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More evidence of genomic problems in cloned mice
  

Few cloned embryos survive to birth, and those that do are plagued with myriad health problems. A new study adds to the growing evidence that biological problems in cloned animals are due to changes in how genes are regulated. The findings suggest that problems occur because genes are not switching on and off according to a normal program of activation, or expression.


Removing the maternal nucleus during nuclear transfer.

The cloning procedure itself does not seem to be to blame, according to researchers at the National Institute on Aging in Baltimore and the Central Institute for Experimental Animals in Kawasaki, Japan. In an upcoming issue of Developmental Biology, the researchers will describe abnormalities in gene expression in the placenta of cloned mouse embryos.

A recent study by Rudolf Jaenisch and his colleagues at the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, found that the program of gene expression in some cloned animals was compromised.

Now, the team led by Minoru Ko, of the Institute on Aging, says that the problems with gene expression in clones are caused by flaws in the structural integrity of the genome and not by the cloning procedure.

Cloning typically involves the transfer of the nucleus from an adult cell to an egg whose nucleus has been removed. But before an embryo can develop, the genome has to be reprogrammed so that only the genes needed for development are activated. In most cases, this is an inefficient process.

Ko and his colleagues wanted to see the extent to which abnormal gene expression contributes to problems in development. When they transferred nuclei from mouse embryonic stem cells in culture, less than two percent of the clones survived. And those that did developed abnormally large and disfigured placentas.

However, when the researchers transferred the nucleus from a fertilized egg at the one-cell stage to an egg without a nucleus, the resulting clones developed normal placentas and 50 percent survived to birth.

The researchers also examined the function of more than 15,000 mouse genes using a technique known as DNA microarray analysis. They identified nearly 2,000 genes in clones derived from cultured embryonic stem cells that were expressed abnormally. Among the genes abnormally expressed were a gene involved in tissue remodeling and other genes known to promote placental growth.

"The results suggest that the developmental abnormalities typically found in cloned animals is due to the status of the donor nucleus," says Ko. When the nucleus being transferred comes from a recently fertilized embryo and not a cultured cell or a mature cell, the resulting clones appear normal, he adds.

"Microarray analysis allows us throw out a larger net to look at gene abnormalities in cloned animals," says Ko. "This is just the beginning. Next, we need to see what is going on earlier in development."

In another development in the field, last week the British researcher Ian Wilmut, who led the cloning of Dolly the sheep, made public plans to use cloning techniques to create human embryos for research purposes. If the project wins approval, the embryos will be used to study "serious genetic illness," according to a statement by the Roslin Institute in Edinburgh.

"Roslin Institute and Professor Ian Wilmut remain strongly opposed to the use of cell nuclear replacement for the cloning of children," the statement says.

See related GNN article
»Cloned Mice Have Genomic Flaws

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Suemizu, H. et al. Expression profiling of placentomegaly associated with nuclear transplantation of mouse ES cells. Dev Biol. In press.

Press release, Roslin Institute, Edinburgh, United Kingdom (October 13, 2002).

Wilmut, I. et al. Somatic cell nuclear transfer. Nature 419, 583-587 (October 10, 2002).

Humpherys, D. et al. Abnormal gene expression in cloned mice derived from embryonic stem cell and cumulus cell nuclei. Proc Natl Acad Sci USA 99, 2889-2894 (October 01, 2002).
 

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