Non-B DNA: a major contributor to small- and large-scale variation in nucleotide substitution frequencies across the genome.
Non-B DNA: a major contributor to small- and large-scale variation in nucleotide substitution frequencies across the genome.
复制标题
DOI：
10.1093/nar/gkaa1269
复制
发表时间：
2021-02-22
影响因子：
14.9
通讯作者：
Makova KD
中科院分区：
文献类型：
--
作者：
Guiblet WM;Cremona MA;Harris RS;Chen D;Eckert KA;Chiaromonte F;Huang YF;Makova KD
大约13%的人类基因组可以折叠成非规范（非B）DNA结构（例如G-quadruplex、Z-DNA等），与重要的细胞过程有关。非B DNA也会阻碍复制，增加错误并促进诱变，但其对全基因组突变率变化的贡献仍未得到研究。在这里，我们进行了一个全面的分析，在非编码，非重复的基因组区域，其±2 kb侧翼区，和1兆碱基窗口内的非B DNA基因座的核苷酸取代频率，使用人类-猩猩分歧和人类单核苷酸多态性。单碱基分辨率下的功能数据分析表明，非B DNA的取代频率通常会升高，并具有特定于每种非B DNA类型的模式。镜像，直接和反向重复有较高的取代频率间隔比重复臂，而G-四链体，特别是稳定的，有较高的取代频率在环比茎。几种非B DNA类型也影响其侧翼区域的取代频率。最后，在多元回归模型中，非B DNA比任何其他预测因子都能解释1兆尺度的多样性或分歧。因此，非B DNA在很大程度上有助于在小规模和大规模的取代频率的变化。我们的研究结果强调了非B DNA在种系突变中的作用，并对进化和遗传疾病产生了影响。Guiblet等人表明，能够形成非典型（非B）DNA结构的基因座是整个基因组核苷酸取代水平变化的主要驱动因素。图像来源：Wilfried Guiblet
Approximately 13% of the human genome can fold into non-canonical (non-B) DNA structures (e.g. G-quadruplexes, Z-DNA, etc.), which have been implicated in vital cellular processes. Non-B DNA also hinders replication, increasing errors and facilitating mutagenesis, yet its contribution to genome-wide variation in mutation rates remains unexplored. Here, we conducted a comprehensive analysis of nucleotide substitution frequencies at non-B DNA loci within noncoding, non-repetitive genome regions, their ±2 kb flanking regions, and 1-Megabase windows, using human-orangutan divergence and human single-nucleotide polymorphisms. Functional data analysis at single-base resolution demonstrated that substitution frequencies are usually elevated at non-B DNA, with patterns specific to each non-B DNA type. Mirror, direct and inverted repeats have higher substitution frequencies in spacers than in repeat arms, whereas G-quadruplexes, particularly stable ones, have higher substitution frequencies in loops than in stems. Several non-B DNA types also affect substitution frequencies in their flanking regions. Finally, non-B DNA explains more variation than any other predictor in multiple regression models for diversity or divergence at 1-Megabase scale. Thus, non-B DNA substantially contributes to variation in substitution frequencies at small and large scales. Our results highlight the role of non-B DNA in germline mutagenesis with implications to evolution and genetic diseases. Guiblet et al. show that loci capable of forming non-canonical (non-B) DNA structures are a major driver of variation in nucleotide substitution levels across the genome. Image credit: Wilfried Guiblet.
登录
查看更多内容
DOI：
10.1038/nrg3296
发表时间：
2012-11
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.9
作者：
Cooper, David N.;Bacolla, Albino;Ferec, Claude;Vasquez, Karen M.;Kehrer-Sawatzki, Hildegard;Chen, Jian-Min
通讯作者：
Chen, Jian-Min
DOI：
10.1073/pnas.1900714116
发表时间：
2019-09-03
影响因子：
11.1
作者：
Agarwal, Ipsita;Przeworski, Molly
通讯作者：
Przeworski, Molly
影响因子：
14.9
作者：
Bacolla A;Zhu X;Chen H;Howells K;Cooper DN;Vasquez KM
通讯作者：
Vasquez KM
影响因子：
46.9
作者：
Chambers, Vicki S.;Marsico, Giovanni;Balasubramanian, Shankar
通讯作者：
Balasubramanian, Shankar