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Selection of sites for field trials of genetically engineered mosquitoes with gene drive.

ABSTRACT: Novel malaria control strategies using genetically engineered mosquitoes (GEMs) are on the horizon. Population modification is one approach wherein mosquitoes are engineered with genes rendering them refractory to the malaria parasite, Plasmodium falciparum, coupled with a low-threshold, Cas9-based gene drive. When released into a wild vector population, GEMs preferentially transmit these parasite-blocking genes to their offspring, ultimately modifying a vector population into a nonvector one. Deploying this technology awaits ecologically contained field trial evaluations. Here, we consider a process for site selection, the first critical step in designing a trial. Our goal is to identify a site that maximizes prospects for success, minimizes risk, and serves as a fair, valid, and convincing test of efficacy and impacts of a GEM product intended for large-scale deployment in Africa. We base site selection on geographic, geological, and biological, rather than social or legal, criteria. We recognize the latter as critically important but not as a first step in selecting a site. We propose physical islands as being the best candidates for a GEM field trial and present an evaluation of 22 African islands. We consider geographic and genetic isolation, biological complexity, island size, and topography and identify two island groups that satisfy key criteria for ideal GEM field trial sites.

SUBMITTER: Lanzaro GC

PROVIDER: S-EPMC8477601 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Gene drive organisms are a recent development created by using methods of genetic engineering; they inherit genetic constructs that are passed on to future generations with a higher probability than with Mendelian inheritance. There are some specific challenges inherent to the environmental risk assessment (ERA) of genetically engineered (GE) gene drive organisms because subsequent generations of these GE organisms might show effects that were not observed or intended in the former generations. Unintended effects can emerge from interaction of the gene drive construct with the heterogeneous genetic background of natural populations and/or be triggered by changing environmental conditions. This is especially relevant in the case of gene drives with invasive characteristics and typically takes dozens of generations to render the desired effect. Under these circumstances, "next generation effects" can substantially increase the spatial and temporal complexity associated with a high level of uncertainty in ERA. To deal with these problems, we suggest the introduction of a new additional step in the ERA of GE gene drive organisms that takes 3 criteria into account: the biology of the target organisms, their naturally occurring interactions with the environment (biotic and abiotic), and their intended biological characteristics introduced by genetic engineering. These 3 criteria are merged to form an additional step in ERA, combining specific "knowns" and integrating areas of "known unknowns" and uncertainties, with the aim of assessing the spatiotemporal controllability of GE gene drive organisms. The establishment of assessing spatiotemporal controllability can be used to define so-called "cut-off criteria" in the risk analysis of GE gene drive organisms: If it is likely that GE gene drive organisms escape spatiotemporal controllability, the risk assessment cannot be sufficiently reliable because it is not conclusive. Under such circumstances, the environmental release of the GE gene drive organisms would not be compatible with the precautionary principle (PP). Integr Environ Assess Manag 2020;00:1-14. © 2020 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Project description:The generation of distiThe generation of distinct messenger RNA isoforms through alternative RNA processing influences the expression and function of genes, often in a cell-type specific manner. Here, we assess the regulatory relationships between transcription initiation, alternative splicing, and 3ʹ end site selection. Applying multiple long-read-sequencing approaches to obtain an assembly accurately representing even the longest transcripts from end to end, we quantify mRNA isoform choice in Drosophila and human tissues, including the transcriptionally complex nervous system. We find that in Drosophila brains as well as in human cerebral organoids, 3ʹ end site choice is globally influenced by the site of transcription initiation. “Dominant promoters”, characterized by specific epigenetic signatures including p300/CBP binding, impose a transcriptional constraint to define splice and polyadenylation variants. In vivo deletion or overexpression of dominant promoters as well as CBP/p300 loss disrupted the 3ʹ end expression landscape. Our study demonstrates the crucial impact of TSS choice on the regulation of transcript diversity and tissue identity.ct messenger RNA isoforms through alternative splicing and alternative 3' end formation influences the expression and function of genes, often in a cell-type specific manner. Here, we quantitatively assess the regulatory relationships between transcription initiation and co-transcriptional processing steps, particularly 3' end formation. Applying multiple long-read-sequencing approaches to obtain an assembly accurately representing even the longest mRNA isoforms from end-to-end, we quantify mRNA isoform choice in Drosophila and human tissues, including the transcriptionally complex nervous system. We find that in Drosophila brains as well as in human cerebral organoids, 3' end site choice is globally influenced by the site of transcription start. We define a subset of TSSs, “dominant promoters” that impose a transcriptional constraint to predetermine splice and polyadenylation variants, which are characterized by specific epigenetic signatures. In vivo deletion or overexpression of dominant promoters disrupted the 3' end expression landscape. Our study demonstrates the crucial impact of transcription initiation site choice on the regulation of transcript diversity and tissue identity.

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Selection of sites for field trials of genetically engineered mosquitoes with gene drive.

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