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How to avoid gene transfer (via jumping genes) when using GMOs?

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Shubhankar Kulkarni
Shubhankar Kulkarni Aug 07, 2020
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Necessity

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Conciseness

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The use of Genetically Modified Organisms (GMOs) is on the rise. This comes with benefits as well as certains risks to humans. The worst case scenario is that jumping genes from the GMOs may transfer to other organisms and probably every natural organism on the Earth.

This has made the use of GMOs unadvisable. How can we use GMOs and also avoid its disadvantages? Or is it best to avoid GMO altogether?

[1]Reply by @AntiAgify https://twitter.com/JanieHsieh/status/1291057092586098689?s=20

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Creative contributions

Daisy-drive systems

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AK
Apoorva Kulkarni Aug 12, 2020
An ideal gene drive system to alter wild populations needs to exclusively affect organisms within a given boundary and be capable of restoring any engineered population to its original genetic state. The current CRISPR-based gene drive systems do not fulfil these objectives and hence pose risk to life on Earth. A recent system that is still at the theoretical stage is the Daisy-drive system. It is an exhaustive gene drive system that will not spread indefinitely and offer enhanced stability to several targeting sequences. It consists of genetic elements arranged in a daisy chain such that each drives the next. “Daisy-drive” systems can locally duplicate any effect but their capacity to spread is limited by the successive loss of non-driving elements from one end of the chain. Releasing daisy-drive organisms constituting a small fraction of the local wild population can drive the desired genetic element nearly to local fixation for a wide range of fitness parameters without self-propagating spread. When these daisy drives are combined with threshold dependence, alteration of the local ecosystems can be controlled (whether, when, and how). Reference: Noble, Charleston, et al. “Daisy-Chain Gene Drives for the Alteration of Local Populations.” Proceedings of the National Academy of Sciences, vol. 116, no. 17, Apr. 2019, pp. 8275–82, doi:10.1073/pnas.1716358116.
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Silencing the jumping genes if not totally avoiding them

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Subash Chapagain
Subash Chapagain Oct 03, 2020
While avoiding the jumping genes in a complete manner might not be that easy, there are a number of ways in which Transposable Elements could be silenced, hence avoiding the risks associated with them.

  • Upregulation of DNA methyltransferase (DNMT) for 5-Methyl-Cytosine (5mC)mediated silencing of transposable elements
It has been reported that eukaryotes, including nematodes, display enrichment of 5-Methyl-Cytosine (5mC) in the loci with Transposable Elements (TEs ). Since DNA methyltransferase enzyme is responsible for methylation of cytosine generating 5-Methyl-Cytosine (5mC), one possible solution to avoid the stochastic expression of transposable element (TEs) would be to overexpress/upregulate the DNMT gene in the GMOs and drive the 5mC mediated TE silencing. For example, DNA methylation is used in flowering plants to silence Transposons. The process begins by transcription of double-stranded TE RNAs by RDR6, followed by DCL2 and DCL4 mediated cleavage of 21-22 nucleotide small RNAs (sRNAs) DRM1/2 (DNMT like enzymes) then generate 5mC at the loci with the jumping genes, resulting in their silencing .

  • De novo TE silencing using piRNAs
PIWI-interacting RNAs (piRNAs) are a class of small non-coding RNA molecules 24-32 nucleotides long and are associated with PIWI proteins, a subfamily of argonaute proteins . piRNAs are involved in spermatogenesis, germ stem-cell maintenance, epigenetic and genomic regulation, and silencing of transposons. In the animal germline, the TE mRNAs are cleaved into piRNAs by specific enzymes, followed by post-transcriptional gene silencing. This transcriptional silencing of TEs via epigenetic modification is achieved by piRNA-loaded enzymes (MIWI2 in mice, PIWI in Drosophila, WAGO in C. Elegans), conferring de novo 5-methylcytosine, eventually resulting in H3K9me2/3, the classical histone protein involved in DNA silencing .

This mechanism can be used if we could engineer piRNAs endogenously/exogenously into the GMO.

[1]Rošic, S. et al. Evolutionary analysis indicates that DNA alkylation damage is a byproduct of cytosine DNA methyltransferase activity. Nat. Genet. 50, 452–459 (2018).

[2]Kim, M. Y. & Zilberman, D. DNA methylation as a system of plant genomic immunity. Trends Plant Sci. 19, 320–326 (2014).

[3]Girard A, Sachidanandam R, Hannon GJ, Carmell MA. A germline-specific class of small RNAs binds mammalian Piwi proteins. Nature. 2006;442(7099):199–202. doi:10.1038/nature04917

[4]Aravin, A. A. et al. A piRNA pathway primed by individual transposons is linked to de novo DNA methylation in mice. Mol. Cell 31, 785–799 (2008).

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Shubhankar Kulkarni
Shubhankar Kulkarnia year ago
Great idea Subash! Will the methyation by the DNMT be localized to the transposable element gene? Will upregulation affect methylation patterns in the neighboring genes and lead to detrimental effects? I think using piRNAs is more beneficial since it is a targeted therapy and will probably have less "side-effects".
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General comments

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Darko Savic
Darko Savica year ago
I guess we will see soon enough how this unfolds. Here we go https://www.sciencenews.org/article/genetically-modified-mosquitoes-florida-test-release
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