Tobin Ivy's research while affiliated with California Institute of Technology and other places

Publications (17)

Article
Full-text available
One strategy for population suppression seeks to use gene drive to spread genes that confer conditional lethality or sterility, providing a way of combining population modification with suppression. Stimuli of potential interest could be introduced by humans, such as an otherwise benign virus or chemical, or occur naturally on a seasonal basis, suc...
Preprint
Full-text available
One strategy for population suppression seeks to use gene drive to spread genes that confer conditional lethality or sterility, providing a way of combining population modification with suppression. Stimuli of potential interest could be introduced by humans, such as an otherwise benign virus or chemical, or occur naturally on a seasonal basis, suc...
Article
Full-text available
Gene drive elements promote the spread of linked traits, providing methods for changing the composition or fate of wild populations. Drive mechanisms that are self-limiting are attractive because they allow control over the duration and extent of trait spread in time and space, and are reversible through natural selection as drive wanes. Self-susta...
Preprint
Full-text available
Self-limiting gene drive allows control over the spread and fate of linked traits. Cleave and Rescue (ClvR) elements create self-sustaining drive and comprise a DNA sequence-modifying enzyme (Cas9-gRNAs, Cleaver) that disrupts an essential gene, and a tightly linked, uncleavable version of the essential gene (Rescue). ClvR spreads by creating condi...
Article
Full-text available
Self-limiting gene drive allows control over the spread and fate of linked traits. Cleave and Rescue (ClvR) elements create self-sustaining drive and comprise a DNA sequence-modifying enzyme (Cas9-gRNAs, Cleaver) that disrupts an essential gene, and a tightly linked, uncleavable version of the essential gene (Rescue). ClvR spreads by creating condi...
Article
Full-text available
Significance Gene drive can spread beneficial traits through populations, but will never be a one-shot project in which one genetic element provides all desired modifications, for an indefinitely long time. Here, we show that gene drive-mediated population modification in Drosophila can be overwritten with new content while eliminating old, using C...
Preprint
Full-text available
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...
Article
Full-text available
Significance There is great interest in spreading beneficial traits throughout wild populations in self-sustaining ways. Here, we describe a synthetic selfish genetic element, CleaveR [Cleave and Rescue ( ClvR )], that is simple to build and can spread a linked gene to high frequency in populations. ClvR is composed of two components. The first, ge...
Article
Replacement of wild insect populations with transgene-bearing individuals unable to transmit disease or survive under specific environmental conditions using gene drive provides a self-perpetuating method of disease prevention. Mechanisms that require the gene drive element and linked cargo to exceed a high threshold frequency in order for spread t...
Article
Full-text available
Significance Homing endonuclease gene (HEG)-based gene drive can bring about population suppression when genes required for viability or fertility are targeted. However, these strategies are vulnerable to failure through mechanisms that create alleles resistant to cleavage but that retain wild-type gene function. We show that resistance allele crea...
Preprint
Full-text available
A gene drive method of particular interest for population suppression utilizes homing endonuclease genes (HEGs), wherein a site-specific nuclease-encoding cassette is copied, in the germline, into a target gene whose loss of function results in loss of viability or fertility in homozygous, but not heterozygous progeny. Earlier work in Drosophila an...
Preprint
Full-text available
Replacement of wild insect populations with transgene-bearing individuals unable to transmit disease or survive under specific environmental conditions provides self-perpetuating methods of disease prevention and population suppression, respectively. Gene drive mechanisms that require the gene drive element and linked cargo exceed a high threshold...

Citations

... Together, these drives could serve as confined modification drive systems. They could also support confined suppression as part of a tethered drive system 16,23 if sufficiently efficient homing suppression drives can be constructed in the target organism or even confined suppression alone if an adequate cargo could be developed 24 . Because development of these methods would be nontrivial, even if functional resistance alleles can be avoided, another option is to use a CRISPR toxin-antidote drive targeting a haplolethal gene (in which two functioning copies are required for an organism to have high fitness). ...
... When cifA and cifB are in different genetic constructs, the drive is self-limiting in time and will be eliminated from the population eventually as long as the cifA allele bears a fitness cost. This makes the variant drive similar to killer-rescue drives [35,37], split drives [38,40,76,77], and daisy-chain gene drives [36,78], which are also self-limiting. The cifA/cifB drive could potentially be easier to engineer than these other systems, which tend to involve complex mechanisms or many different alleles, though more experience with self-limiting drives in non-model organisms is needed before this can be confidently assessed. ...
... To overcome the accumulation of drive resistance alleles, toxin-antidote (TA) based systems, in which embryos are essentially "poisoned" and only those embryos harboring the TA genetic cassette are rescued, were engineered (Champer et al., 2020a;Oberhofer et al., 2020aOberhofer et al., , 2020bOberhofer et al., , 2019. Generally these designs utilize a toxin consisting of a non-homing GD harboring multiple gRNAs targeting a vital gene, and an "addictive" antidote that is a re-coded, cleavage-immune version of the targeted gene. ...
... 6 Strains of Drosophila with reciprocal translocations have been engineered, and these showed the expected frequency-dependent spread in lab populations. 32 Nuclease-Based Systems: Chromosome Shredding. In Aedes and Culex mosquitoes, there is a naturally occurring driving Y chromosome that, in some crosses, is transmitted to more than 90% of a male's progeny. ...
... Although, if anticipated or identified in early-stage field trails, a meiotic drive induced linkage between elements could also be leveraged, lowering the required release frequencies 63 . Nonetheless, in regards to risk-assessment of rare recombination events, the genomic distance at which two split-drive elements become strongly linked is presumably still much more permissive for a meiotic drive mechanism as opposed to a homing mechanism. ...
... allele harboring the HGD) as a template for DNA repair. This enables 68 the HGD to home, or copy, itself into the recipient allele ( To overcome the accumulation of drive resistant alleles, CRISPR based toxin-antidote (TA) 91 drives, in which embryos are essentially "poisoned" and only those embryos harboring the TA 92 genetic cassette are rescued, were described ( Figure S8 in ) and 93 engineered (Champer et al., 2020a;Oberhofer et al., 2020aOberhofer et al., , 2020bOberhofer et al., , 2019. Generally these 94 designs utilize a toxin consisting of a non-homing GD harboring multiple gRNAs targeting a vital 95 gene, and an "addictive" antidote that is a re-coded, cleavage-immune version of the targeted 96 gene. ...
... Even though the gene drive is not copied by drive conversion as in homing drives, it still can increase in relative frequency by disrupting and removing wild-type alleles. These include the highly similar TARE (Toxin-Antidote Recessive Embryo) 15,16 and ClvR (Cleave and Rescue) 17,18 systems that are experimentally demonstrated and target a haplosufficient gene (in which one functioning copy is sufficient for an organism to retain high fitness). Such drives only gain an introduction threshold when they have fitness costs 19 , which refers to the necessary number of drive individuals that must be released for the drive to be successful. ...
... A range of gene drives have been designed to be less invasive by nature, or to mitigate risks to an extent. Some stop spreading after a certain number of generations and are thus self-limiting [26][27][28] , some require high introduction frequencies [29][30][31] , some can stop or remove a gene drive that is already present in a population 32,33 , and some target locally fixed alleles so that the gene drive cannot spread in non-target populations 34 . With the advance of such containable gene drives, we can start to consider gene drive technology as a potential tool for controlling invasive social insects like the Asian hornet. ...
... The development of CRISPR has enabled the construction of homing suppression drives in Anopheles mosquitoes 5,6 and flies 7,8 . These function by cutting the wild-type allele with Cas9 and then being copied to the cut site during homology-directed repair, thus converting germline cells to a drive homozygous state and ensuring that most offspring receive a drive allele. ...
... Various types of toxin-antidote drives have also been modeled [18][19][20][21][22][23][24]. Some of these have been proven to be capable of spreading in Drosophila experiments [25][26][27][28][29][30][31]. However, more research is needed to find suitable promoters and target sites and to successfully construct these new types of drives with desired properties in target species. ...