Scientific News  Biology Biotechnologies BIG-BOTTOMED SHEEP HAVE A RARE GENETIC MUTATION THAT BUILDS MUSCLE, NOT FAT.
BIG-BOTTOMED SHEEP HAVE A RARE GENETIC MUTATION
THAT BUILDS MUSCLE, NOT FAT.
 Scientists have discovered an
elusive, mutated
gene named for the Greek goddess, Aphrodite Kallipygos, that causes certain
sheep to have unusually big and muscular bottoms. They hope the genetic mutation
will illuminate how muscle and fat are deposited in these animals and possibly
in humans.
The discovery is especially exciting, said the
researchers, because the unusual gene has evaded all the traditional means of
detection for nearly a decade. In fact, the gene appears to represent one of
numerous stealth genes, called “imprinted,” that have yet to be discovered
but which could produce a wide range of diseases.
Researchers from the U.S.
Department of Agriculture and Duke University
Medical Center discovered a gene called “callipyge,” (pronounced cal - ah -
PEEJ) meaning “beautiful buttocks” in Greek, because the sheep have large,
muscular bottoms with very little fat. Such an attribute could prove beneficial
in breeding these sheep because it enables them to convert food into muscle 30
percent more efficiently than normal sheep. Moreover, the gene could explain
specific processes that give rise to obesity and fat metabolism, said Randy
Jirtle, Ph.D., professor of radiation oncology at
Duke and co-author of the study.
“These sheep are, in effect, pumping iron
without lifting weights,” explained Jirtle. “They are converting food into
muscle in their hind regions, instead of converting food into fat.”
Results of the study, funded by the USDA
and the National Institutes of Health, are published in the October 2002 issue
of Genome
Research.
Excited as they are to have unearthed the gene
behind the big-bottomed sheep, the scientists say their discovery has equally
dramatic implications for mining the human genome. The callipyge gene appears to
be among a rare subset that eludes traditional methods of identification and
mapping, said USDA geneticist Brad Freking, Ph.D., lead investigator of the
study.
Called imprinted genes because they are literally
stamped with markings that inactivate one parent’s copy, such genes are quite
rare and unusual in the way they operate. They often work only in specific
tissues and at defined intervals during an animal’s development, said Susan
Murphy, Ph.D., a Duke University Medical Center co-author.
“Finding imprinted genes can depend on when and
where in the body you search for them,” said Murphy. “If you look for an
imprinted gene in a mature animal when that gene is only expressed during fetal
development, then you may miss it entirely.”
The researchers sought an imprinted gene because
the big-bottomed sheep inherited a functional copy of the mutated gene from
their father alone -- the mother’s copy is turned off. Silencing of one
parental copy is characteristic of imprinted genes.
For 10 years, the researchers searched likely
regions where the callipyge gene and its mutation might reside; namely, in known
genes on sheep chromosome 18, according to previous research. But their efforts
turned up intact genes with no mutations. Finally, the team of researchers tried
a novel approach.
They compared a specific DNA sequence from inbred
offspring of the original big-bottomed sheep against the DNA of normal sheep to
look for minute genetic variations, called “markers.” While they found 600
distinct “markers,” only one was unique to the callipyge sheep: a single
base change from A to G in the DNA sequence. Further testing showed this
mutation alone clearly gave rise to the sheep’s big-bottom stature.
Yet the mutation appeared to reside in a “gene
desert,” where no known gene had previously been mapped, said Freking.
Interestingly, when they compared this sequence in the sheep to the same region
of humans and mice, they found that the DNA sequences surrounding the callipyge
mutation were highly similar in all three species.
“The more similar the region, the more likely
the genetic sequence was conserved for an important biological reason,” said
Jirtle. So, the scientists searched deeper for evidence of a gene’s presence.
They tested whether the DNA in this conserved region was used as a template to
make RNA within the callipyge sheeps’ affected tissue. Finding RNA would
signal the presence of a gene, since RNA is generally made from a gene in the
process of producing a protein.
Surprisingly, they found an RNA “transcript”
or copy, suggesting that the mutation is located in a previously unidentified
gene.
“This is the first time in animals where a
mutation has been found that leads to the identification of a new gene, rather
than analyzing a known gene to find its mutation,” said Jirtle. “As
scientists, we are missing many genes and their mutations by using the
traditional approach of linkage analysis to locate and analyze candidate genes.”
Now that that they have found the callipyge gene,
the next major step is determining how it gives rise to the big-bottomed trait
or “phenotype.” Researchers have long known that a nearby gene, called
DLK-1, is over-expressed in the hind quarters of callipyge sheep. Yet DLK-1 has
no mutations. Thus, the researchers speculate that the mutated callipyge gene is
inappropriately regulating the expression of DLK-1 and/or other imprinted genes
in this domain.
“We believe the regulation of this imprinted
domain is flawed, rather than other genes in this domain being mutated,” said
Jirtle. “Mutated callipyge is having a downstream effect on DLK-1, and
potentially on other imprinted genes in this region, that in some manner stunts
fat cells from maturing while enhancing hind quarter musculature.”
DLK-1 has been studied in other contexts because
it is overexpressed in neuroendocrine tumors such as pheochromocytoma and
neuroblastoma, and also is involved in the maturation of fat cells and the
adrenal gland, said Jirtle. DLK-1 is imprinted, lending further credence to the
assumption that callipyge is also imprinted.
“Imprinted genes are like mushrooms, because
they are present in groups,” said Jirtle. “Moreover, they display a domino
effect, in that one mutation of an imprinted gene could knock out five or 10
genes in one hit, especially when they are all regulated as a group.”
“These are incredibly powerful and subtle genes
that bring you into a whole different realm of thinking about gene regulation,”
said Jirtle. “In a way, we are at the end of the beginning. We know the
specific gene mutation that leads to large bottoms in sheep, but now we have to
find how it operates.”
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Publishing date: September 25, 2002
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