Local DNA dynamics shape mutational patterns of mononucleotide repeats in human genomes.
Local DNA dynamics shape mutational patterns of mononucleotide repeats in human genomes.
复制标题
局部DNA动力学塑造人类基因组中单核苷酸重复序列的突变模式。
DOI：
10.1093/nar/gkv364
复制
发表时间：
2015-05-26
影响因子：
14.9
通讯作者：
Vasquez KM
中科院分区：
文献类型：
--
作者：
Bacolla A;Zhu X;Chen H;Howells K;Cooper DN;Vasquez KM
单碱基替换（SBS）和插入/缺失对于产生群体多样性至关重要，并且可能导致遗传性疾病和癌症。虽然在全基因组范围内，SBS受细胞因子的影响，但在精细尺度上，SBS受局部DNA序列背景的影响，尽管侧翼序列的作用通常不清楚。在此，我们使用生物信息学，分子动力学和混合量子力学/分子力学分析序列上下文依赖的诱变在monopoltide重复（A-tracts和G-tracts）在人类人口的变化和癌症基因组。SBS和插入/缺失主要发生在A束的第一个和最后一个碱基对，而它们集中在G束的第二个和第三个碱基对。这些位置对应于沿着沿着A束的最灵活的位点，并且对应于其中由通过氧化失去电子产生的“空穴”最有可能定位在G束中的位点。对于A束，大多数SBS发生在束侧翼的碱基对的方向上。我们的结论是，本地DNA结构的内在特征，即碱基对的灵活性和电荷转移，使特定的核苷酸沿着montetide运行容易受到碱基修饰，然后产生突变。因此，局部DNA动力学有助于人类群体中的表型变异和疾病。
Single base substitutions (SBSs) and insertions/deletions are critical for generating population diversity and can lead both to inherited disease and cancer. Whereas on a genome-wide scale SBSs are influenced by cellular factors, on a fine scale SBSs are influenced by the local DNA sequence-context, although the role of flanking sequence is often unclear. Herein, we used bioinformatics, molecular dynamics and hybrid quantum mechanics/molecular mechanics to analyze sequence context-dependent mutagenesis at mononucleotide repeats (A-tracts and G-tracts) in human population variation and in cancer genomes. SBSs and insertions/deletions occur predominantly at the first and last base-pairs of A-tracts, whereas they are concentrated at the second and third base-pairs in G-tracts. These positions correspond to the most flexible sites along A-tracts, and to sites where a ‘hole’, generated by the loss of an electron through oxidation, is most likely to be localized in G-tracts. For A-tracts, most SBSs occur in the direction of the base-pair flanking the tracts. We conclude that intrinsic features of local DNA structure, i.e. base-pair flexibility and charge transfer, render specific nucleotides along mononucleotide runs susceptible to base modification, which then yields mutations. Thus, local DNA dynamics contributes to phenotypic variation and disease in the human population.
登录
查看更多内容
来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
4.1
作者：
Kalé, L;Skeel, R;Schulten, K
通讯作者：
Schulten, K
影响因子：
4.5
作者：
Bacolla A;Temiz NA;Yi M;Ivanic J;Cer RZ;Donohue DE;Ball EV;Mudunuri US;Wang G;Jain A;Volfovsky N;Luke BT;Stephens RM;Cooper DN;Collins JR;Vasquez KM
通讯作者：
Vasquez KM
影响因子：
3.3
作者：
Ananda, Guruprasad;Walsh, Erin;Makova, Kateryna D.
通讯作者：
Makova, Kateryna D.
影响因子：
5.5
作者：
Laino, T;Mohamed, F;Parrinello, M
通讯作者：
Parrinello, M