Japanese researchers have transplanted an entire human chromosome into a mouse, and its genes appear to be functioning normally in their new host. This dramatic development, which surprised even the researchers who carried it out, is being hailed as a landmark achievement, which could lead to advances ranging from how we understand genetic diseases such as Down syndrome, to how complex gene families work together.
For years, researchers have been able to transfer isolated human genes into a mouse chromosome. But they could not insert both the foreign gene and the instructions for where that gene should be expressed--making it difficult to interpret results from mouse models. Isao Ishida, a geneticist at the Kirin brewing company in Japan, and his colleagues overcame these regulatory difficulties by developing a way to add a whole chromosome--regulatory sequences and all--to mouse cells. That's about 50 times the amount of DNA transferable with previous techniques.
Ishida's group, which reports its results in the June issue of Nature Genetics, first tagged individual human chromosomes with a gene conferring resistance to the antibiotic neomycin. They then inserted these tagged chromosomes into specialized mouse cells called A9 cells that are prone to fragmenting into microcells that contain a single chromosome. Next, they fused these microcells with embryonic mouse cells, hoping that the embryonic cell would pick up the human chromosome. The researchers then used neomycin to kill off any embryonic cells that didn't contain a tagged human chromosome. Because the survivors were unable to grow into embryos themselves, the researchers mixed them with multicelled mouse embryos and implanted the conglomerate into a mouse uterus.
Mice containing a human chromosome were born 21 days later. These animals properly expressed a group of human immune genes in their thyroid, human heart muscle genes in the heart, and human liver genes in the liver. Ishida says the expression of genes from this chromosome was "very specialized," a big surprise even to him, he says, as this means that mouse cells interpret the human regulatory sequences correctly. The researchers are already planning follow-up studies to better understand just how this interpretation takes place.
Ishida says his technique "will provide valuable animal models to study developmental, congenital, and biological anomalies," because researchers can now study genes, and gene families, that are being expressed in the proper tissues. The work could also lead to advances in understanding diseases such as Down syndrome, caused by extra copies of chromosome 21, according to Sohaila Rastan of SmithKline Beecham Pharmaceuticals, in Essex, United Kingdom. Ishida's work, says Rastan, "represents a large step" in using mice to study human genes.