Imprinting and Developmental Problems in Cloned Animals

IMPRINTING AND DEVELOPMENTAL PROBLEMS IN CLONED ANIMALS

Even after the technological problems have been conquered, most attempts at cloning animals still fail. Successful nuclear transplantation involves reprogramming a nucleus from a differentiated cell. This is a complex process and the low success rate is probably due to failure to properly reprogram. Recent investigations implicate DNA methylation as the major factor.

Methylation patterns in cloned embryos are not identical to those in natural embryos. This is even true for most successfully cloned animals. However, Dolly and other cloned animals have given rise to genetically normal offspring, so cloning does not introduce permanent genetic alterations into an animal’s germline.

Methylation generally shuts down eukaryotic genes that are not required in a particular tissue or at a particular stage in development. Methylation is also involved in imprinting, the regulatory mechanism that activates only the maternal or paternal copy of a gene. There are about 40 imprinted genes in humans. Usually, when the paternal copy is active fetal growth is promoted; whereas, when the maternal copy is active fetal growth is limited. Not surprisingly, incorrect imprinting patterns cause aberrant fetal growth and development as seen in many embryos derived from cloning.

Cloned mammals often display large-offspring syndrome. Their limbs, interior organs, and overall body size are abnormally large. The resulting animals are unhealthy. This syndrome is associated with incorrect imprinting of IGF2R, the gene for insulin growth factor 2 receptor. This gene normally shows maternal imprinting in mammals. In fetuses with large-offspring syndrome, the IGF2R gene showed altered methylation, and its expression was lower than normal. Curiously, the IGF2R gene is not imprinted in primates, so humans and monkeys should be less susceptible to large-offspring syndrome and might be expected to show less damage on cloning, at least from this particular cause.