion of sex chromosome missegregation. Allelic shift analyses identified X chromosome alleles that are preferentially retained in mLOX, demonstrating variation at many loci under cellular selection. A polygenic score including 44 allelic shift loci correctly inferred the retained X chromosomes in 80.7% of mLOX cases in the top decile. Our results support a model in which germline variants predispose female individuals to acquiring mLOX, with the allelic content of the X chromosome possibly shaping the magnitude of clonal expansion.
(© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
Databáze: MEDLINE
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