Regulating the expression of gene drives is key to increasing their invasive potential and the mitigation of resistance

Autor: Andrea Crisanti, Ioanna Morianou, Tony Nolan, Nace Kranjc, Andrew Hammond, Kyros Kyrou, Matthew Gribble, Roberto Galizi, Andrea Beaghton, Xenia Karlsson, Austin Burt
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Cancer Research
Life Cycles
DNA End-Joining Repair
Heredity
Hydrolases
Physiology
Eggs
QH426-470
Disease Vectors
Biochemistry
Mosquitoes
Germline
0302 clinical medicine
Medical Conditions
Larvae
Reproductive Physiology
Medicine and Health Sciences
Genetics (clinical)
Genetics
0303 health sciences
education.field_of_study
Heterozygosity
biology
Eukaryota
Penetrance
Enzymes
Insects
Drosophila melanogaster
Infectious Diseases
Fecundity
Regulatory sequence
Larva
qu_450
Research Article
Heterozygote
Arthropoda
Nucleases
Population
qu_58.5
03 medical and health sciences
Population Metrics
DNA-binding proteins
Animals
Humans
Allele
education
Molecular Biology
Gene
QH426
Ecology
Evolution
Behavior and Systematics
Alleles
Germ-Line Mutation
030304 developmental biology
Nuclease
Biology and life sciences
Population Biology
qu_4
Organisms
Proteins
Gene drive
Endonucleases
Invertebrates
Malaria
Insect Vectors
Species Interactions
Culicidae
Fertility
Genetic Loci
Mutation
biology.protein
Enzymology
Genetic Fitness
CRISPR-Cas Systems
qu_470
Zoology
Entomology
030217 neurology & neurosurgery
Developmental Biology
Zdroj: PLoS Genetics
PLoS Genetics, Vol 17, Iss 1, p e1009321 (2021)
ISSN: 1553-7404
1553-7390
Popis: Homing-based gene drives use a germline source of nuclease to copy themselves at specific target sites in a genome and bias their inheritance. Such gene drives can be designed to spread and deliberately suppress populations of malaria mosquitoes by impairing female fertility. However, strong unintended fitness costs of the drive and a propensity to generate resistant mutations can limit a gene drive’s potential to spread. Alternative germline regulatory sequences in the drive element confer improved fecundity of carrier individuals and reduced propensity for target site resistance. This is explained by reduced rates of end-joining repair of DNA breaks from parentally deposited nuclease in the embryo, which can produce heritable mutations that reduce gene drive penetrance. We tracked the generation and selection of resistant mutations over the course of a gene drive invasion of a population. Improved gene drives show faster invasion dynamics, increased suppressive effect and later onset of target site resistance. Our results show that regulation of nuclease expression is as important as the choice of target site when developing a robust homing-based gene drive for population suppression.
Author summary Gene drives are selfish genetic elements that are able to drastically bias their own inheritance. They can rapidly invade populations, even starting from a very low frequency. Recent advances have allowed the engineering of gene drives deliberately designed to spread genetic traits of choice into populations of malaria-transmitting mosquito species–for example traits that impair a mosquito’s ability to reproduce or its ability to transmit parasites. The class of gene drive in question uses a very precise cutting and copying mechanism, termed ‘homing’, that allows it to increase its numbers in the cells that go on to form sperm or eggs, thereby increasing the chances that a copy of the gene drive is transmitted to offspring. However, while this type of gene drive can rapidly invade a mosquito population, mosquitoes can also eventually become resistant to the gene drive in some cases. Here we show that restricting the cutting activity of the gene drive to the germline tissue is crucial to maintaining its potency and we illustrate how failure to restrict this activity can lead to the generation of mutations that can make mosquitoes resistant to the gene drive.
Databáze: OpenAIRE
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