In the fight against the invasive house mouse on islands, scientists are using the rodents’ own genes against it.
With the right tweaks, the introduction of a few hundred genetically engineered mice could wipe out an island’s invasive mouse population in about 25 years, researchers report in the Nov. 15 Proceedings of the National Academy of Sciences. The trick is to add the changes to a section of mouse DNA that’s inherited far more often than it should.
Scientists have created similar non-hereditable genes – so-called gene drives – in the laboratory. The chunks are designed to be passed to most or all of an animal’s offspring instead of the usual half, rendering those offspring sterile as well. Scientists have used gene drives to reduce mosquito and fruit fly populations (SN: 12/17/18).
But mammals are a different story. Scientists have previously synthesized a gene drive that is passed on in mice about 80 percent of the time (SN: 01/23/19). But the drive isn’t powerful enough to quickly stop a population.
Luckily, nature handled it. A haplotype is a naturally occurring group of genes that is passed on as a unit during replication. The genome of the house mouse (Mus musculus) has a specific haplotype, called the t-haplotype, that is passed on to offspring more than 95 percent of the time, instead of the typical 50 percent.
This natural gene drive has advantages, says Anna Lindholm, a biologist at the University of Zurich, who was not involved in the study. It “evolved naturally and persists in the wild, and we haven’t found resistance to it in wild populations,” she says. It is also not found in species other than M. musculus, meaning it is unlikely to spread to other noninvasive mice.
Molecular biologist Paul Thomas and his colleagues decided to attack the t-haplotype using the cut-and-paste molecular tool called CRISPR/Cas9 (SN: 08/24/16). They used CRISPR to insert the gene sequence for the CRISPR tool itself into the t-haplotype. When a male mouse carrying the altered t-haplotype mates with a female, the inserted genes for the CRISPR tool kick into action. It uses a special genetic guide to target and inactivate the gene for the hormone prolactin – rendering all baby female mice infertile.
Best of all, the natural t haplotype can also sterilize males, says Thomas of the University of Adelaide in Australia. Males with two copies – homozygous males – do not reproduce at all.
“If you managed to spread out in a population, you could end up with homozygous males who are infertile,” he says. “And with the added CRISPR element, we get homozygous females that are also infertile.”
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To find out how well the t-haplotype mice are doing on an island where mice are ravaging biodiversity, the scientists used a computer simulation of an island with 200,000 mice. The team found that adding just 256 mice with the CRISPR-altered t-haplotype could successfully zero out the mouse population in about 25 years. Even without CRISPR, adding mice with the normal t haplotype could strain the population in about 43 years.
But models are not mice. In a final test, Thomas and his colleagues turned the model into reality. The team altered the t-haplotype in a small group of mice in the lab and used genetic testing to show that these mice would pass on their new genetics 95 percent of the time.
“It’s a clever idea to build on the t-haplotype’s natural drive system and use CRISPR not to propagate the construct, but to damage genes that are necessary for female fertility,” says Lindholm. “This is a major advance in the development of new tools to control invasive mouse populations.”
The next step, Thomas says, will be to test the effects in real populations of mice in secure enclosures to see if the genetically modified t can stop mice from reproducing. The scientists also want to ensure that any genetically engineered mice released into the wild have a safety mechanism in place so that other mice elsewhere are unaffected.
The final version could target tiny mutations unique to an island where the pest population is isolated, Thomas suggests. If the mouse escaped to the mainland, its altered genes would not affect the native mice. The scientists also want to consult with people living in the area, as officials did when genetically engineered mosquitoes were released in Florida (SN: 05/14/21).
Finally, he notes that 25 years is a long wait for some vulnerable island populations. “We’d like to see CRISPR work faster,” he says. “It’s still a work in progress.”