Genetic drivers and cellular selection of female mosaic X chromosome loss

被引：13

作者：

Liu, Aoxing ^{[1
,2
,3
,4
,5
]}

Genovese, Giulio ^{[4
,5
,6
]}

Zhao, Yajie ^{[7
]}

Pirinen, Matti ^{[1
,8
,9
]}

Zekavat, Seyedeh M. ^{[4
,10
,11
]}

Kentistou, Katherine A. ^{[7
]}

Yang, Zhiyu ^{[1
]}

Yu, Kai ^{[12
]}

Vlasschaert, Caitlyn ^{[13
]}

Liu, Xiaoxi ^{[14
]}

Brown, Derek W. ^{[12
,15
]}

Hudjashov, Georgi ^{[16
]}

Gorman, Bryan R. ^{[17
,18
]}

Dennis, Joe ^{[19
]}

Zhou, Weiyin ^{[12
,20
]}

Momozawa, Yukihide ^{[21
]}

Pyarajan, Saiju ^{[17
,22
]}

Tuzov, Valdislav ^{[16
]}

Pajuste, Fanny-Dhelia ^{[16
,23
]}

Aavikko, Mervi ^{[1
]}

Sipila, Timo P. ^{[1
]}

Ghazal, Awaisa ^{[1
]}

Huang, Wen-Yi ^{[12
]}

Freedman, Neal D. ^{[12
]}

Song, Lei ^{[12
]}

Gardner, Eugene J. ^{[7
]}

Sankaran, Vijay G. ^{[4
,24
,25
]}

Palotie, Aarno ^{[1
,2
,4
,5
]}

Ollila, Hanna M. ^{[1
,3
,4
,26
]}

Tukiainen, Taru ^{[1
]}

Chanock, Stephen J. ^{[12
]}

Magi, Reedik ^{[16
]}

Natarajan, Pradeep ^{[3
,4
,10
]}

Daly, Mark J. ^{[1
,2
,3
,4
,5
]}

Bick, Alexander ^{[27
]}

McCarroll, Steven A. ^{[4
,5
,6
]}

Terao, Chikashi ^{[14
,28
,29
]}

Loh, Po-Ru ^{[4
,22
,30
]}

Ganna, Andrea ^{[1
,2
,4
,5
]}

Perry, John R. B. ^{[7
]}

Machiela, Mitchell J. ^{[12
]}

Metspalu, Andres ^{[16
]}

Esko, Tonu ^{[16
]}

Nelis, Mari ^{[16
]}

Milani, Lili ^{[16
]}

Ahearn, Thomas U. ^{[12
]}

Andrulis, Irene L. ^{[31
,32
]}

Anton-Culver, Hoda ^{[33
]}

Antoniou, Antonis C. ^{[19
]}

de Gonzalez, Amy Berrington ^{[34
]}

机构：

[1] Univ Helsinki, Inst Mol Med Finland FIMM, HiLIFE, Helsinki, Finland

[2] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[3] Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA

[4] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA

[5] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA

[6] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA

[7] Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England

[8] Univ Helsinki, Dept Publ Hlth, Helsinki, Finland

[9] Univ Helsinki, Dept Math & Stat, Helsinki, Finland

[10] Massachusetts Gen Hosp, Res Ctr, Boston, MA 02114 USA

[11] Harvard Med Sch, Massachusetts Eye & Ear, Dept Ophthalmol, Boston, MA 02115 USA

[12] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA

[13] Queens Univ, Dept Med, Kingston, ON, Canada

[14] RIKEN Ctr Integrat Med Sci, Lab Stat & Translat Genet, Yokohama, Kanagawa, Japan

[15] NCI, Canc Prevent Fellowship Program, Div Canc Prevent, Rockville, MD USA

[16] Univ Tartu, Inst Genom, Estonian Genome Ctr, Tartu, Estonia

[17] VA Boston Healthcare Syst, VA Cooperat Studies Program, Ctr Data & Computat Sci C DACS, Boston, MA USA

[18] Booz Allen Hamilton, Mclean, VA USA

[19] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England

[20] Frederick Natl Lab Canc Res, Canc Genom Res Lab, Frederick, MD USA

[21] RIKEN Ctr Integrat Med Sci, Lab Genotyping Dev, Yokohama, Kanagawa, Japan

[22] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA

[23] Univ Tartu, Inst Mol & Cell Biol, Tartu, Estonia

[24] Harvard Med Sch, Div Hematol Oncol, Boston Childrens Hosp, Boston, MA 02115 USA

[25] Harvard Med Sch, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[26] Massachusetts Gen Hosp, Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA

[27] Vanderbilt Univ, Med Ctr, Dept Med, Div Genet Med, Nashville, TN USA

[28] Shizuoka Prefectural Gen Hosp, Clin Res Ctr, Shizuoka, Japan

[29] Univ Shizuoka, Sch Pharmaceut Sci, Dept Appl Genet, Shizuoka, Japan

[30] Harvard Med Sch, Brigham & Womens Hosp, Ctr Data Sci, Boston, MA 02115 USA

[31] Mt Sinai Hosp, Fred A Litwin Ctr Canc Genet, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada

[32] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada

[33] Univ Calif Irvine, Dept Med, Genet Epidemiol Res Inst, Irvine, CA 92717 USA

[34] Inst Canc Res, Div Genet & Epidemiol, London, England

[35] Hannover Med Sch, Dept Radiat Oncol, Hannover, Germany

[36] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany

[37] NN Alexandrov Res Inst Oncol & Med Radiol, Minsk, BELARUS

[38] Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Copenhagen Gen Populat Study, Herlev, Denmark

[39] Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Clin Biochem, Herlev, Denmark

[40] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark

[41] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany

[42] German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany

[43] Natl Ctr Tumor Dis NCT, Heidelberg, Germany

[44] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany

[45] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany

[46] Univ Med Ctr Hamburg Eppendorf, Univ Canc Ctr Hamburg UCCH, Canc Epidemiol Grp, Hamburg, Germany

[47] QIMR Berghofer Med Res Inst, Canc Div, Brisbane, Qld, Australia

[48] Univ Utah, Dept Internal Med, Salt Lake City, UT 84112 USA

[49] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT 84112 USA

[50] City Hope Natl Med Ctr, City Hope Comprehens Canc Ctr, Duarte, CA USA

来源：

NATURE | 2024年 / 631卷 / 8019期

基金：

英国医学研究理事会; 芬兰科学院; 欧洲研究理事会; 日本学术振兴会;

关键词：

INACTIVATION; ASSOCIATION; LANDSCAPE; SURVIVAL; BIOBANK; REGION; COMMON; BLOOD; RISK;

D O I：

10.1038/s41586-024-07533-7

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：134 / +

页数：24

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