美国国立癌症研究所Mitchell J. Machiela等研究人员合作揭示女性嵌合X染色体缺失的遗传驱动因素和细胞选择。2024年6月12日，《自然》杂志在线发表了这项成果。

研究人员表示，X染色体嵌合缺失（mLOX）是女性白细胞中最常见的克隆性体细胞改变，但人们对其遗传决定因素或表型后果知之甚少。

为了解决这个问题，研究人员使用了来自8个生物库的883574名女性参与者的数据；其中12%的参与者在约2%的白细胞中检测到了mLOX。患有mLOX的女性参试者罹患骨髓性和淋巴性白血病的风险增加。基因分析发现了56个与mLOX相关的常见变异基因，这些基因与染色体错误分离、癌症易感性和自身免疫性疾病有关。外显子序列分析发现了FBXO10中罕见的错义变异，这些变异使罹患mLOX的风险增加了两倍。只有一小部分关联与嵌合Y染色体缺失相同，这表明性染色体错配的形成和克隆扩增是由不同的生物过程驱动的。

等位基因位移分析确定了在mLOX中优先保留的X染色体等位基因，表明许多位点在细胞选择下发生了变异。包括44个等位基因位点在内的多基因评分正确推断出80.7%的mLOX病例中保留的X染色体位于前十分之一。这些研究结果支持这样一种模式，即生殖系变异使女性个体易患mLOX，而X染色体的等位基因含量可能会影响克隆扩增的程度。

附：英文原文

Title: Genetic drivers and cellular selection of female mosaic X chromosome loss

Author: 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, Sipil, Timo P., Ghazal, Awaisa, Huang, Wen-Yi, Freedman, Neal D., Song, Lei, Gardner, Eugene J., Sankaran, Vijay G., Palotie, Aarno, Ollila, Hanna M., Tukiainen, Taru, Chanock, Stephen J., Mgi, 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.

Issue&Volume: 2024-06-12

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. A large-scale meta-analysis across eight biobank datasets identifies common genetic variants associated with mosaic loss of the X chromosome in female participants.

DOI: 10.1038/s41586-024-07533-7

Source: https://www.nature.com/articles/s41586-024-07533-7