Genetic drivers and cellular selection of female mosaic X chromosome loss.
СтатьяПоддержка исследования: вне правительства СШАResearch Support, N.I.H., IntramuralНазвание и аннотация: Перевод в очереди
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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, FinnGen, Estonian Biobank Research Team, Breast Cancer Association Consortium, Million Veteran Program, 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
Аннотация
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.