Daisy-chain gene drives: The role of low cut-rate, resistance mutations, and maternal deposition.
Daisy-chain gene drives: The role of low cut-rate, resistance mutations, and maternal deposition.
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DOI：
10.1371/journal.pgen.1010370
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发表时间：
2022-09
期刊：
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
--
作者：
通过基因驱动进行遗传性状的渐渗可以作为一种有效且广泛适用的生物防治方法。然而，对于许多应用，可以扩散到特定目标群体之外的自我延续基因驱动器可能是不期望的并且妨碍使用。菊花链基因驱动器已被提出作为调整基因驱动器的侵入性的手段，允许其有效地传播到目标群体中，但在此之外是自我限制的。菊花链基因驱动器由多个独立的驱动元件组成，其中每个元件，除了一个之外，都会偏向另一个的遗传，形成一个链。在理想的继承偏置条件下，被释放的驱动元素保持以相同的配置链接，除了链中最后剩余的链接之外，生成它们的大多数元素的副本。通过数学建模的人口迁移连接，我们已经评估了抗性等位基因的影响，不同的健身成本，减少切割率，和产妇沉积两种替代菊花链基因驱动设计。我们发现，菊花链基因驱动的自限性使得它们的传播高度依赖于遗传偏置机制的效率和保真度。特别地，切割速率的降低和非致死抗性等位基因的形成可导致驱动元件失去其连锁构型。这严重降低了驱动的侵入性，并允许幻影切割，其中上游驱动元件切割下游目标基因座，尽管相应的驱动元件不存在，产生并偏向额外抗性等位基因的遗传。这种体模切割可以通过替代的间接菊花链设计来减轻。我们进一步发现，虽然占主导地位的健身成本和产妇沉积减少菊花链的入侵，如果克服增加释放频率，他们可以减少到邻近人群的驱动器的传播。通过将性状渐渗到野生种群中来减少有害物种的危害常常受到大量饲养和释放修饰个体的困难的限制。基因驱动提供了一个机会，可以大大减少传播特定修饰所需的释放频率。然而，除了一些特定的例外，对目标物种进行统一修饰是不必要或不可取的。自限性基因驱动器，如菊花链基因驱动器，已被广泛讨论作为一个潜在的解决方案，允许驱动器释放的侵入性调整到目标人群。在这里，我们通过计算模型研究了当受到与基于CRISPR-Cas9的遗传偏倚相关的常见低效率时，菊花链基因驱动器的表现。与自我延续的驱动器相比，菊花链基因驱动器对导致其单独元件过早分离的因素敏感。特别是DNA切割率的降低和抗性等位基因形成的增加。我们发现，在驱动机制中的低效率的影响通常是更明显的驱动器时，在低频率。由于迁移率低，这大大减少了菊花链基因驱动器传播到邻近的非目标人群中。
The introgression of genetic traits through gene drive may serve as a powerful and widely applicable method of biological control. However, for many applications, a self-perpetuating gene drive that can spread beyond the specific target population may be undesirable and preclude use. Daisy-chain gene drives have been proposed as a means of tuning the invasiveness of a gene drive, allowing it to spread efficiently into the target population, but be self-limiting beyond that. Daisy-chain gene drives are made up of multiple independent drive elements, where each element, except one, biases the inheritance of another, forming a chain. Under ideal inheritance biasing conditions, the released drive elements remain linked in the same configuration, generating copies of most of their elements except for the last remaining link in the chain. Through mathematical modelling of populations connected by migration, we have evaluated the effect of resistance alleles, different fitness costs, reduction in the cut-rate, and maternal deposition on two alternative daisy-chain gene drive designs. We find that the self-limiting nature of daisy-chain gene drives makes their spread highly dependent on the efficiency and fidelity of the inheritance biasing mechanism. In particular, reductions in the cut-rate and the formation of non-lethal resistance alleles can cause drive elements to lose their linked configuration. This severely reduces the invasiveness of the drives and allows for phantom cutting, where an upstream drive element cuts a downstream target locus despite the corresponding drive element being absent, creating and biasing the inheritance of additional resistance alleles. This phantom cutting can be mitigated by an alternative indirect daisy-chain design. We further find that while dominant fitness costs and maternal deposition reduce daisy-chain invasiveness, if overcome with an increased release frequency, they can reduce the spread of the drive into a neighbouring population. Reducing the harm of pest species by the introgression of traits into a wild population is often limited by the difficulties of mass rearing and release of modified individuals. Gene drives present an opportunity to substantially reduce the release frequencies required to spread a particular modification. However, uniform modification of a target species is, with a few specific exceptions, not necessary or desirable. Self-limiting gene drives, such as daisy-chain gene drives, have been widely discussed as a potential solution, allowing the invasiveness of a drive release to be tuned to the target population. Here, we investigate through computational modelling how daisy-chain gene drives perform when subjected to commonly observed inefficiencies associated with CRISPR-Cas9-based inheritance biasing. Compared to a self-perpetuating drive, daisy-chain gene drives are sensitive to factors that cause their separate elements to segregate prematurely. In particular, a reduction in the DNA cut-rate and an increase in the formation of resistance alleles. We find that the effect of inefficiencies in the drive mechanism is generally more pronounced when the drive is at low frequencies. With low rates of migration, this substantially reduces daisy-chain gene drives spread into a neighbouring non-target population.
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影响因子：
16.6
作者：
Hammond A;Pollegioni P;Persampieri T;North A;Minuz R;Trusso A;Bucci A;Kyrou K;Morianou I;Simoni A;Nolan T;Müller R;Crisanti A
通讯作者：
Crisanti A
影响因子：
46.9
作者：
Hendel A;Bak RO;Clark JT;Kennedy AB;Ryan DE;Roy S;Steinfeld I;Lunstad BD;Kaiser RJ;Wilkens AB;Bacchetta R;Tsalenko A;Dellinger D;Bruhn L;Porteus MH
通讯作者：
Porteus MH
影响因子：
56.9
作者：
Jinek, Martin;Chylinski, Krzysztof;Charpentier, Emmanuelle
通讯作者：
Charpentier, Emmanuelle
影响因子：
46.9
作者：
Kyrou K;Hammond AM;Galizi R;Kranjc N;Burt A;Beaghton AK;Nolan T;Crisanti A
通讯作者：
Crisanti A
DOI：
10.1073/pnas.1521077112
发表时间：
2015-12-08
影响因子：
11.1
作者：
Gantz, Valentino M.;Jasinskiene, Nijole;James, Anthony A.
通讯作者：
James, Anthony A.