Arndt Peter F, Burge Christopher B, Hwa Terence
Department of Physics, University of California at San Diego, La Jolla, CA 92093, USA.
J Comput Biol. 2003;10(3-4):313-22. doi: 10.1089/10665270360688039.
We introduce a model of DNA sequence evolution which can account for biases in mutation rates that depend on the identity of the neighboring bases. An analytic solution for this class of models is developed by adopting well-known methods of nonlinear dynamics. Results are presented for the CpG-methylation-deamination process, which dominates point substitutions in vertebrates. The dinucleotide frequencies generated by the model (using empirically obtained mutation rates) match the overall pattern observed in noncoding DNA. A web-based tool has been constructed to compute single- and dinucleotide frequencies for arbitrary neighbor-dependent mutation rates. Also provided is the backward procedure to infer the mutation rates using maximum likelihood analysis given the observed single- and dinucleotide frequencies. Reasonable estimates of the mutation rates can be obtained very efficiently, using generic noncoding DNA sequences as input, after masking out long homonucleotide subsequences. Our method is much more convenient and versatile to use than the traditional method of deducing mutation rates by counting mutation events in carefully chosen sequences. More generally, our approach provides a more realistic but still tractable description of noncoding genomic DNA and may be used as a null model for various sequence analysis applications.
我们引入了一种DNA序列进化模型，该模型可以解释取决于相邻碱基身份的突变率偏差。通过采用著名的非线性动力学方法，开发了此类模型的解析解。给出了CpG甲基化-脱氨过程的结果，该过程在脊椎动物的点突变中占主导地位。模型生成的二核苷酸频率（使用经验获得的突变率）与非编码DNA中观察到的总体模式相匹配。已构建了一个基于网络的工具，用于计算任意邻域依赖突变率的单核苷酸和二核苷酸频率。还提供了反向程序，以便在给定观察到的单核苷酸和二核苷酸频率的情况下，使用最大似然分析来推断突变率。在屏蔽掉长的同核苷酸子序列后，使用通用的非编码DNA序列作为输入，可以非常有效地获得突变率的合理估计。我们的方法比通过在精心选择的序列中计数突变事件来推导突变率的传统方法更方便、更通用。更一般地说，我们的方法为非编码基因组DNA提供了更现实但仍易于处理的描述，并且可以用作各种序列分析应用的零模型。
