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Will cloned animals suffer premature aging--the story at the end of clones' chromosomes.

Xu J, Yang X - Reprod. Biol. Endocrinol. (2003)

View Article: PubMed Central - HTML - PubMed

Affiliation: Evergen Biotechnologies, Inc, 1392 Storrs Road, Unit 4213, University of Connecticut Incubator Program, Storrs, CT 06269, USA. jxu@evergen.com

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Scientists have long worried that cloned animals might inherit its age from its cell donor, thus being born old and die early... In this way telomere length is fully transmitted from generation to generation (for example, a child is born with telomeres the similar length as those his father or grand father were born with, although a father's would be considerably shorter than his son's) while most somatic cells, body cells not involved in reproduction, erode the ends of their chromosomes with each cell division... The results corresponded to the reasoning quite well: the somatic donor cell does not have telomerase activity – telomere length can not be restored – clones should be born with telomere length similar to that of their donor cells... Although results equivalent to Dolly's were found by Kato et. al., when they observed many characteristics of ageing in male clones derived from a 10 year old bull (numerous wrinkles in the skin, thick bone structure and rough hairs) as well as shortened telomeres, many other research teams soon discovered that telomere restoration can take place in cloned animals... The fact that cloning could extend telomere length drew media attention and swung the pendulum of popular, and scientific, opinion from pessimism to optimism: if indeed, telomere length is the indicator of an individual's life span, and our understanding of the elongation mechanism is or will be good enough to make the process controllable, the nuclear transfer technique is offering us the possibility to rejuvenate cells thus making the dream of immortality closer to a reality... Other explanations include oxidative damage, accumulation of genomic changes, Mitochondrial DNA mutations, etc. (for review, see )... In a further deviation from the above mentioned results, Tian et. al. and Betts et. al. found that telomere lengths of their clones' were not different from those of control animals; they were neither longer, nor shorter... In this study, they produced 14 cloned cattle using nuclei of donor cells derived from muscle, oviduct, mammary and ear skin... All three types (normal, shorter, longer) of telomeres were found when different donor cell types were compared... In Dolly's study, the animal produced from fetal tissue appeared to have telomere lengths non-distinguishable from normal controls, while the other two, including Dolly, which originated from adult cells, were found to have shorter telomeres... After many groups have demonstrated the various possibilities of cloning, it is at the point of investigating the molecular basis of telomere/telomerase (and other epigenetic) programming/reprogramming events in embryo development (and through nuclear transfer) and only this can provide a conclusive answer to questions such as 'how old was Dolly'... Both the live (15.38 kb) and dead (15.87 kb) clones had telomeres of the same lengths as controls (14.73 kb)... The dead clones were found to have abnormal X chromosomes inactivation in a later study, indicating that the high fatality rate of clones is related to abnormal gene expression during embryo development.

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Telomeres shorten in somatic cells with each cell division.
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Figure 1: Telomeres shorten in somatic cells with each cell division.

Mentions: The ends of eukaryotic chromosomes are capped with copies of a hexamer repeat sequence (5'TTAGGG3' in human) and associated proteins [3]. These structures are known as telomeres. Telomeres stabilize the ends of chromosomes during replication [4]. Conventional DNA polymerases replicate DNA only in the 5' to 3' direction and cannot initiate de novo synthesis of a DNA chain [5]. The DNA polymerases that replicate eukaryotic chromosomes use an 8- to 12-base stretch of RNA to prime DNA synthesis. As a consequence, after DNA replication, one end of a linear chromosome will be replicated to the very end, whereas the other end will have a short 8- to 12-base gap generated by removal of the RNA primer. Because a conventional DNA polymerase can not fill in this 5' gap, in every subsequent cell division a given DNA end will be incompletely replicated. In yeast, the end of a linear chromosome will shorten by an average of 4 to 6 bases per cell division unless telomeres act as substrates for an alternative replication mechanism (for example, telomerase is able to add telomeric repeats onto the ends of chromosomes) [3]. In human fibroblast cell culture, telomere length decreases at a rate of 48 ± 21 base pairs per population doubling [6,7]. In vivo, Hastie et al [8] studied human lymphocytes and found that the rate of telomere loss is about 33 base pairs per year. Many scientists propose the telomere as a "mitotic clock" [8-10], whose length correlates with the number of cell divisions and indicates the molecular age of the cell (Fig. 1).


Will cloned animals suffer premature aging--the story at the end of clones' chromosomes.

Xu J, Yang X - Reprod. Biol. Endocrinol. (2003)

Telomeres shorten in somatic cells with each cell division.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC305328&req=5

Figure 1: Telomeres shorten in somatic cells with each cell division.
Mentions: The ends of eukaryotic chromosomes are capped with copies of a hexamer repeat sequence (5'TTAGGG3' in human) and associated proteins [3]. These structures are known as telomeres. Telomeres stabilize the ends of chromosomes during replication [4]. Conventional DNA polymerases replicate DNA only in the 5' to 3' direction and cannot initiate de novo synthesis of a DNA chain [5]. The DNA polymerases that replicate eukaryotic chromosomes use an 8- to 12-base stretch of RNA to prime DNA synthesis. As a consequence, after DNA replication, one end of a linear chromosome will be replicated to the very end, whereas the other end will have a short 8- to 12-base gap generated by removal of the RNA primer. Because a conventional DNA polymerase can not fill in this 5' gap, in every subsequent cell division a given DNA end will be incompletely replicated. In yeast, the end of a linear chromosome will shorten by an average of 4 to 6 bases per cell division unless telomeres act as substrates for an alternative replication mechanism (for example, telomerase is able to add telomeric repeats onto the ends of chromosomes) [3]. In human fibroblast cell culture, telomere length decreases at a rate of 48 ± 21 base pairs per population doubling [6,7]. In vivo, Hastie et al [8] studied human lymphocytes and found that the rate of telomere loss is about 33 base pairs per year. Many scientists propose the telomere as a "mitotic clock" [8-10], whose length correlates with the number of cell divisions and indicates the molecular age of the cell (Fig. 1).

View Article: PubMed Central - HTML - PubMed

Affiliation: Evergen Biotechnologies, Inc, 1392 Storrs Road, Unit 4213, University of Connecticut Incubator Program, Storrs, CT 06269, USA. jxu@evergen.com

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Scientists have long worried that cloned animals might inherit its age from its cell donor, thus being born old and die early... In this way telomere length is fully transmitted from generation to generation (for example, a child is born with telomeres the similar length as those his father or grand father were born with, although a father's would be considerably shorter than his son's) while most somatic cells, body cells not involved in reproduction, erode the ends of their chromosomes with each cell division... The results corresponded to the reasoning quite well: the somatic donor cell does not have telomerase activity – telomere length can not be restored – clones should be born with telomere length similar to that of their donor cells... Although results equivalent to Dolly's were found by Kato et. al., when they observed many characteristics of ageing in male clones derived from a 10 year old bull (numerous wrinkles in the skin, thick bone structure and rough hairs) as well as shortened telomeres, many other research teams soon discovered that telomere restoration can take place in cloned animals... The fact that cloning could extend telomere length drew media attention and swung the pendulum of popular, and scientific, opinion from pessimism to optimism: if indeed, telomere length is the indicator of an individual's life span, and our understanding of the elongation mechanism is or will be good enough to make the process controllable, the nuclear transfer technique is offering us the possibility to rejuvenate cells thus making the dream of immortality closer to a reality... Other explanations include oxidative damage, accumulation of genomic changes, Mitochondrial DNA mutations, etc. (for review, see )... In a further deviation from the above mentioned results, Tian et. al. and Betts et. al. found that telomere lengths of their clones' were not different from those of control animals; they were neither longer, nor shorter... In this study, they produced 14 cloned cattle using nuclei of donor cells derived from muscle, oviduct, mammary and ear skin... All three types (normal, shorter, longer) of telomeres were found when different donor cell types were compared... In Dolly's study, the animal produced from fetal tissue appeared to have telomere lengths non-distinguishable from normal controls, while the other two, including Dolly, which originated from adult cells, were found to have shorter telomeres... After many groups have demonstrated the various possibilities of cloning, it is at the point of investigating the molecular basis of telomere/telomerase (and other epigenetic) programming/reprogramming events in embryo development (and through nuclear transfer) and only this can provide a conclusive answer to questions such as 'how old was Dolly'... Both the live (15.38 kb) and dead (15.87 kb) clones had telomeres of the same lengths as controls (14.73 kb)... The dead clones were found to have abnormal X chromosomes inactivation in a later study, indicating that the high fatality rate of clones is related to abnormal gene expression during embryo development.

Show MeSH