Genetic drivers and cellular selection of female mosaic X chromosome loss

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

doi:10.1038/s41586-024-07533-7

Genetic drivers and cellular selection of female mosaic X chromosome loss

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

Department of Clinical Biochemistry

31 Citations (Scopus)

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.

Original language	English
Journal	Nature
Volume	631
Issue number	8019
Pages (from-to)	134-141
Number of pages	8
ISSN	0028-0836
DOIs	https://doi.org/10.1038/s41586-024-07533-7
Publication status	Published - Jul 2024

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

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10.1038/s41586-024-07533-7

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Liu, A., Genovese, G., Zhao, Y., Pirinen, M., Zekavat, S. M., Kentistou, K. A., Yang, Z., Yu, K., Vlasschaert, C., Liu, X., Brown, D. W., Hudjashov, G., Gorman, B. R., Dennis, J., Zhou, W., Momozawa, Y., Pyarajan, S., Tuzov, V., Pajuste, F.-D., ... FinnGen (2024). Genetic drivers and cellular selection of female mosaic X chromosome loss. Nature, 631(8019), 134-141. https://doi.org/10.1038/s41586-024-07533-7

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, F-D, Aavikko, M, Sipilä, TP, Ghazal, A, Huang, W-Y, Freedman, ND, Song, L, Gardner, EJ, Sankaran, VG, Palotie, A, Ollila, HM, Tukiainen, T, Chanock, SJ, Mägi, R, Natarajan, P, Daly, MJ, Bick, A, McCarroll, SA, Terao, C, Loh, P-R, Ganna, A, Perry, JRB, Machiela, MJ & FinnGen 2024, 'Genetic drivers and cellular selection of female mosaic X chromosome loss', Nature, vol. 631, no. 8019, pp. 134-141. https://doi.org/10.1038/s41586-024-07533-7

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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.",

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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 Bojesen, \{Stig Egil\} and FinnGen",

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",

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number = "8019",

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TY - JOUR

T1 - Genetic drivers and cellular selection of female mosaic X chromosome loss

AU - Liu, Aoxing

AU - Genovese, Giulio

AU - Zhao, Yajie

AU - Pirinen, Matti

AU - Zekavat, Seyedeh M

AU - Kentistou, Katherine A

AU - Yang, Zhiyu

AU - Yu, Kai

AU - Vlasschaert, Caitlyn

AU - Liu, Xiaoxi

AU - Brown, Derek W

AU - Hudjashov, Georgi

AU - Gorman, Bryan R

AU - Dennis, Joe

AU - Zhou, Weiyin

AU - Momozawa, Yukihide

AU - Pyarajan, Saiju

AU - Tuzov, Valdislav

AU - Pajuste, Fanny-Dhelia

AU - Aavikko, Mervi

AU - Sipilä, Timo P

AU - Ghazal, Awaisa

AU - Huang, Wen-Yi

AU - Freedman, Neal D

AU - Song, Lei

AU - Gardner, Eugene J

AU - Sankaran, Vijay G

AU - Palotie, Aarno

AU - Ollila, Hanna M

AU - Tukiainen, Taru

AU - Chanock, Stephen J

AU - Mägi, Reedik

AU - Natarajan, Pradeep

AU - Daly, Mark J

AU - Bick, Alexander

AU - McCarroll, Steven A

AU - Terao, Chikashi

AU - Loh, Po-Ru

AU - Ganna, Andrea

AU - Perry, John R B

AU - Machiela, Mitchell J

AU - FinnGen

A2 - Bojesen, Stig Egil

PY - 2024/7

Y1 - 2024/7

N2 - 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.

AB - 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.

KW - Adult

KW - Female

KW - Humans

KW - Male

KW - Middle Aged

KW - Alleles

KW - Aneuploidy

KW - Autoimmune Diseases/genetics

KW - Biological Specimen Banks

KW - Chromosome Segregation/genetics

KW - Chromosomes, Human, X/genetics

KW - Chromosomes, Human, Y/genetics

KW - Clone Cells/metabolism

KW - Exome/genetics

KW - F-Box Proteins/genetics

KW - Genetic Predisposition to Disease/genetics

KW - Germ-Line Mutation

KW - Leukemia/genetics

KW - Leukocytes/metabolism

KW - Models, Genetic

KW - Mosaicism

KW - Multifactorial Inheritance/genetics

KW - Mutation, Missense/genetics

UR - https://www.scopus.com/pages/publications/85197973294

UR - https://www.nature.com/articles/s41586-024-08215-0

U2 - 10.1038/s41586-024-07533-7

DO - 10.1038/s41586-024-07533-7

M3 - Journal article

C2 - 38867047

SN - 0028-0836

VL - 631

SP - 134

EP - 141

JO - Nature

JF - Nature

IS - 8019

ER -

Genetic drivers and cellular selection of female mosaic X chromosome loss

Abstract

Keywords

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