Neighboring-nucleotide effects on the rates of germ-line single-base-pair substitution in human genes
Neighboring-nucleotide effects on the rates of germ-line single-base-pair substitution in human genes
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DOI：
10.1086/301965
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发表时间：
1998-08-01
影响因子：
9.8
通讯作者：
Cooper, DN
中科院分区：
文献类型：
--
作者：
Krawczak, M;Ball, EV;Cooper, DN
人类基因突变数据库（HGMD）记录了547个不同人类基因编码区的7271个不同病变的单碱基对替换谱，分析了最近邻效应对相对突变率的影响。由于其回顾性性质，HGMD允许仅以相对条件估计突变率。因此，为了以迭代的方式获得这些估计，设计了一种新的方法，同时纠正了差异密码子使用的混淆效应以及不同类型的氨基酸替代以不同的概率引起临床注意的事实。除了CpG二核苷酸的高易变性（反映在过渡率是lease突变率的5倍）之外，仅观察到周围DNA序列对相对单碱基对取代率的微妙和局部限制影响，其延伸距离不超过2 bp。两条DNA链之间的差异可以通过以下事实得到证明：当取代率以5‘和3’侧链核苷酸为条件估计时，96对可能的互补取代事件中有10对出现了显著的速率差异。突变偏倚，倾向于向侧翼碱基的替换，kla现象使人联想到错位突变，是明显的，并表现出方向性和阅读框敏感性。在核苷酸取代附近没有观察到重复序列基序的特定优势，但DNA三胞胎的相对易变性和热力学稳定性之间存在适度的相关性，这表明在高稳定性区域的DNA复制效率低下或错位中间体的短暂稳定。
The spectrum of single-base-pair substitutions logged in The Human Gene Mutation Database (HGMD), comprising 7,271 different lesions in the coding regions of 547 different human genes, was analyzed for nearest-neighbor effects on relative mutation rates. Owing to its retrospective nature, HGMD allows mutation rates to be estimated only in relative terms. Therefore, a novel methodology was devised in order to obtain these estimates in iterative fashion, correcting, at the same time, for the confounding effects of differential codon usage and for the fact that different types of amino acid replacement come to clinical attention with different probabilities. Over and above the hypermutability of CpG dinucleotides, reflected in transition rates five times the lease mutation rate, only a subtle and locally confined influence of the surrounding DNA sequence on relative single-base-pair substitution rates was observed, which extended no farther than 2 bp from the substitution site. A disparity between the two DNA strands was evidenced by the fact that, when substitution rates were estimated conditional on the 5' and 3' flanking nucleotides, a significant rate difference emerged for 10 of 96 possible pairs of complementary substitutional events. Mutational bias, favoring substitutions toward flanking bases, kla phenomenon reminiscent of misalignment mutagenesis, was apparent and exhibited both directionality and reading-frame sensitivity. No specific preponderance of repeat-sequence motifs was observed in the vicinity of nucleotide substitutions, but a moderate correlation between the relative mutability and thermodynamic stability of DNA triplets emerged, suggesting either inefficient DNA replication in regions of high stability or the transient stabilization of misaligned intermediates.