Contrasting Determinants of Mutation Rates in Germline and Soma.
Contrasting Determinants of Mutation Rates in Germline and Soma.
复制标题
DOI：
10.1534/genetics.117.1114
复制
发表时间：
2017-09
期刊：
影响因子：
3.3
通讯作者：
Przeworski M
中科院分区：
文献类型：
--
作者：
Chen C;Qi H;Shen Y;Pickrell J;Przeworski M
许多基因组特征影响胚系和胞体的区域突变率。为了检验某些因素在这两种组织中的表现是否不同。最近对体细胞和胚系突变的研究发现了许多影响点突变的因素，包括CpG甲基化、表达水平、复制时间和GC含量。有趣的是，SOMA和生殖系之间的一些影响似乎不同：特别是，尽管有报道称突变率随着肿瘤中表达水平的降低而下降，但在生殖系中尚未检测到明显的影响。然而，他们采取了不同的方法来分析数据，因此很难知道这些明显的差异是否真实存在。为了进行更清晰的比较，我们考虑了一个统计模型，其中编码区的突变率是通过GC含量、表达水平、复制时间和两个组蛋白抑制标记来预测的。我们将这一模型应用于一组在外显体中发现的胚系突变和四种类型肿瘤中的外显子体细胞突变。突变的大多数决定因素是共同的：值得注意的是，我们检测到表达水平对生殖系和体细胞突变率的影响。此外，在所有被考虑的组织中，高表达水平与更大的突变链不对称性相关。然而，突变率随着睾丸(更暂时的是卵巢)表达水平的增加而增加，而在体细胞组织中随着表达水平的降低而降低。这种对比表明，在胞体和生殖系转录过程中，损伤或修复率存在差异。
A number of genomic features influence regional mutation rates in germline and soma. To examine if some factors behave differently in the two tissue... Recent studies of somatic and germline mutations have led to the identification of a number of factors that influence point mutation rates, including CpG methylation, expression levels, replication timing, and GC content. Intriguingly, some of the effects appear to differ between soma and germline: in particular, whereas mutation rates have been reported to decrease with expression levels in tumors, no clear effect has been detected in the germline. Distinct approaches were taken to analyze the data, however, so it is hard to know whether these apparent differences are real. To enable a cleaner comparison, we considered a statistical model in which the mutation rate of a coding region is predicted by GC content, expression levels, replication timing, and two histone repressive marks. We applied this model to both a set of germline mutations identified in exomes and to exonic somatic mutations in four types of tumors. Most determinants of mutations are shared: notably, we detected an effect of expression levels on both germline and somatic mutation rates. Moreover, in all tissues considered, higher expression levels are associated with greater strand asymmetry of mutations. However, mutation rates increase with expression levels in testis (and, more tentatively, in ovary), whereas they decrease with expression levels in somatic tissues. This contrast points to differences in damage or repair rates during transcription in soma and germline.