@article{5d3ae2197598479087528e2687c4eb95,
title = "Genetic drivers and cellular selection of female mosaic X chromosome loss",
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.",
keywords = "Adult, Female, Humans, Male, Middle Aged, Alleles, Aneuploidy, Autoimmune Diseases/genetics, Biological Specimen Banks, Chromosome Segregation/genetics, Chromosomes, Human, X/genetics, Chromosomes, Human, Y/genetics, Clone Cells/metabolism, Exome/genetics, F-Box Proteins/genetics, Genetic Predisposition to Disease/genetics, Germ-Line Mutation, Leukemia/genetics, Leukocytes/metabolism, Models, Genetic, Mosaicism, Multifactorial Inheritance/genetics, Mutation, Missense/genetics",
author = "Aoxing Liu and Giulio Genovese and Yajie Zhao and Matti Pirinen and Zekavat, {Seyedeh M} and Kentistou, {Katherine A} and Zhiyu Yang and Kai Yu and Caitlyn Vlasschaert and Xiaoxi Liu and Brown, {Derek W} and Georgi Hudjashov and Gorman, {Bryan R} and Joe Dennis and Weiyin Zhou and Yukihide Momozawa and Saiju Pyarajan and Valdislav Tuzov and Fanny-Dhelia Pajuste and Mervi Aavikko and Sipil{\"a}, {Timo P} and Awaisa Ghazal and Wen-Yi Huang and Freedman, {Neal D} and Lei Song and Gardner, {Eugene J} and Sankaran, {Vijay G} and Aarno Palotie and Ollila, {Hanna M} and Taru Tukiainen and Chanock, {Stephen J} and Reedik M{\"a}gi and Pradeep Natarajan and Daly, {Mark J} and Alexander Bick and McCarroll, {Steven A} and Chikashi Terao and Po-Ru Loh and Andrea Ganna and Perry, {John R B} and Machiela, {Mitchell J} and FinnGen and Bojesen, {Stig Egil}",
note = "{\textcopyright} 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",
year = "2024",
month = jul,
doi = "10.1038/s41586-024-07533-7",
language = "English",
volume = "631",
pages = "134--141",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Research",
number = "8019",
}