Heterogeneous polymerase fidelity and mismatch repair bias genome variation and composition.
Heterogeneous polymerase fidelity and mismatch repair bias genome variation and composition.
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DOI：
10.1101/gr.178335.114
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发表时间：
2014-11
期刊：
影响因子：
7
通讯作者：
Kunkel TA
中科院分区：
文献类型：
--
作者：
Lujan SA;Clausen AR;Clark AB;MacAlpine HK;MacAlpine DM;Malc EP;Mieczkowski PA;Burkholder AB;Fargo DC;Gordenin DA;Kunkel TA
在重建进化史、校准分子钟和预测基因与疾病之间的联系时，必须考虑突变异质性。选择压力和各种DNA交易被用来解释物种之间、种群内和组织特异性肿瘤中遗传变异的异质性分布。为了研究这种异质性与前导链和滞后链复制保真度和错配修复的变化之间的关系，我们在没有选择压力的情况下在8个二倍体酵母菌株中积累了40，000个自发突变。我们发现，复制酶的错误率不同叉方向，编码状态，核小体接近，和序列上下文。此外，错误率和DNA错配修复效率都因错配类型、负责的聚合酶、复制时间和复制起点接近度而异。突变模式暗示复制不忠是体细胞和种系进化中变异的一个驱动因素，表明基因组稳定性和组成的相互调节机制，并预测未来在特定癌症中的观察结果。
Mutational heterogeneity must be taken into account when reconstructing evolutionary histories, calibrating molecular clocks, and predicting links between genes and disease. Selective pressures and various DNA transactions have been invoked to explain the heterogeneous distribution of genetic variation between species, within populations, and in tissue-specific tumors. To examine relationships between such heterogeneity and variations in leading- and lagging-strand replication fidelity and mismatch repair, we accumulated 40,000 spontaneous mutations in eight diploid yeast strains in the absence of selective pressure. We found that replicase error rates vary by fork direction, coding state, nucleosome proximity, and sequence context. Further, error rates and DNA mismatch repair efficiency both vary by mismatch type, responsible polymerase, replication time, and replication origin proximity. Mutation patterns implicate replication infidelity as one driver of variation in somatic and germline evolution, suggest mechanisms of mutual modulation of genome stability and composition, and predict future observations in specific cancers.
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影响因子：
64.8
作者：
通讯作者：
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影响因子：
4.3
作者：
Kenigsberg, Ephraim;Bar, Amir;Tanay, Amos
通讯作者：
Tanay, Amos
影响因子：
2
作者：
Gierlik, A;Kowalczuk, M;Cebrat, S
通讯作者：
Cebrat, S
影响因子：
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通讯作者：
Tomlinson IP
影响因子：
14.9
作者：
Fortune JM;Stith CM;Kissling GE;Burgers PM;Kunkel TA
通讯作者：
Kunkel TA