Genetic drivers and cellular selection of female mosaic X chromosome loss

Aoxing Liu; Giulio Genovese; Yajie Zhao; Matti Pirinen; Seyedeh M Zekavat; Katherine A Kentistou; Zhiyu Yang; Kai Yu; Caitlyn Vlasschaert; Xiaoxi Liu; Derek W Brown; Georgi Hudjashov; Bryan R Gorman; Joe Dennis; Weiyin Zhou; Yukihide Momozawa; Saiju Pyarajan; Valdislav Tuzov; Fanny-Dhelia Pajuste; Mervi Aavikko; Timo P Sipilä; Awaisa Ghazal; Wen-Yi Huang; Neal D Freedman; Lei Song; Eugene J Gardner; FinnGen; Estonian Biobank Research Team; Breast Cancer Association Consortium; Million Veteran Program; Vijay G Sankaran; Aarno Palotie; Hanna M Ollila; Taru Tukiainen; Stephen J Chanock; Reedik Mägi; Pradeep Natarajan; Mark J Daly; Alexander Bick; Steven A McCarroll; Chikashi Terao; Po-Ru Loh; Andrea Ganna; John R B Perry; Mitchell J Machiela

doi:10.1038/s41586-024-07533-7

Genetic drivers and cellular selection of female mosaic X chromosome loss

Nature. 2024 Jul;631(8019):134-141. doi: 10.1038/s41586-024-07533-7. Epub 2024 Jun 12.

Authors

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

Andres Metspalu, Tõnu Esko, Mari Nelis, Lili Milani

Affiliations

¹ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland. [email protected].
² Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. [email protected].
³ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA. [email protected].
⁴ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
⁵ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
⁶ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
⁷ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
⁸ Department of Genetics, Harvard Medical School, Boston, MA, USA. [email protected].
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. [email protected].
³⁹ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. [email protected].
⁴⁰ Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. [email protected].
⁴¹ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland. [email protected].
⁴² Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. [email protected].
⁴³ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
⁴⁴ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
⁴⁵ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK. [email protected].
⁴⁶ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA. [email protected].

^# Contributed equally.

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

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.

MeSH terms

Adult
Alleles
Aneuploidy*
Autoimmune Diseases / genetics
Biological Specimen Banks
Chromosome Segregation / genetics
Chromosomes, Human, X* / genetics
Chromosomes, Human, Y / genetics
Clone Cells* / metabolism
Clone Cells* / pathology
Exome / genetics
F-Box Proteins / genetics
Female
Genetic Predisposition to Disease / genetics
Germ-Line Mutation
Humans
Leukemia / genetics
Leukocytes* / metabolism
Male
Middle Aged
Models, Genetic
Mosaicism*
Multifactorial Inheritance / genetics
Mutation, Missense / genetics

Substances

F-Box Proteins
FBXO10 protein, human