The MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
Center for Quantitative Biology, Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
Proc Natl Acad Sci U S A. 2021 Oct 26;118(43). doi: 10.1073/pnas.2019060118.
Most genetic changes have negligible reversion rates. As most mutations that confer resistance to an adverse condition (e.g., drug treatment) also confer a growth defect in its absence, it is challenging for cells to genetically adapt to transient environmental changes. Here, we identify a set of rapidly reversible drug-resistance mutations in that are caused by microhomology-mediated tandem duplication (MTD) and reversion back to the wild-type sequence. Using 10,000× coverage whole-genome sequencing, we identify nearly 6,000 subclonal MTDs in a single clonal population and determine, using machine learning, how MTD frequency is encoded in the genome. We find that sequences with the highest-predicted MTD rates tend to generate insertions that maintain the correct reading frame, suggesting that MTD formation has shaped the evolution of coding sequences. Our study reveals a common mechanism of reversible genetic variation that is beneficial for adaptation to environmental fluctuations and facilitates evolutionary divergence.
大多数遗传变化的回复率都微不足道。由于大多数赋予对不利条件（例如药物治疗）的抗性的突变在不存在该条件时也会导致生长缺陷，因此细胞很难在遗传上适应短暂的环境变化。在这里，我们鉴定了一组由微同源介导的串联重复（MTD）引起的快速可逆的耐药性突变，这些突变可以回复到野生型序列。使用 10,000×覆盖全基因组测序，我们在单个克隆群体中鉴定了近 6,000 个亚克隆 MTD，并使用机器学习确定了基因组中 MTD 频率的编码方式。我们发现，预测的 MTD 速率最高的序列往往会产生插入，从而保持正确的阅读框，这表明 MTD 的形成塑造了编码序列的进化。我们的研究揭示了一种常见的可遗传变异机制，这种机制有利于适应环境波动，并促进进化分歧。
