Mutants with heterozygote disadvantage can prevent spread of transgenic animals

Nov 21, 2011
Simulated release of 13 transgenic individuals in two populations that consist of 25 individuals each, which are connected via migration (horizontal axis: frequency of the mutated gene in population 1; vertical axis: frequency of mutated gene in population 2). Left: At a migration rate of 1 percent, both populations behave as desired in release trials: in population 1, the frequency of the mutation very quickly decreases and approaches zero. In population 2, however, there is a high probability that the mutated gene will dominate over the natural gene variant, and this state is maintained for a long time (yellow). As a result, at this migration rate, the time to extinction is very long in both populations. Right: At a migration rate of 10%, the mutation is very likely to be quickly lost in both populations. Credit: Phillip M. Altrock/MPI for Evolutionary Biology

Genetically modified animals are designed to contain the spread of pathogens. One prerequisite for the release of such organisms into the environment is that the new gene variant does not spread uncontrollably, suppressing natural populations. Scientists at the Max Planck Institute for Evolutionary Biology in Plon, Germany, have now established that certain mutations are maintained over an extended period if two separate populations exchange individuals with one another on a small scale. The new gene variant may remain confined to one of the two populations. The migration rate between the populations determines how long the new gene variant is expected to survive in the environment. These new findings may help to achieve greater safety when conducting release experiments involving genetically modified animals.

Genetically modified must not be allowed to spread uncontrollably. Scientists are therefore keen to take advantage of a mechanism that will localise the spread of mutants. Mutants with a heterozygote disadvantage, as it is known, reduce the evolutionary fitness of their carriers to varying degrees if they are only available to one gene copy (heterozygote) or exist in both gene copies (homozygote). In their study, the Max Planck scientists assumed a fitness loss of 50 percent (compared to wildtypes) for mutant heterozygotes and a 10 percent fitness loss for mutant homozygotes.

A mutant with a heterozygote disadvantage can be maintained in a population if it occurs frequently enough for sufficient homozygote to be produced. Above this value, it can suppress the non-mutated completely and the mutated form becomes extinct. Populations containing mutants with heterozygote disadvantage develop into one of two stable states. These mutant types therefore seem to be well-suited for the safe release of genetically modified organisms. After all, as soon as sufficient numbers of mutants exist in the environment, these replace the natural variant in a local population. If such genes are joined to resistance genes to combat pathogens, mosquito populations could be rendered resistant to Malaria, for example. By releasing the wildtype at a later stage, the transgenic animals can therefore also be removed again more easily from the environment. In population genetics this is known as underdominance.

The researchers then analyzed computer-based simulations showing the effect of mutants with heterozygote disadvantage on two populations of equal size, which, as in nature, are subject to statistical fluctuations. In doing so, they paid particular attention to the gene flow arising from the mobility of the individuals. At times, such a mutation can survive in a stable state in a population. However, this only happens if the migration rate is less than 5 percent. "Our calculations have also shown that mutants are best released into both populations even if the goal is to establish the new genetic variant in only one of them in the long term. If, for example, 75 percent of transgenic animals are distributed to the target population and the remaining 25 percent to a neighbouring population, the transgenic individuals may find it easier to gain traction on a long-term basis in the target population," explains Philipp Altrock from the Max Planck Institute for .

Scientists in the USA, Brazil, Malaysia and the Cayman Islands have been conducting field experiments on the use of genetically modified animals for several years. These include, for example, experiments involving mosquitoes, to protect against infectious diseases such as malaria or dengue fever, and transgenic plant pests. Similar experiments are planned in another nine countries. To date, the males from various insect species, which are generally infertile, are released. In this way, the effective size of the wild population is limited. "One of the disadvantages of this method is that it needs to be repeated very frequently as the transgenic animals cannot reproduce," says Arne Traulsen from the Max Planck Institute in Plön. In addition, in the case of mosquitoes, a few parent individuals can already have a large share of the next generation.

In contrast, mutants with heterozygote disadvantage can survive for many generations. Resistance genes linked to such would therefore be more efficient. The safety aspect also increases, as proliferation across a target population is very unlikely. "Nevertheless, the fitness of the transgenic , the sizes, and the migration rates must be known. These factors can most likely be determined for release experiments on maritime islands," says Arne Traulsen.

Explore further: MaxBin: Automated sorting through metagenomes

More information: Altrock PM, Traulsen A, Reed FA, 2011, Stability Properties of Underdominance in Finite Subdivided Populations. PLoS Comput Biol 7(11): e1002260. doi:10.1371/journal.pcbi.1002260

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