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Population analyses of mosaic X chromosome loss identify genetic drivers and widespread signatures of cellular selection

Mosaic loss of the X chromosome (mLOX) is the most commonly occurring clonal somatic alteration detected in the leukocytes of women, yet little is known about its genetic determinants or phenotypic consequences. To address this, we estimated mLOX in >900,000 women across eight biobanks, identifyi...

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Autores principales: Liu, Aoxing, Genovese, Giulio, Zhao, Yajie, Pirinen, Matti, Zekavat, Maryam M., Kentistou, Katherine, Yang, Zhiyu, Yu, Kai, Vlasschaert, Caitlyn, Liu, Xiaoxi, Brown, Derek W., Hudjashov, Georgi, Gorman, Bryan, Dennis, Joe, Zhou, Weiyin, Momozawa, Yukihide, Pyarajan, Saiju, Tuzov, Vlad, Pajuste, Fanny-Dhelia, Aavikko, Mervi, Sipilä, Timo P., Ghazal, Awaisa, Huang, Wen-Yi, Freedman, Neal, Song, Lei, Gardner, Eugene J., 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9915812/
https://www.ncbi.nlm.nih.gov/pubmed/36778285
http://dx.doi.org/10.1101/2023.01.28.23285140
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author Liu, Aoxing
Genovese, Giulio
Zhao, Yajie
Pirinen, Matti
Zekavat, Maryam M.
Kentistou, Katherine
Yang, Zhiyu
Yu, Kai
Vlasschaert, Caitlyn
Liu, Xiaoxi
Brown, Derek W.
Hudjashov, Georgi
Gorman, Bryan
Dennis, Joe
Zhou, Weiyin
Momozawa, Yukihide
Pyarajan, Saiju
Tuzov, Vlad
Pajuste, Fanny-Dhelia
Aavikko, Mervi
Sipilä, Timo P.
Ghazal, Awaisa
Huang, Wen-Yi
Freedman, Neal
Song, Lei
Gardner, Eugene J.
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.
author_facet Liu, Aoxing
Genovese, Giulio
Zhao, Yajie
Pirinen, Matti
Zekavat, Maryam M.
Kentistou, Katherine
Yang, Zhiyu
Yu, Kai
Vlasschaert, Caitlyn
Liu, Xiaoxi
Brown, Derek W.
Hudjashov, Georgi
Gorman, Bryan
Dennis, Joe
Zhou, Weiyin
Momozawa, Yukihide
Pyarajan, Saiju
Tuzov, Vlad
Pajuste, Fanny-Dhelia
Aavikko, Mervi
Sipilä, Timo P.
Ghazal, Awaisa
Huang, Wen-Yi
Freedman, Neal
Song, Lei
Gardner, Eugene J.
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.
author_sort Liu, Aoxing
collection PubMed
description Mosaic loss of the X chromosome (mLOX) is the most commonly occurring clonal somatic alteration detected in the leukocytes of women, yet little is known about its genetic determinants or phenotypic consequences. To address this, we estimated mLOX in >900,000 women across eight biobanks, identifying 10% of women with detectable X loss in approximately 2% of their leukocytes. Out of 1,253 diseases examined, women with mLOX had an elevated risk of myeloid and lymphoid leukemias and pneumonia. Genetic analyses identified 49 common variants influencing mLOX, implicating genes with established roles in chromosomal missegregation, cancer predisposition, and autoimmune diseases. Complementary exome-sequence analyses identified rare missense variants in FBXO10 which confer a two-fold increased risk of mLOX. A small fraction of these associations were shared with mosaic Y chromosome loss in men, suggesting different biological processes drive the formation and clonal expansion of sex chromosome missegregation events. Allelic shift analyses identified alleles on the X chromosome which are preferentially retained, demonstrating that variation at many loci across the X chromosome is under cellular selection. A novel polygenic score including 44 independent X chromosome allelic shift loci correctly inferred the retained X chromosomes in 80.7% of mLOX cases in the top decile. Collectively our results support a model where germline variants predispose women to acquiring mLOX, with the allelic content of the X chromosome possibly shaping the magnitude of subsequent clonal expansion.
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spelling pubmed-99158122023-02-11 Population analyses of mosaic X chromosome loss identify genetic drivers and widespread signatures of cellular selection Liu, Aoxing Genovese, Giulio Zhao, Yajie Pirinen, Matti Zekavat, Maryam M. Kentistou, Katherine Yang, Zhiyu Yu, Kai Vlasschaert, Caitlyn Liu, Xiaoxi Brown, Derek W. Hudjashov, Georgi Gorman, Bryan Dennis, Joe Zhou, Weiyin Momozawa, Yukihide Pyarajan, Saiju Tuzov, Vlad Pajuste, Fanny-Dhelia Aavikko, Mervi Sipilä, Timo P. Ghazal, Awaisa Huang, Wen-Yi Freedman, Neal Song, Lei Gardner, Eugene J. 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. medRxiv Article Mosaic loss of the X chromosome (mLOX) is the most commonly occurring clonal somatic alteration detected in the leukocytes of women, yet little is known about its genetic determinants or phenotypic consequences. To address this, we estimated mLOX in >900,000 women across eight biobanks, identifying 10% of women with detectable X loss in approximately 2% of their leukocytes. Out of 1,253 diseases examined, women with mLOX had an elevated risk of myeloid and lymphoid leukemias and pneumonia. Genetic analyses identified 49 common variants influencing mLOX, implicating genes with established roles in chromosomal missegregation, cancer predisposition, and autoimmune diseases. Complementary exome-sequence analyses identified rare missense variants in FBXO10 which confer a two-fold increased risk of mLOX. A small fraction of these associations were shared with mosaic Y chromosome loss in men, suggesting different biological processes drive the formation and clonal expansion of sex chromosome missegregation events. Allelic shift analyses identified alleles on the X chromosome which are preferentially retained, demonstrating that variation at many loci across the X chromosome is under cellular selection. A novel polygenic score including 44 independent X chromosome allelic shift loci correctly inferred the retained X chromosomes in 80.7% of mLOX cases in the top decile. Collectively our results support a model where germline variants predispose women to acquiring mLOX, with the allelic content of the X chromosome possibly shaping the magnitude of subsequent clonal expansion. Cold Spring Harbor Laboratory 2023-01-31 /pmc/articles/PMC9915812/ /pubmed/36778285 http://dx.doi.org/10.1101/2023.01.28.23285140 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Liu, Aoxing
Genovese, Giulio
Zhao, Yajie
Pirinen, Matti
Zekavat, Maryam M.
Kentistou, Katherine
Yang, Zhiyu
Yu, Kai
Vlasschaert, Caitlyn
Liu, Xiaoxi
Brown, Derek W.
Hudjashov, Georgi
Gorman, Bryan
Dennis, Joe
Zhou, Weiyin
Momozawa, Yukihide
Pyarajan, Saiju
Tuzov, Vlad
Pajuste, Fanny-Dhelia
Aavikko, Mervi
Sipilä, Timo P.
Ghazal, Awaisa
Huang, Wen-Yi
Freedman, Neal
Song, Lei
Gardner, Eugene J.
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.
Population analyses of mosaic X chromosome loss identify genetic drivers and widespread signatures of cellular selection
title Population analyses of mosaic X chromosome loss identify genetic drivers and widespread signatures of cellular selection
title_full Population analyses of mosaic X chromosome loss identify genetic drivers and widespread signatures of cellular selection
title_fullStr Population analyses of mosaic X chromosome loss identify genetic drivers and widespread signatures of cellular selection
title_full_unstemmed Population analyses of mosaic X chromosome loss identify genetic drivers and widespread signatures of cellular selection
title_short Population analyses of mosaic X chromosome loss identify genetic drivers and widespread signatures of cellular selection
title_sort population analyses of mosaic x chromosome loss identify genetic drivers and widespread signatures of cellular selection
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9915812/
https://www.ncbi.nlm.nih.gov/pubmed/36778285
http://dx.doi.org/10.1101/2023.01.28.23285140
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