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

Authors

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, ...show more 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

Affiliations

• Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland. liuaoxin@broadinstitute.org.
• Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. giulio@broadinstitute.org.
• MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
• Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
• Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
• Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
• Department of Medicine, Queen's University, Kingston, Ontario, Canada.
• Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
• Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
• Center for Data and Computational Sciences (C-DACS), VA Cooperative Studies Program, VA Boston Healthcare System, Boston, MA, USA.

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.