| December 3, 2002
It May Take A Mouse to Understand
The Behavior of "Jumping Genes"
Mouse Model May Also Aid In Discovery of Gene Function
PA) -Researchers at the University of Pennsylvania
School of Medicine have bred a mouse to model human
L1 retrotransposons, the so-called "jumping genes."
Retrotransposons are small stretches of DNA that are
copied from one location in the genome and inserted
elsewhere, typically during the genesis of sperm and
egg cells. The L1 variety of retrotransposons, in particular,
are responsible for about one third of the human genome.
The mouse model of L1 retrotransposition is expected
to increase our understanding of the nature of jumping
genes and their implication in disease. According to
the Penn researchers, the mouse model may also prove
to be a useful tool for studying how a gene functions
by knocking it out through L1 insertion. Their report
is in the December issue of Nature Genetics and
currently available online (see below for URL).
"There are about a half million L1 sequences in
the human genome, of which 80 to 100 remain an active
source of mutation," said Haig H. Kazazian,
Jr., MD, Chair of Penn's Department of Genetics
and senior author in the study. "This animal model
will help us better understand how this happens, as
well as provide a useful tool for discovering the function
of known genes."
In humans, retrotransposons cause mutations in germ
line cells, such as sperm, which continually divide
and multiply. Like an errant bit of computer code that
gets reproduced and spread online, retrotransposons
are adept at being copied from one location and placed
elsewhere in the chromosomes. When retrotransposons
are inserted into important genes, they can cause disease,
such as hemophilia and muscular dystrophy. On the other
hand, retrotransposons have been around for 500 to 600
million years, and have contributed a lot to evolutionary
"In the grand scheme of evolution, retrotransposons
have behaved like fickle gods, arbitrarily wreaking
havoc in some and benefiting others," said Kazazian.
"Retrotransposons can cause new genes to emerge
that may benefit an organism - or they can kill by knocking
out important genes. Overall, however, it seems that
they are neutral and add to the apparent sloppiness
of the genome."
For some time, researchers have been trying to understand
how retrotransposons affect the genome and, in addition,
what science may learn from the techniques they employ.
According to Kazazian and his colleagues, the mouse
model displays high-frequency chromosome to chromosome
retrotransposition of human L1s, which behave in exactly
the same way as they do in humans. While the current
tissue culture model works well, it does not mimic the
way retrotransposons jump in chromosomes.
The researchers believe that by understanding the mechanics
of retrotransposition, they might be able to use similar
techniques for genetic therapies in humans. They also
hope to learn more about the basic mysteries behind
retrotransposition, such as why L1 retrotransposons
only seem to effect the germ line and not any other
type of cell in the body.
As science refines the content of the mouse genome database,
Kazazian foresees that this model will also be useful
for determining the function of different genes. As
new genes are identified, their purpose can be resolved
by using retrotransposons to knock them out of commission.
"Such knowledge has direct impact in humans,"
said Kazazian, "Information important to determining
the nature of human diseases and developing new therapeutics
can be extrapolated from our knowledge of the mouse
Funding for this research was provided by grants from
the National Institutes of Health.
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Editor's Note: Subscribers to Nature Genetics
may find the article online at www.nature.com/ng/
-- in the Advance Online Publication section.