Journal Article

Genetic drivers and cellular selection of female mosaic X chromosome loss

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

2024

Overview

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. A large-scale meta-analysis across eight biobank datasets identifies common genetic variants associated with mosaic loss of the X chromosome in female participants.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 45/43 / 631/181/735 / 631/208/205/2138 / 631/208/457/649 / 692/53 / Adult / Age / Alleles / Aneuploidy / Autoimmune diseases / Autoimmune Diseases - genetics / Basic Medicine / Biobanks / Biological activity / Biological Specimen Banks / Body mass index / Cancer / Cell cycle / Chromosome Segregation - genetics / Chromosomes / Chromosomes, Human, X - genetics / Chromosomes, Human, Y - genetics / Clone Cells - metabolism / Clone Cells - pathology / Cloning / Disease / Exome - genetics / F-Box Proteins - genetics / Female / Females / Genetic analysis / Genetic Predisposition to Disease - genetics / Genomes / Germ-Line Mutation / Humanities and Social Sciences / Humans / Leukemia / Leukemia - genetics / Leukocytes / Leukocytes - metabolism / Male / Medical and Health Sciences / Medical Genetics and Genomics (including Gene Therapy) / Medical screening / Medicin och hälsovetenskap / Medicinsk genetik och genomik (Här ingår: Genterapi) / Medicinska och farmaceutiska grundvetenskaper / Middle Aged / Models, Genetic / Mosaicism / multidisciplinary / Multifactorial Inheritance - genetics / Mutation, Missense - genetics / Risk analysis / Science / Science (multidisciplinary) / Sex chromosomes / X chromosomes / Y chromosomes