Simoni Alekos, Siniscalchi Carla, Chan Yuk-Sang, Huen David S, Russell Steven, Windbichler Nikolai, Crisanti Andrea
Department of Life Sciences, Imperial College London, South Kensington Campus, London SW7 2AZ, UK.
Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK.
Nucleic Acids Res. 2014 Jun;42(11):7461-72. doi: 10.1093/nar/gku387. Epub 2014 May 6.
Selfish genes are DNA elements that increase their rate of genetic transmission at the expense of other genes in the genome and can therefore quickly spread within a population. It has been suggested that selfish elements could be exploited to modify the genome of entire populations for medical and ecological applications. Here we report that transcription activator-like effector nuclease (TALEN) and zinc finger nuclease (ZFN) can be engineered into site-specific synthetic selfish elements (SSEs) and demonstrate their transmission of up to 70% in the Drosophila germline. We show here that SSEs can spread via DNA break-induced homologous recombination, a process known as 'homing' similar to that observed for homing endonuclease genes (HEGs), despite their fundamentally different modes of DNA binding and cleavage. We observed that TALEN and ZFN have a reduced capability of secondary homing compared to HEG as their repetitive structure had a negative effect on their genetic stability. The modular architecture of ZFNs and TALENs allows for the rapid design of novel SSEs against specific genomic sequences making them potentially suitable for the genetic engineering of wild-type populations of animals and plants, in applications such as gene replacement or population suppression of pest species.
自私基因是指那些以基因组中其他基因为代价来提高自身遗传传递速率的DNA元件，因此能够在种群中迅速传播。有人提出，可以利用自私元件来改造整个种群的基因组，以用于医学和生态学应用。在此，我们报告转录激活样效应核酸酶（TALEN）和锌指核酸酶（ZFN）可以被设计成位点特异性的合成自私元件（SSE），并证明它们在果蝇生殖系中的传递率高达70%。我们在此表明，SSE可以通过DNA断裂诱导的同源重组进行传播，这一过程被称为“归巢”，类似于归巢内切酶基因（HEG）所观察到的情况，尽管它们在DNA结合和切割方式上有根本差异。我们观察到，与HEG相比，TALEN和ZFN的二次归巢能力有所降低，因为它们的重复结构对其遗传稳定性有负面影响。ZFN和TALEN的模块化结构允许针对特定基因组序列快速设计新型SSE，使其有可能适用于动植物野生型种群的基因工程，如基因替换或害虫种群抑制等应用。
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