|MadSci Network: General Biology|
This is a great question, which is a matter of some importance as animal cloning becomes more important for the production of biologically-based pharmaceuticals.
It appears that the principal reason for the shortened lifespan of cloned animals is that they have accumulated errors in gene expression. The process of normal reproduction resets what is called "epigenetic" information. Epigenetic modification of the genome is a kind of chemical modification (typically methylation) that does not alter the sequence of DNA, but which changes its capacity to be expressed.
Here is a reference:
1. Josef Fulka Jr., Norikazu Miyashita, Takashi Nagai & Atsuo Ogura (2004) Do cloned mammals skip a reprogramming step? Nature Biotechnology 22: 25 - 26.
To quote from this reference:
During reproduction, reprogramming occurs in two steps. The first reprogramming event results in the initial de-differentiation of the transferred nucleus, making it competent to direct the development of the embryo. The second reprogramming event has at least three roles: first, epigenetic errors are erased (by as yet unknown mechanisms); second, genomic imprinting is erased and reestablished; and third, telomere length is adjusted definitively, following elongation at the first reprogramming and subsequent gametogenesis.
We presume that cloned animals die earlier not because they are biologically too old, but because they accumulate abnormalities in expression of different genes. When single cells are isolated from cloned fetuses or animals, their proliferation and viability are normal. This has also been recently shown in intestine-derived cloned blastulae from amphibians that were transferred to normal host embryos; after several months, the transferred cells contributed to several host tissues.
To explain this further, the first reprogramming event occurs when a somatic nucleus transferred to an enucleated egg finds itself in a cellular environment that has a different collection of proteins influencing gene activity. The transferred nucleus responds to this altered set of regulatory proteins by undertaking a different program of genetic activity, from whatever its differentiated state was to a totipotent state.
The second reprogramming event, to erase epigenetic errors and imprinting (chiefly methylation), and to adjust telomere length, ordinarily occurs in the germ line during the development of sperm and egg cells. The factors responsible for the second reprogramming event are not present in the fertilized egg. The result of this is an abnormal pattern of gene expression that affects development. Most cloned animals do not make it to live birth, and many late-term animals have developmental abnormalities.
If you are not familiar with imprinting, it is the process by which particular genes (several hundred in the genome) are marked by methylation to be "silent" in either the extraembryonic tissues or in the embryo, depending on whether they were inherited maternally or paternally. It is not obvious why there should be uniparental expression of particular genes, but the current thinking is that it represents a biological solution to the inherent conflict between the sexes in placental mammals, where it is in the "interest" of the paternal genome to maximize growth of offspring, and in the "interest" of the maternal genome to conserve maternal resources to produce as many offspring as possible.
Please see also:
This answer, and the references that I have cited, have many terms that might be unfamiliar to you. You may find the MGI Glossary useful.
Mouse Genome Informatics
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