Mouse of a Different YAC: Yeast Artificial Chromosomes Make Possible Bigger Gene Transfers

By Pennisi, Elizabeth | Science News, June 5, 1993 | Go to article overview

Mouse of a Different YAC: Yeast Artificial Chromosomes Make Possible Bigger Gene Transfers


Pennisi, Elizabeth, Science News


Eleven years ago, scientists shocked the public when they produced larger-than-life mice by inserting a rat gene for growth hormone. Transgenic animals, then considered a miracle of genetic engineering, quickly took their place as laboratory workhorses essential in many types of research and in the production of medically useful compounds. Mice engineered to carry the gene responsible for cystic fibrosis, for instance, count as one of several animal models that researchers study as they pursue treatments for human diseases.

But until recently, transgenic mice carried only small pieces of foreign genetic material -- genes no more than 50,000 base pairs long -- in their cells. Genes responsible for many important disorders, such as muscular dystrophy and hemophilia, cover 1 million or more base pairs of nucleotides, the basic building blocks for DNA. Scientists just didn't know how to make enough copies of such giant strands of DNA; nor had they figured out how to get mammoth chunks of genetic material into mice.

Now, several research groups have pushed back the frontiers of transgenicity, creating mice that thrive not only with large genes but also, in some cases, with the entire genetic repertoire, or genome, of yeast inside the nucleus of each cell. These successes pave the way for a new generation of transgenic animals capable of mimicking human disease or producing proteins and antibodies that pass for our own. The new technology may also speed progress in understanding how genes work and in tying particular genes to specific biological problems.

"It gives you a way to assess genes on the level of a whole organism," says Roger H. Reeves, a geneticist at Johns Hopkins University School of Medicine in Baltimore. "It allows the information from the Human Genome Project [an ongoing effort to identify all human genes] to be applied across all areas of disease."

These advances make use of techniques developed six years ago at Washington University in St. Louis, when molecular geneticist Maynard V. Olson and student David Burke realized that yeast would readily make multiple copies of synthetic DNA inserted into them. "There had been a lot of work done during the preceding 10 years defining the components required for DNA molecules to function as chromosomes in yeast," recalls Olson, now at the University of Washington in Seattle. Burke put that knowledge to use and made the first yeast artificial chromosomes, dubbed YACs.

YACs contain tiny bits of DNA that make them look--and replicate--like the yeast's own genetic material. "You have all the elements of a natural chromosome," says Gunther Schutz, a molecular biologist at the German Cancer Research Center in Heidelberg. In addition to these bits, extra DNA from other organisms, including mice and even people, can make up the core of each YAC. The core can extend for quite a stretch without upsetting the yeast's genetic operations, Schutz adds.

Olson's group and scientists at about 10 other research laboratories have since generated large YAC "libraries" by chopping up mouse or human chromosomes and splicing the pieces to yeast genetic material. Then the yeast cells do the work of making millions of copies of that YAC as they replicate. Scientists seeking to study a particular gene can borrow YACs from these libraries for use in their experiments.

But not until this spring have molecular geneticists used YACs for moving big genes into other organisms and shown that those genes pass on to succeeding generations. In March, three teams independently reported successes with slightly different techniques; several others are close on the heels of these first achievements.

"This was the missing step -- putting [YACs] into the mice," says Rudolf Jaenisch of the Whitehead Institute for Biomedical Research in Cambridge, Mass. And while genetic engineers have yet to transfer genes that number a million base pairs, researchers think such transfers are now possible. …

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