美国布里格姆妇女医院Shamil R. Sunyaev研究组发现，在碱基对分辨率上的突变率模型确定了聚合酶III转录的致突变作用。该项研究成果发表在2023年11月30日出版的《自然—遗传学》上。

他们提出了Roulette，一个碱基对分辨率的全基因组突变率模型，其中包含了已知的局部突变率决定因素。Roulette被证明比现有的模型更准确。他们使用Roulette，通过纳入人类突变率的全部范围，来完善欧洲人口增长的估计。与模型预测的显著偏差分析显示，几乎所有由聚合酶III (Pol III)转录的基因的突变率增加了10倍，这提示了一种新的致突变机制。

他们还检测到转录因子结合位点的突变率升高，这些位点仅限于睾丸中活跃使用的位点和位于启动子中的位点。

据悉，根据基因组位置、序列背景和DNA链的不同，新生突变的发生率有很大的不同。估计选择强度、推断人口历史和绘制罕见疾病基因图的方法的成功与否，在很大程度上取决于对局部突变率的假设。

附：英文原文

Title: A mutation rate model at the basepair resolution identifies the mutagenic effect of polymerase III transcription

Author: Seplyarskiy, Vladimir, Koch, Evan M., Lee, Daniel J., Lichtman, Joshua S., Luan, Harding H., Sunyaev, Shamil R.

Issue&Volume: 2023-11-30

Abstract: De novo mutations occur at substantially different rates depending on genomic location, sequence context and DNA strand. The success of methods to estimate selection intensity, infer demographic history and map rare disease genes, depends strongly on assumptions about the local mutation rate. Here we present Roulette, a genome-wide mutation rate model at basepair resolution that incorporates known determinants of local mutation rate. Roulette is shown to be more accurate than existing models. We use Roulette to refine the estimates of population growth within Europe by incorporating the full range of human mutation rates. The analysis of significant deviations from the model predictions revealed a tenfold increase in mutation rate in nearly all genes transcribed by polymerase III (Pol III), suggesting a new mutagenic mechanism. We also detected an elevated mutation rate within transcription factor binding sites restricted to sites actively used in testis and residing in promoters.

DOI: 10.1038/s41588-023-01562-0

Source: https://www.nature.com/articles/s41588-023-01562-0