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差异性DNA不匹配修复是人类基因组中突变率变化的基础

Fran Supek¹, Ben Lehner²

¹1] EMBL-CRG Systems Biology Unit, Centre for Genomic Regulation (CRG), 08003 Barcelona, Spain [2] Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain [3] Division of Electronics, Rudjer Boskovic Institute, 10000 Zagreb, Croatia.

|February 25, 2015

概括

癌症基因组研究表明,突变率因DNA区域而异. 可变DNA不匹配修复 (MMR) 解释了这一点,而不是突变供应的差异,影响了癌症基因组进化.

科学领域:

基因组学就是基因组学.
癌症生物学癌症生物学
分子遗传学分子遗传学

背景情况:

人体突变率在人类基因组中表现出显著的区域差异.
在迟复制的异性染色体中观察到高的突变率,而在早期复制的欧性染色体中观察到较低的突变率.
驱动这种大规模突变率异质性的潜在机制在很大程度上是未知的.

研究的目的:

研究人类基因组突变率区域差异背后的因果机制.
确定差异性DNA修复或差异性突变供应是否对突变率异质性负责.
确定导致基因组区域间突变率差异的特定分子过程.

主要方法:

从652个人类瘤的基因组中分析了大约1700万个单核酸变异.
检查与复制时间和基因表达相关的突变模式.
在DNA不匹配修复 (MMR) 失活之前和之后,晚期与早期复制区域的突变丰富的比较.

主要成果:

大基底分辨率的区域性自体突变率在癌症类型中通常是稳定的.
突变速率的变化与复制时间和基因表达的变化相关.
在MMR无活化后,突变不再以晚复制的异性染色素相比早期复制的欧性染色素优先丰富.

结论:

可变DNA不匹配修复 (MMR) 是人类基因组中大规模区域突变率变化的主要驱动因素.
差异性DNA修复,而不是差异性突变供应,解释了突变率异质性.
了解MMR的作用对于理解癌症基因组进化和开发向疗法至关重要.

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