. 2024 Jul;631(8019):134-141.

doi: 10.1038/s41586-024-07533-7. Epub 2024 Jun 12.

Genetic drivers and cellular selection of female mosaic X chromosome loss

Aoxing Liu^#^{1

2

3

4

5}, Giulio Genovese^#^{6

7

8}, Yajie Zhao^#⁹, Matti Pirinen^{10

11

12}, Seyedeh M Zekavat^{13

14

15}, Katherine A Kentistou⁹, Zhiyu Yang¹⁰, Kai Yu¹⁶, Caitlyn Vlasschaert¹⁷, Xiaoxi Liu¹⁸, Derek W Brown^{16

19}, Georgi Hudjashov²⁰, Bryan R Gorman^{21

22}, Joe Dennis²³, Weiyin Zhou^{16

24}, Yukihide Momozawa²⁵, Saiju Pyarajan^{21

26}, Valdislav Tuzov²⁰, Fanny-Dhelia Pajuste^{20

27}, Mervi Aavikko¹⁰, Timo P Sipilä¹⁰, Awaisa Ghazal¹⁰, Wen-Yi Huang¹⁶, Neal D Freedman¹⁶, Lei Song¹⁶, Eugene J Gardner⁹; FinnGen; Estonian Biobank Research Team; Breast Cancer Association Consortium; Million Veteran Program; Vijay G Sankaran^{13

28

29}, Aarno Palotie^{10

30

13

31}, Hanna M Ollila^{10

32

13

33}, Taru Tukiainen¹⁰, Stephen J Chanock¹⁶, Reedik Mägi²⁰, Pradeep Natarajan^{32

13

14}, Mark J Daly^{10

30

32

13

31}, Alexander Bick³⁴, Steven A McCarroll^{13

31

35}, Chikashi Terao^{18

36

37}, Po-Ru Loh^{38

39

40}, Andrea Ganna^{41

42

43

44}, John R B Perry⁴⁵, Mitchell J Machiela⁴⁶

Collaborators, Affiliations

Collaborators

Andres Metspalu, Tõnu Esko, Mari Nelis, Lili Milani, Thomas U Ahearn, Irene L Andrulis, Hoda Anton-Culver, Antonis C Antoniou, Amy Berrington de Gonzalez, Natalia V Bogdanova, Stig E Bojesen, Manjeet K Bolla, Hermann Brenner, Jenny Chang-Claude, Georgia Chenevix-Trench, Sarah V Colonna, Fergus J Couch, Angela Cox, Kamila Czene, Mary B Daly, Peter Devilee, Thilo Dörk, Alison M Dunning, Miriam Dwek, Douglas F Easton, Diana M Eccles, Peter A Fasching, Olivia Fletcher, Manuela Gago-Dominguez, Montserrat García-Closas, Mark S Goldberg, Anna González-Neira, Pascal Guénel, Christopher A Haiman, Per Hall, Ute Hamann, Antoinette Hollestelle, Reiner Hoppe, John L Hopper, Anna Jakubowska, Helena Jernström, Esther M John, Rudolf Kaaks, Elza K Khusnutdinova, Cari M Kitahara, Peter Kraft, Vessela N Kristensen, Diether Lambrechts, Annika Lindblom, Arto Mannermaa, Usha Menon, Kyriaki Michailidou, Rachel A Murphy, Heli Nevanlinna, Nadia Obi, Kenneth Offit, Paolo Peterlongo, Paul D P Pharoah, Dijana Plaseska-Karanfilska, Gad Rennert, Atocha Romero, Emmanouil Saloustros, Marjanka K Schmidt, Rita K Schmutzler, Jennifer Stone, Rulla M Tamimi, Lauren R Teras, Mary Beth Terry, Melissa A Troester, Celine M Vachon, Qin Wang, Clarice R Weinberg, Robert Winqvist, Alicja Wolk

Affiliations

¹ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland. liuaoxin@broadinstitute.org.
² Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. liuaoxin@broadinstitute.org.
³ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA. liuaoxin@broadinstitute.org.
⁴ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. liuaoxin@broadinstitute.org.
⁵ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. liuaoxin@broadinstitute.org.
⁶ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. giulio@broadinstitute.org.
⁷ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. giulio@broadinstitute.org.
⁸ Department of Genetics, Harvard Medical School, Boston, MA, USA. giulio@broadinstitute.org.
⁹ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
¹⁰ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
¹¹ Department of Public Health, University of Helsinki, Helsinki, Finland.
¹² Department of Mathematics and Statistics, University of Helsinki, Helsinki, Finland.
¹³ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁴ Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
¹⁵ Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
¹⁶ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
¹⁷ Department of Medicine, Queen's University, Kingston, Ontario, Canada.
¹⁸ Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
¹⁹ Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute, Rockville, MD, USA.
²⁰ Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
²¹ Center for Data and Computational Sciences (C-DACS), VA Cooperative Studies Program, VA Boston Healthcare System, Boston, MA, USA.
²² Booz Allen Hamilton, McLean, VA, USA.
²³ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
²⁴ Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
²⁵ Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
²⁶ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
²⁷ Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
²⁸ Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
²⁹ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
³⁰ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
³¹ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³² Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
³³ Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA.
³⁴ Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
³⁵ Department of Genetics, Harvard Medical School, Boston, MA, USA.
³⁶ Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan.
³⁷ Department of Applied Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
³⁸ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. poruloh@broadinstitute.org.
³⁹ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. poruloh@broadinstitute.org.
⁴⁰ Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. poruloh@broadinstitute.org.
⁴¹ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland. andrea.ganna@helsinki.fi.
⁴² Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. andrea.ganna@helsinki.fi.
⁴³ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. andrea.ganna@helsinki.fi.
⁴⁴ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. andrea.ganna@helsinki.fi.
⁴⁵ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK. john.perry@mrc-epid.cam.ac.uk.
⁴⁶ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA. mitchell.machiela@nih.gov.

^# Contributed equally.

PMID: 38867047
DOI: 10.1038/s41586-024-07533-7

Genetic drivers and cellular selection of female mosaic X chromosome loss

Aoxing Liu et al. Nature. 2024 Jul.

. 2024 Jul;631(8019):134-141.

doi: 10.1038/s41586-024-07533-7. Epub 2024 Jun 12.

Authors

Collaborators

Andres Metspalu, Tõnu Esko, Mari Nelis, Lili Milani, Thomas U Ahearn, Irene L Andrulis, Hoda Anton-Culver, Antonis C Antoniou, Amy Berrington de Gonzalez, Natalia V Bogdanova, Stig E Bojesen, Manjeet K Bolla, Hermann Brenner, Jenny Chang-Claude, Georgia Chenevix-Trench, Sarah V Colonna, Fergus J Couch, Angela Cox, Kamila Czene, Mary B Daly, Peter Devilee, Thilo Dörk, Alison M Dunning, Miriam Dwek, Douglas F Easton, Diana M Eccles, Peter A Fasching, Olivia Fletcher, Manuela Gago-Dominguez, Montserrat García-Closas, Mark S Goldberg, Anna González-Neira, Pascal Guénel, Christopher A Haiman, Per Hall, Ute Hamann, Antoinette Hollestelle, Reiner Hoppe, John L Hopper, Anna Jakubowska, Helena Jernström, Esther M John, Rudolf Kaaks, Elza K Khusnutdinova, Cari M Kitahara, Peter Kraft, Vessela N Kristensen, Diether Lambrechts, Annika Lindblom, Arto Mannermaa, Usha Menon, Kyriaki Michailidou, Rachel A Murphy, Heli Nevanlinna, Nadia Obi, Kenneth Offit, Paolo Peterlongo, Paul D P Pharoah, Dijana Plaseska-Karanfilska, Gad Rennert, Atocha Romero, Emmanouil Saloustros, Marjanka K Schmidt, Rita K Schmutzler, Jennifer Stone, Rulla M Tamimi, Lauren R Teras, Mary Beth Terry, Melissa A Troester, Celine M Vachon, Qin Wang, Clarice R Weinberg, Robert Winqvist, Alicja Wolk

Affiliations

¹ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland. liuaoxin@broadinstitute.org.
² Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. liuaoxin@broadinstitute.org.
³ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA. liuaoxin@broadinstitute.org.
⁴ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. liuaoxin@broadinstitute.org.
⁵ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. liuaoxin@broadinstitute.org.
⁶ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. giulio@broadinstitute.org.
⁷ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. giulio@broadinstitute.org.
⁸ Department of Genetics, Harvard Medical School, Boston, MA, USA. giulio@broadinstitute.org.
⁹ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
¹⁰ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
¹¹ Department of Public Health, University of Helsinki, Helsinki, Finland.
¹² Department of Mathematics and Statistics, University of Helsinki, Helsinki, Finland.
¹³ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁴ Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
¹⁵ Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
¹⁶ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
¹⁷ Department of Medicine, Queen's University, Kingston, Ontario, Canada.
¹⁸ Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
¹⁹ Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute, Rockville, MD, USA.
²⁰ Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
²¹ Center for Data and Computational Sciences (C-DACS), VA Cooperative Studies Program, VA Boston Healthcare System, Boston, MA, USA.
²² Booz Allen Hamilton, McLean, VA, USA.
²³ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
²⁴ Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
²⁵ Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
²⁶ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
²⁷ Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
²⁸ Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
²⁹ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
³⁰ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
³¹ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³² Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
³³ Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA.
³⁴ Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
³⁵ Department of Genetics, Harvard Medical School, Boston, MA, USA.
³⁶ Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan.
³⁷ Department of Applied Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
³⁸ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. poruloh@broadinstitute.org.
³⁹ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. poruloh@broadinstitute.org.
⁴⁰ Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. poruloh@broadinstitute.org.
⁴¹ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland. andrea.ganna@helsinki.fi.
⁴² Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. andrea.ganna@helsinki.fi.
⁴³ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. andrea.ganna@helsinki.fi.
⁴⁴ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. andrea.ganna@helsinki.fi.
⁴⁵ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK. john.perry@mrc-epid.cam.ac.uk.
⁴⁶ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA. mitchell.machiela@nih.gov.

^# Contributed equally.

PMID: 38867047
DOI: 10.1038/s41586-024-07533-7

Erratum in

Author Correction: Genetic drivers and cellular selection of female mosaic X chromosome loss.
Liu A, Genovese G, Zhao Y, Pirinen M, Zekavat SM, Kentistou KA, Yang Z, Yu K, Vlasschaert C, Liu X, Brown DW, Hudjashov G, Gorman BR, Dennis J, Zhou W, Momozawa Y, Pyarajan S, Tuzov V, Pajuste FD, Aavikko M, Sipilä TP, Ghazal A, Huang WY, Freedman ND, Song L, Gardner EJ; FinnGen; Estonian Biobank Research Team; Breast Cancer Association Consortium; Million Veteran Program; Sankaran VG, Palotie A, Ollila HM, Tukiainen T, Chanock SJ, Mägi R, Natarajan P, Daly MJ, Bick A, McCarroll SA, Terao C, Loh PR, Ganna A, Perry JRB, Machiela MJ. Liu A, et al. Nature. 2024 Dec;636(8043):E7. doi: 10.1038/s41586-024-08215-0. Nature. 2024. PMID: 39627447 No abstract available.

Abstract

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.

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References

1. Machiela, M. J. et al. Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome. Nat. Commun. 7, 11843 (2016). - PubMed - PMC - DOI
1. Zekavat, S. M. et al. Hematopoietic mosaic chromosomal alterations increase the risk for diverse types of infection. Nat. Med. 27, 1012–1024 (2021). - PubMed - PMC - DOI
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1. Lyon, M. F. Gene action in the X-chromosome of the mouse (Mus musculus L.). Nature 190, 372–373 (1961). - PubMed - DOI
1. Tukiainen, T. et al. Landscape of X chromosome inactivation across human tissues. Nature 550, 244–248 (2017). - PubMed - PMC - DOI

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Genetic drivers and cellular selection of female mosaic X chromosome loss

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Genetic drivers and cellular selection of female mosaic X chromosome loss

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