Contact

Duke Health News

919-660-1306

Durham, N.C. - By comparing genes in the opossum and the
platypus, Duke University Medical Center researchers have
uncovered evidence that questions the origin of "genomic
imprinting" - a process by which a gene's expression is
governed solely by which parent donated the gene copy, rather
than by the classic laws of Mendelian genetics, in which genes
are either dominant or recessive.

The findings also resolve questions surrounding the
structure of the mammalian evolutionary tree and may open the
door to better evaluation of carcinogenic agents.

The theory of the evolution of genomic imprinting holds that
imprinted genes, which usually are related to growth and
development, represent a genetic "battle of the sexes" - a
competition between paternally imprinted genes that lead to
enhanced fetal growth and maternally imprinted genes that
restrict growth, saving nutrients for the mother herself.

According to this theory, animals without a lengthy fetal
development stage - such as marsupials, whose infants leave the
womb while still embryonic and develop in external pouches, and
egg-laying monotremes, the most primitive order of mammals -
were not expected to be imprinted.

However, in the April 21 issue of the journal Molecular Cell, a research team
led by graduate student Keith Killian and principal
investigator Randy Jirtle reports that a particular gene,
called M6P/IGF2R, is imprinted in the marsupial opossum but not
in the platypus, a monotreme. Until now, imprinted genes had
not been examined in such primitive mammals.

"This finding suggests that M6P/IGF2R imprinting evolved a
lot farther back than we thought, in a precursor animal between
what are currently the monotremes and marsupials," Jirtle said.
He is a professor of radiation oncology and associate professor
of pathology at Duke University Medical Center and a member of
the Duke Comprehensive Cancer Center.

The M6P/IGF2R gene codes for the receptor for another
molecule, called "insulin-like growth factor 2" (IGF2), whose
gene is also imprinted in many mammals. Both genes are involved
in growth, but imprinted M6P/IGF2R is maternally expressed,
while IGF2 is paternally expressed.

The researchers' finding that M6P/IGF2R is imprinted in the
opossum, but not in the platypus, supports the idea that
imprinting is due to a "battle of the sexes," but the primary
requirement seems to be competition for survival among the
young, rather than a lengthy fetal development period.

"Young opossum must crawl to reach the pouch and latch on,
and this is consistent with a battle of the sexes for nutrient
allocation as a reason for imprinted genes," said Jirtle. "For
the opossum, it's literally a race for life. But since opossum
have only a 13-day gestation period, a lengthy fetal
development stage is not necessary for imprinting to
arise."

Unlike puppies or piglets, once newborn opossum latch on to
the mother's nipple, they can't let go until they grow large
enough to open their mouths. Since there are only a dozen
nipples for up to 50 babies in a single litter, competition is
important. The faster a baby opossum can climb, the more likely
it is to survive, and the more likely its genes will be passed
on. On the other hand, there's no active competition on the
part of young platypus.

While competition to ensure genes' survival can explain why
imprinting first evolved for marsupials, it doesn't answer why
imprinted genes still exist in higher mammals, such as humans.
In lower mammals a single group of offspring can be fathered by
more than one male, but in higher mammals that is very
unlikely, making competition between offspring to keep their
fathers' genes in the pool unnecessary.

"About 30 imprinted genes are known, but there may be as
many as 500. We don't know if humans need these imprinted
genes, or if we would be OK without them," Jirtle said.
"Nevertheless, we have them and as a result of their limited
expression,they become targets for developmental diseases and
cancer."

If something happens to the functional copy of an imprinted
gene, there's no back-up as with other genes. "These are growth
promoting and growth inhibiting genes, for the most part,"
Jirtle explained. "If the balance is altered, you could lose a
tumor suppressing gene or turn on an oncogenic one."

In fact, mutations of IGF2 and M6P/IGF2R appear to be early
steps in a wide variety of cancers, scientists say. In many
tumors, both copies of growth-inducing IGF2 are turned on,
despite the gene being imprinted in humans. For M6P/IGF2R,
which is not imprinted in humans, both copies normally
function. However, in more than 60 percent of human liver
cancers, 30 percent of breast cancers and 50 percent of lung
cancers at least one copy of this growth-suppressing gene
doesn't work.

Since humans have two functioning M6P/IGF2R genes, but mice
have only one due to imprinting, it's reasonable to think that
humans should be more resistant to cancer-causing agents. Right
now, however, possible carcinogens are tested on mice. Jirtle
and Killian want to develop a "better" mouse - one with two
working copies of M6P/IGF2R that might better reflect human
susceptibility to cancer-causing agents.

Another of the study's findings should help them figure out
how to turn on the mouse's silent M6P/IGF2R gene. While other
researchers have reported finding the region of DNA that
controls the imprinting of M6P/IGF2R in mice, this entire
region was missing in the opossum. Since Killian has no doubt
that the gene they cloned in the opossum is in fact the
homologue of M6P/IGF2R, the current finding likely means that
the actual controlling region has yet to be found.

"The proposed controlling element is not there in the
opossum," Jirtle explained. "Either the opossum has a
completely different, unique, and as-yet-unidentified mechanism
to control imprinting of this gene, or the proposed region in
the mouse is not the actual controlling region."

If they can find the region in the opossum that turns the
imprinted genes on and off, and if they can then locate that
region in the mouse, the researchers could potentially develop
a strain of mice that can't imprint the M6P/IGF2R gene. If so,
they'll have found their better mouse.

The scientists' studies of imprinting also have important
implications for understanding the mammalian evolutionary tree,
Jirtle said.

The presence of imprinted genes in the opossum but not
platypus suggests that marsupials are more closely related to
eutherians - the name for mammals whose offspring develop in
the womb - than they are to monotremes. This relationship
supports the proposed version of the mammalian evolutionary
tree in which monotremes branched off the main evolutionary
trunk before marsupials; rather than another version that
places marsupials and monotremes as two twigs on a single
branch.

In order for the second proposed evolutionary tree to be
correct, given the current finding, imprinting would have had
to evolve twice - once on the marsupial twig and again on the
eutherian branch - in a process called convergent evolution.
That's very unlikely, say the scientists.

Jirtle and Killian also say the findings demonstrate the
validity of using primitive mammals to learn about genes'
evolution and function.

"Marsupials can be an important tool in understanding
genetics and imprinting," said Killian, an MD/PhD candidate.
"Mice and humans are too closely related to distinguish some
evolutionary developments from random events."

Co-authors on the paper are James Jirtle of Duke University
Medical Center, James Byrd and Richard MacDonald of the
University of Nebraska Medical Center, Barry Munday of the
University of Tasmania (Australia), and Michael Stoskopf of
North Carolina State University.