Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125.
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125;
Proc Natl Acad Sci U S A. 2020 Apr 21;117(16):9013-9021. doi: 10.1073/pnas.1921698117. Epub 2020 Apr 3.
Gene drive-based strategies for modifying populations face the problem that genes encoding cargo and the drive mechanism are subject to separation, mutational inactivation, and loss of efficacy. Resilience, an ability to respond to these eventualities in ways that restore population modification with functional genes, is needed for long-term success. Here, we show that resilience can be achieved through cycles of population modification with "" () selfish genetic elements. comprises a DNA sequence-modifying enzyme such as Cas9/gRNAs that disrupts endogenous versions of an essential gene and a recoded version of the essential gene resistant to cleavage. spreads by creating conditions in which those lacking die because they lack functional versions of the essential gene. Cycles of modification can, in principle, be carried out if two elements targeting different essential genes are located at the same genomic position, and one of them, , carries a transgene from an earlier element, should spread within a population of , while also bringing about a decrease in its frequency. To test this hypothesis, we first show that multiple s, each targeting a different essential gene, function when located at a common chromosomal position in We then show that when several of these also carry the from a different , they spread to transgene fixation in populations fixed for the latter and at its expense. Therefore, genetic modifications of populations can be overwritten with new content, providing an ongoing point of control.
基于基因驱动的种群修改策略面临着这样的问题，即携带货物的基因和驱动机制容易发生分离、突变失活和效力丧失。为了长期成功，需要有恢复种群修饰的功能基因的弹性。在这里，我们表明，通过使用“()自私遗传元件”进行种群修饰的循环可以实现弹性。包含 DNA 序列修饰酶（如 Cas9/gRNAs），该酶破坏必需基因的内源性版本和对切割具有抗性的必需基因的重编码版本。通过创造缺乏 的条件来传播，因为它们缺乏必需基因的功能性版本。如果两个靶向不同必需基因的 元件位于同一基因组位置，则可以进行修饰循环，并且其中一个元件 ，携带来自较早元件的 转基因，而 应该在 种群中传播，同时降低其频率。为了验证这一假设，我们首先表明，当位于 中的共同染色体位置时，多个 s 靶向不同的必需基因可以发挥作用。然后，我们表明，当其中的几个还携带来自不同 的 时，它们会在后者固定的种群中传播并固定到转基因，并且以其为代价。因此，种群的遗传修饰可以用新的内容覆盖，提供持续的控制点。
