Polak Paz, Arndt Peter F
Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany.
Genome Res. 2008 Aug;18(8):1216-23. doi: 10.1101/gr.076570.108. Epub 2008 May 7.
A regional analysis of nucleotide substitution rates along human genes and their flanking regions allows us to quantify the effect of mutational mechanisms associated with transcription in germ line cells. Our analysis reveals three distinct patterns of substitution rates. First, a sharp decline in the deamination rate of methylated CpG dinucleotides, which is observed in the vicinity of the 5' end of genes. Second, a strand asymmetry in complementary substitution rates, which extends from the 5' end to 1 kbp downstream from the 3' end, associated with transcription-coupled repair. Finally, a localized strand asymmetry, an excess of C-->T over G-->A substitution in the nontemplate strand confined to the first 1-2 kbp downstream of the 5' end of genes. We hypothesize that higher exposure of the nontemplate strand near the 5' end of genes leads to a higher cytosine deamination rate. Up to now, only the somatic hypermutation (SHM) pathway has been known to mediate localized and strand-specific mutagenic processes associated with transcription in mammalia. The mutational patterns in SHM are induced by cytosine deaminase, which just targets single-stranded DNA. This DNA conformation is induced by R-loops, which preferentially occur at the 5' ends of genes. We predict that R-loops are extensively formed in the beginning of transcribed regions in germ line cells.
对人类基因及其侧翼区域的核苷酸替换率进行区域分析，使我们能够量化与生殖细胞中转录相关的突变机制的影响。我们的分析揭示了三种不同的替换率模式。第一，在基因5'端附近观察到甲基化CpG二核苷酸脱氨率急剧下降。第二，互补替换率的链不对称性，从5'端延伸至3'端下游1 kbp处，与转录偶联修复相关。最后，一种局部链不对称性，即非模板链中C→T替换超过G→A替换，局限于基因5'端下游的前1 - 2 kbp。我们推测基因5'端附近非模板链的更高暴露导致更高的胞嘧啶脱氨率。到目前为止，在哺乳动物中，只有体细胞超突变（SHM）途径已知介导与转录相关的局部和链特异性诱变过程。SHM中的突变模式由胞嘧啶脱氨酶诱导，该酶仅靶向单链DNA。这种DNA构象由R环诱导，R环优先出现在基因的5'端。我们预测R环在生殖细胞转录区域的起始处广泛形成。
