Genetic drivers and cellular selection of female mosaic X chromosome loss

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

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, 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 () and Mitchell J. Machiela ()
Additional contact information
Aoxing Liu: University of Helsinki
Giulio Genovese: Broad Institute of MIT and Harvard
Yajie Zhao: University of Cambridge
Matti Pirinen: University of Helsinki
Seyedeh M. Zekavat: Broad Institute of MIT and Harvard
Katherine A. Kentistou: University of Cambridge
Zhiyu Yang: University of Helsinki
Kai Yu: National Cancer Institute
Caitlyn Vlasschaert: Queen’s University
Xiaoxi Liu: RIKEN Center for Integrative Medical Sciences
Derek W. Brown: National Cancer Institute
Georgi Hudjashov: University of Tartu
Bryan R. Gorman: VA Boston Healthcare System
Joe Dennis: University of Cambridge
Weiyin Zhou: National Cancer Institute
Yukihide Momozawa: RIKEN Center for Integrative Medical Sciences
Saiju Pyarajan: VA Boston Healthcare System
Valdislav Tuzov: University of Tartu
Fanny-Dhelia Pajuste: University of Tartu
Mervi Aavikko: University of Helsinki
Timo P. Sipilä: University of Helsinki
Awaisa Ghazal: University of Helsinki
Wen-Yi Huang: National Cancer Institute
Neal D. Freedman: National Cancer Institute
Lei Song: National Cancer Institute
Eugene J. Gardner: University of Cambridge
Vijay G. Sankaran: Broad Institute of MIT and Harvard
Aarno Palotie: University of Helsinki
Hanna M. Ollila: University of Helsinki
Taru Tukiainen: University of Helsinki
Stephen J. Chanock: National Cancer Institute
Reedik Mägi: University of Tartu
Pradeep Natarajan: Massachusetts General Hospital
Mark J. Daly: University of Helsinki
Alexander Bick: Vanderbilt University Medical Center
Steven A. McCarroll: Broad Institute of MIT and Harvard
Chikashi Terao: RIKEN Center for Integrative Medical Sciences
Po-Ru Loh: Broad Institute of MIT and Harvard
Andrea Ganna: University of Helsinki
John R. B. Perry: University of Cambridge
Mitchell J. Machiela: National Cancer Institute

Nature, 2024, vol. 631, issue 8019, 134-141

Abstract: Abstract Mosaic loss of the X chromosome (mLOX) is the most common clonal somatic alteration in leukocytes of female individuals1,2, 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.

Date: 2024
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DOI: 10.1038/s41586-024-07533-7

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