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研究揭示单基因和多基因遗传在克隆选择过程中的作用
2020-06-28 13:46

美国麻省理工学院和哈佛大学广泛研究所Steven A. McCarroll、Giulio Genovese和哈佛医学院Po-Ru Loh团队合作取得一项新突破。他们的最新研究提出了单基因和多基因遗传成为克隆选择的工具。该项研究成果在线发表在2020年6月24日的《自然》上。

为了鉴定赋予突变克隆选择性优势的基因、突变和生物学过程,研究人员分析了来自英国生物库482,789名参与者血液DNA的基因分型数据。研究人员鉴定了19,632个常染色体镶嵌染色体突变,并分析了这些突变与遗传变异的关系。研究人员在7个基因中发现了52个遗传性、罕见有效的编码或剪接变体,这些变体增加了具有特定获得性复制中性丧失(CN-LOH)突变细胞克隆性造血功能的脆弱性。

在MPL处,获得性突变系统性地取代了其风险等位基因或将其复制到同源染色体上(在FH、NBN、MRE11、ATM、SH2B3和TM2D3处)。其中三个基因(MRE11、NBN和ATM)编码MRN–ATM途径的组分,从而限制了DNA损伤和端粒损伤后的细胞分裂。另外两个基因(MPL和SH2B3)编码调节干细胞自我更新的蛋白质。

此外,研究人员发现整个基因组中CN-LOH突变往往会导致等位基因染色体片段化,这些等位基因促进造血细胞的扩增,以取代其同源(等位基因)对应物,从而增加了对血细胞增殖性状的多基因驱动。用其同源对应物替代染色体片段这种易得突变似乎与普遍遗传变异相互作用,从而对终身细胞生成产生了挑战。

据悉,随着年龄的增长,通常人体会产生含有体细胞突变(克隆性造血)的克隆扩增血细胞,这增加了患血液癌的风险。迄今为止,鉴定出的血液克隆在所有染色体上均包含多种多样的镶嵌染色体改变(杂合性缺失、重复和CN-LOH),但促使大多数克隆扩展选择性优势的来源仍然未知。

附:英文原文

Title: Monogenic and polygenic inheritance become instruments for clonal selection

Author: Po-Ru Loh, Giulio Genovese, Steven A. McCarroll

Issue&Volume: 2020-06-24

Abstract: Clonally expanded blood cells that contain somatic mutations (clonal haematopoiesis) are commonly acquired with age and increase the risk of blood cancer1,2,3,4,5,6,7,8,9. The blood clones identified so far contain diverse large-scale mosaic chromosomal alterations (deletions, duplications and copy-neutral loss of heterozygosity (CN-LOH)) on all chromosomes1,2,5,6,9, but the sources of selective advantage that drive the expansion of most clones remain unknown. Here, to identify genes, mutations and biological processes that give selective advantage to mutant clones, we analysed genotyping data from the blood-derived DNA of 482,789 participants from the UK Biobank10. We identified 19,632 autosomal mosaic chromosomal alterations and analysed these for relationships to inherited genetic variation. We found 52 inherited, rare, large-effect coding or splice variants in 7 genes that were associated with greatly increased vulnerability to clonal haematopoiesis with specific acquired CN-LOH mutations. Acquired mutations systematically replaced the inherited risk alleles (at MPL) or duplicated them to the homologous chromosome (at FH, NBN, MRE11, ATM, SH2B3 and TM2D3). Three of the genes (MRE11, NBN and ATM) encode components of the MRN–ATM pathway, which limits cell division after DNA damage and telomere attrition11,12,13; another two (MPL and SH2B3) encode proteins that regulate the self-renewal of stem cells14,15,16. In addition, we found that CN-LOH mutations across the genome tended to cause chromosomal segments with alleles that promote the expansion of haematopoietic cells to replace their homologous (allelic) counterparts, increasing polygenic drive for blood-cell proliferation traits. Readily acquired mutations that replace chromosomal segments with their homologous counterparts seem to interact with pervasive inherited variation to create a challenge for lifelong cytopoiesis.

DOI: 10.1038/s41586-020-2430-6

Source: https://www.nature.com/articles/s41586-020-2430-6

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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