Re: why was a sheep picked as an animal to clone?

Ian Wilmut of the Roslin Institute, the scientist who cloned Dolly, has 
written a book on the project:

Wilmut, I., Campbell, K. & Tudge, C. (2000)
The second creation: The age of biological control by the scientists who 
cloned Dolly.
London: Headline Book Publishing. ISBN 0747275300 (paperback), 0747221359 
(hardback) 

This would be a great source of information on the topic.

There is an excellent brief history of cloning and genetic modification at 
one of the Roslin Institute's web pages:
 http://www.ri.bbsrc.ac.uk/library/research/cloning/archive/
history.html

Here you will see that the first animal to be cloned was the frog, in 1952. 
In the press reports about Dolly as the first cloned animal, we encounter 
the use of the word 'animal' as a synonym for 'mammal' by non-scientists.

There was a report of the cloning of mice in 1977, but this work was not 
reproducible by other scientists. It is possible that this was legitimate 
research, but work that cannot be reproduced by other scientists is regarded 
with suspicion in the scientific community.

There was a strong incentive to get cloning to work in sheep, because 
transgenic sheep that produced various proteins of pharmaceutical interest 
in their milk had been produced. These transgenic sheep had been produced by 
injecting a gene construct into the egg pronucleus. Such transgenics contain 
many copies of the gene construct, usually present as tandem arrays in 
random genomic locations. 

Transgenics of this kind are useful in mice, but much more useful are 
targeted mutations. In mice, these are produced by modifying cultured 
embryonic stem cells, then producing chimeric embryos, which are then bred 
to recover the genetically modified mice. It takes three generations to get 
from a cultured cell to homozygous modified mice. The first generation is 
chimeric; the second generation, bred from chimeras, is heterozygous; the 
third generation, bred from heterozygotes, has some homozygous mice (if 
these are viable). There is a cartoon of this technique at:
 http://
www.ri.bbsrc.ac.uk/molbiol/mcwhir/embryoni.htm

A generation in mouse is much shorter than in sheep, so it was seen as very 
important to figure out a way to get modified sheep tissue culture cells to 
serve as nuclear donors for embryos. This would let researchers skip a 
generation, which in sheep is effectively a year.

So the success with Dolly was a combination of an incentive to get the work 
done, which the very much larger community of mouse researchers did not 
have, and hard work by skilled people. It is likely that many scientists 
were discouraged from attempting cloning of other mammals because they 
'knew' that it wouldn't work. Scientists 'knew' this because of the 
discovery of 'imprinting'. This is the name given to the phenomenon that the 
same genes are not equivalent when inherited from the mother vs. the father. 
A clear demonstration of this is Prader-Willi syndrome in humans. Infants 
inheriting a chromosomal deletion (the absence of a group of genes on 
chromosome 15) from their fathers are afflicted with this syndrome, while 
the same deletion inherited from their mothers does not cause the syndrome 
(it causes a clinically distinct syndrome). Even more striking are cases of 
uniparental disomy, in which an infant has inherited two copies of a normal 
chromosome 15 from the father and no chromosome 15 from the mother; these 
infants also have Prader-Willi syndrome, even though they are not missing 
any genes. Please see the entry for Prader-Willi at OMIM:
  http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?176270

The phenomenon of imprinting is widespread in mammals, involving several 
different chromosome regions. This made most scientists think that mammals 
couldn't be cloned, because you would have to take the donor nucleus from a 
male or a female cell, and in either case you wouldn't be transmitting genes 
from the other sex.

Once Dolly was cloned, however, scientists figured out that they 'knew' 
something wrong, and many other cloning experiments followed. See my MadSci 
answer on this at:
 /cgi-bin/circR?/posts/
archives/984508482.Ge.r.html

I have used many genetic terms in this answer. You might find this online 
Glossary useful:
 http://
www.informatics.jax.org/userdocs/glossary.shtml

Thank you for an interesting question.

Yours,

Paul Szauter
Mouse Genome Informatics