Biologists at the University of California, San Diego have developed a new method for generating mutations in both copies of a gene in a single generation that could rapidly accelerate genetic research on diverse species and provide scientists with a powerful new tool to control insect borne diseases such as malaria as well as animal and plant pests.

Their achievement was published today in an advance online paper in the journal Science. It was accomplished by two biologists at UC San Diego working on the fruit fly Drosophila melanogaster who employed a new genomic technology to change how mutations could spread through a population--a concept long established in plants by the father of modern genetics, Gregor Mendel.

"Mendel conducted classic genetic experiments with peas that revealed the fundamental of inheritance in many organisms including humans," explains Ethan Bier, a professor of biology at UC San Diego whose graduate student, Valentino Gantz, developed the method. "According to these simple rules of inheritance, the fertilized egg receives one copy of most genes from our mothers and one from our fathers so that the resulting individual has two copies of each gene."

One advantage of having two copies of a gene is that if one copy carries a non-functional mutation, then the other "good" copy typically can provide sufficient activity to sustain normal function. Thus, most mutations resulting in loss of gene function are known as recessive, meaning that an organism must inherit two mutant copies of the gene from its parents before an overt defect is observed, as is the case in humans with muscular dystrophy, cystic fibrosis or Tay Sachs disease.

"Because individuals carrying a single mutant copy of a gene often mate with an individual with two normal copies of gene, defects can be hidden for a generation and then show up in the grandchildren," Bier adds. "This is how genetics has been understood for over a century in diverse organisms including humans, most animals we are familiar with, and many plants."

But in the past two years, Bier and other molecular biologists have witnessed a veritable revolution in genome manipulation. "It is now routine to generate virtually any change in the genome of an organism of choice at will," he notes. "The technology is based on a bacterial anti-viral defense mechanism known as the Cas9/CRISPR system."

By employing this development in their experiments with laboratory fruit flies, Gantz and Bier demonstrated that by arranging the standard components of this anti-viral defense system in a novel configuration, a mutation generated on one copy of a chromosome in fruit flies spreads automatically to the other chromosome. The end result, Bier says, is that both copies of a gene could be inactivated "in a single shot."

The two biologists call their new genetic method the "mutagenic chain reaction," or MCR.

"MCR is remarkably active in all cells of the body with one result being that such mutations are transmitted to offspring via the germline with 95 percent efficiency," says Gantz, the first author of the paper. "Thus, nearly all gametes of an MCR individual carry the mutation in contrast to a typical mutant carrier in which only half of the reproductive cells are mutant."

Bier says "there are several profound consequences of MCR. First, the ability to mutate both copies of a gene in a single generation should greatly accelerate genetic research in diverse species. For example, to generate mutations in two genes at once in an organism is typically time consuming, because it requires two generations, and involved, because it requires genetic testing to identify rare progeny carrying both mutations. Now, one should simply be able to cross individuals harboring two different MCR mutants to each other and all their direct progeny should be mutant for both genes."

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New genetic method promises to advance gene research and control insect pests

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