Gene Drive

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Gene Drive scheme

Gene Drive (Engl. For Genantrieb ) referred methods to accelerate the spread of genes in populations . While a gene that occurs only once in the genome is normally passed on to 50% of the offspring, with Gene Drive it is 100%. Gene drive technologies were first proposed by Austin Burt in 2003 and have so far been used primarily in yeasts , mosquitoes and fruit flies .

principle

The gene drive generates a disproportionate inheritance in living beings that go through a development stage with a haploid genome (simple set of chromosomes ). In animals this stage of development is meiosis , but most of the time they have a double set of chromosomes. The gene drive consists of an enzyme (an endonuclease ) that cuts a certain DNA sequence from the second strand of a chromosome without a gene drive. In a subsequent DNA repair , the strand with Gene Drive (one chromosome has two DNA strands) serves as a repair template for the cut DNA strands and the template is copied onto the other strand. This leads to a disproportionate spread, because all offspring carry the gene drive.

The Gene Drive can be used, among other things, to insert new genes. However, if a DNA sequence is removed by two cuts and the removed DNA sequence was essential, a lethal factor occurs in all offspring. The parent generation becomes sterile because the offspring die during development. Gene drive systems are used to introduce individual genes into a population either analogously to gene therapy to supplement the genome or to create infertility.

mechanism

Various methods are used to increase the diffusion of genes, e.g. B. modified self-serving DNA such as homing endonucleases , the MEDEA and a modified CRISPR / Cas method .

Lethal factor

First, a genome editing mechanism (a sequence-specific endonuclease ) is generated that binds and cuts the target DNA sequence, if possible only on one sequence in the genome (on two alleles ). Alternatively, a new cleavage site of the endonuclease can be inserted into the genome, which would otherwise not occur there. The gene for this mechanism is then inserted into the target DNA sequence on the first of two chromosomes . The target DNA is an essential gene into which the genome editing mechanism has been inserted, whereby the essential gene is divided and inactivated. In contrast, naturally occurring self-serving DNA has a group I intron or intein , which means that the surrounding gene is not inactivated. At the same time, the gene lies in one of the endonuclease's recognition sequences, which prevents the endonuclease gene from being cut out. A gene is selected as the target DNA sequence for sterilization, the gene knockout of which is not lethal on only one of the two alleles, but is lethal in the case of a complete knockout ( homozygous negative). Furthermore, a meiosis- specific promoter is used, which increases the gene expression of the endonuclease in the germ line. The gene drive system spreads from one allele to the second. Due to the lethal factor in the germline , infertility occurs if both alleles carry the gene drive system ( homozygosity ).

Additional genes

In addition, other genes can also be inserted into the gene drive system ( cargo genes ). For example, resistance factors to parasites or viruses can be introduced into a population of insects. The Gene Drive system can be used to change the sex proportions (male / female) in a population.

Gene drive inactivation

By using another gene-Drive System ( English Cas9-triggered chain ablation , short CATCHA based on Cas9 ), a Gene-drive system be inactivated in a population. If there is no recognition sequence of the original gene drive in the second gene drive, but the second gene drive has the recognition sequences from the first gene drive, then the second gene drive removes the first gene drive, but not vice versa.

safety

Due to the spread of gene drive systems within a species , handling and production in Germany are subject to biological safety level 2 . One problem with the gene drive is maintaining a selection pressure on the cargo gene (e.g. a resistance factor) if this does not bring the host a selection advantage, because a gene drive system with a mutated and inactivated or even removed cargo gene would spread in competition in the population and displace the original. A study published in 2018 reported that it had solved this problem. A mosquito population of the species Anopheles gambiae was completely eradicated in the laboratory .

Another problem is a possible accidental release , which would cause a gene drive system to spread to populations in the wild. The transition to a population in the wild can be avoided by using a recognition sequence that only occurs in the laboratory strain and not otherwise in the species . In the case of inducible promoters without basal expression , the gene drive system is inherited like other DNA without a gene drive in the absence of the inducer .

In August 2016 published a group of environmental organizations , dealing with synthetic biology deal, the Civil Society Working Group on Gene Drives ( Civil Society Working Group on Gene-Drives ) the manifesto Reckless Driving: Gene drives and the end of nature ( Reckless driving: gene Drives and the end of nature ) to warn of the ecological and social consequences of technology.

Precautionary principle

In mid-December 2016, the 13th “Conference of the Parties to the Convention on Biological Diversity ” (COP CBD, Conference of the Parties or “UN Species Conservation Summit”) in Cancún ( Mexico ) decided to apply the precautionary principle to gene drives as well. In July 2020, the final report of the German-Austrian research project GeneTip, funded by the Federal Ministry of Education and Research, on risk assessment in terms of the precautionary principle at Gene Drives was published.

Applications

Gene drive systems have been used in yeast , mosquitoes and fruit flies . Possible applications are in gene therapy .

Simplified illustration of the extermination of a population of 4 individuals by infertility. Healthy individuals are green, carriers of the recessive "infertility gene" are red, and infertile individuals are marked in white.

The Bill & Melinda Gates Foundation is trying to develop a method based on the gene editing technique CRISPR / Cas9 to eradicate the carrier of malaria , the Anopheles mosquito, with the help of the gene drive principle in order to fight malaria. In a very simplified way, the mechanism for exterminating the species works by the fact that all offspring of a manipulated mosquito are carriers of a recessive gene , which however only leads to impairment (e.g. infertility or only male offspring) if the father and mother are carriers of the gene. The gene drive ensures that both parents carry the harmful gene, which significantly increases the likelihood of inheriting the harmful gene.

literature

reception

Broadcast reports

Web links

Individual evidence

  1. ↑ a b c d e f g h A. Burt: Site-specific selfish genes as tools for the control and genetic engineering of natural populations. In: Proceedings. Biological sciences / The Royal Society. Volume 270, number 1518, May 2003, pp. 921-928, doi : 10.1098 / rspb.2002.2319 , PMID 12803906 , PMC 1691325 (free full text).
  2. ^ AK Lindholm, KA Dyer, RC Firman, L. Fishman, W. Forstmeier, L. Holman, H. Johannesson, U. Knief, H. Kokko, AM Larracuente, A. Manser, C. Montchamp-Moreau, VG Petrosyan, A. Pomiankowski, DC Presgraves, LD Safronova, A. Sutter, RL Unckless, RL Verspoor, N. Wedell, GS Wilkinson, TA Price: The Ecology and Evolutionary Dynamics of Meiotic Drive. In: Trends in ecology & evolution. Volume 31, Number 4, April 2016, pp. 315–326, doi : 10.1016 / j.tree.2016.02.001 , PMID 26920473 .
  3. ↑ KM Esvelt, AL Smidler, F. Catteruccia, GM Church: Concerning RNA-guided gene drives for the alteration of wild populations. In: eLife. [Electronic publication before printing] July 2014, doi : 10.7554 / eLife.03401 , PMID 25035423 , PMC 4117217 (free full text).
  4. ^ VM Gantz, E. Bier: Genome editing. The mutagenic chain reaction: a method for converting heterozygous to homozygous mutations. In: Science. Volume 348, number 6233, April 2015, pp. 442–444, doi : 10.1126 / science.aaa5945 , PMID 25908821 , PMC 4687737 (free full text).
  5. ↑ N. Windbichler, M. Menichelli, PA Papathanos, SB Thyme, H. Li, UY Ulge, BT Hovde, D. Baker, RJ Monnat, A. Burt, A. Crisanti: A synthetic homing endonuclease-based gene drive system in the human malaria mosquito. In: Nature. Volume 473, number 7346, May 2011, pp. 212-215, doi : 10.1038 / nature09937 , PMID 21508956 , PMC 3093433 (free full text).
  6. ↑ a b A. Hammond, R. Galizi, K. Kyrou, A. Simoni, C. Siniscalchi, D. Katsanos, M. Gribble, D. Baker, E. Marois, S. Russell, A. Burt, N. Windbichler , A. Crisanti, T. Nolan: A CRISPR-Cas9 gene drive system targeting female reproduction in the malaria mosquito vector Anopheles gambiae. In: Nature Biotechnology . Volume 34, number 1, January 2016, pp. 78-83, doi : 10.1038 / nbt.3439 , PMID 26641531 . PMC 4913862 (free full text).
  7. ^ A b Y. S. Chan, DA Naujoks, DS Huen, S. Russell: Insect population control by homing endonuclease-based gene drive: an evaluation in Drosophila melanogaster. In: Genetics. Volume 188, number 1, May 2011, pp. 33-44, doi : 10.1534 / genetics.111.127506 , PMID 21368273 , PMC 3120159 (free full text).
  8. ↑ VM Gantz, N. Jasinskiene, O. Tatarenkova, A. Fazekas, VM Macias, E. Bier, AA James: Highly efficient Cas9-mediated gene drive for population modification of the malaria vector mosquito Anopheles stephensi. In: Proceedings of the National Academy of Sciences . Volume 112, number 49, December 2015, pp. E6736 – E6743, doi : 10.1073 / pnas.1521077112 , PMID 26598698 , PMC 4679060 (free full text).
  9. ^ ZN Adelman, Z. Tu: Control of Mosquito-Borne Infectious Diseases: Sex and Gene Drive. In: Trends in parasitology. Volume 32, number 3, March 2016, pp. 219-229, doi : 10.1016 / j.pt.2015.12.003 , PMID 26897660 , PMC 4767671 (free full text).
  10. ^ B. Wu, L. Luo, XJ Gao: Cas9-triggered chain ablation of cas9 as a gene drive brake. In: Nature Biotechnology . Volume 34, Number 2, February 2016, pp. 137-138, doi : 10.1038 / nbt.3444 , PMID 26849513 .
  11. ↑ a b ZKBS : Az. 45310.0111, February 2016: Statement by the ZKBS on the classification of genetic engineering work for the production and use of higher organisms with recombinant gene drive systems . Retrieved February 28, 2016.
  12. ↑ Kyros Kyrou, Andrew M Hammond, Roberto Galizi, Nace Kranjc, Austin Burt, Andrea K Beaghton, Tony Nolan, Andrea Crisanti: A CRISPR – Cas9 gene drive targeting doublesex causes complete population suppression in caged Anopheles gambiae mosquitoes. In: Nature Biotechnology. 2018, doi : 10.1038 / nbt.4245 .
  13. ↑ OS Akbari, HJ Bellen, E. Bier, SL Bullock, A. Burt, GM Church, KR Cook, P. Duchek, OR Edwards, KM Esvelt, VM Gantz, KG Golic, SJ Gratz, MM Harrison, KR Hayes, AA James, TC Kaufman, J. Knoblich, HS Malik, KA Matthews, KM O'Connor-Giles, AL Parks, N. Perrimon, F. Port, S. Russell, R. Ueda, J. Wildonger: BIOSAFETY. Safeguarding gene drive experiments in the laboratory. In: Science. Volume 349, number 6251, August 2015, pp. 927-929, doi : 10.1126 / science.aac7932 , PMID 26229113 , PMC 4692367 (free full text).
  14. ↑ : synbiowatch.org: Reckless Driving: Gene drives and the end of nature (September 2, 2016)
  15. ↑ badische-zeitung.de , Wirtschaft , December 20, 2016, Christian Mihatsch: UN conference sets the course for the preservation of animal and plant diversity (December 20, 2016)
  16. ^ A b V. M. Gantz, E. Bier: The dawn of active genetics. In: BioEssays: news and reviews in molecular, cellular and developmental biology. Volume 38, number 1, January 2016, pp. 50-63, doi : 10.1002 / bies.201500102 , PMID 26660392 .
  17. ↑ deutschlandfunk.de , Research Current , November 1, 2016, Ralf Krauter : Genes in the Service of Dramaturgy (December 20, 2016)