Failures in genetic programming may cause death and defects in cloned animals

Defects in a process called gene imprinting may explain why cloned animal embryos often fail to survive or give rise to animals with significant birth defects, a new report has said.

Despite recent success in the cloning of various animals, the use of adult somatic cells as the source of donor nuclei has faced obstacles, among them high rates of abortion, high birth weight among cloned offspring, and an increased likelihood of perinatal death. These shortcomings may be the result of incomplete genetic reprogramming of the donor DNA, according to a new study by Dr Yong-Mahn Han of the Korea Research Institute of Bioscience and Biotechnology and colleagues (Nature Genetics 2001;28:173-7).

In normal reproduction, both parents contribute genes to an offspring. One copy of a gene, either from the mother or the father, is expressed, or turned on. The other copy is turned off through a process of methylation that consists of the addition of extra carbon groups.

Soon after an embryo is formed, the methylation markers on the genes that it inherits are removed in a process called demethylation, so that the slate is wiped clean and new genetic imprinting can take place on the DNA. In cloned reproduction, however, where both sets of genes come from the same “parent,” these normal processes frequently go awry.

To arrive at these conclusions, the researchers monitored the reprogramming process that acts on a genome transplanted from adult cow cells to enucleated cow egg cells by analysing genomic methylation patterns. They found that, compared with normal cow embryos, cloned cow embryos displayed unusual patterns of genetic imprinting or methylation. In addition, the researchers could not detect any signs of demethylation in the cloned embryos.

The study provides an answer to the question of why the cloning of animals is still an inefficient process. Demethylation of cloned embryos does not occur during early development, which may result in the high failure of cloned embryos.

Of course, some cloned animals do live, although the survival rate is low. This suggests that normal demethylation does occur in some cases. The researchers said that the discovery that demethylation does not work properly in cloned embryos may help researchers to identify ways of improving the survival rate of cloned animals.

“The implication is that our data offer a clue to improve the efficiency of cloning animals. They give answers about the reason why the efficiency of cloning animals is so low,” Dr Han said. “Cloned animals have already succeeded in a variety of species such as cattle, pig, sheep, goats, and mice. Our data show that a few embryos are being demethylated during early development,” he said.