Backgrounder: Epigenetics and Imprinted Genes: Jdowner1@jhmi - Edu
Backgrounder: Epigenetics and Imprinted Genes: Jdowner1@jhmi - Edu
Backgrounder: Epigenetics and Imprinted Genes: Jdowner1@jhmi - Edu
There is far more to genetics than the sequence of building blocks in the DNA
molecules that make up our genes and chromosomes. The "more" is known as
epigenetics.
What is epigenetics?
Epigenetics, literally "on" genes, refers to all modifications to genes other than
changes in the DNA sequence itself. Epigenetic modifications include addition of
molecules, like methyl groups, to the DNA backbone. Adding these groups changes
the appearance and structure of DNA, altering how a gene can interact with
important interpreting (transcribing) molecules in the cell's nucleus.
Because they change how genes can interact with the cell's transcribing machinery,
epigenetic modifications, or "marks," generally turn genes on or off, allowing or
preventing the gene from being used to make a protein. On the other hand,
mutations and bigger changes in the DNA sequence (like insertions or deletions)
change not only the sequence of the DNA and RNA, but may affect the sequence
of the protein as well. (Mutations in the sequence can prevent a gene from being
recognized, amounting to its being turned off, but only if the mutations affect
specific regions of the DNA.)
There are different kinds of epigenetic "marks," chemical additions to the genetic
sequence. The addition of methyl groups to the DNA backbone is used on some
genes to distinguish the gene copy inherited from the father and that inherited from
the mother. In this situation, known as "imprinting," the marks both distinguish the
gene copies and tell the cell which copy to use to make proteins.
What is "imprinting?"
"Imprinted genes" don't rely on traditional laws of Mendelian genetics, which
describe the inheritance of traits as either dominant or recessive. In Mendelian
genetics, both parental copies are equally likely to contribute to the outcome. The
impact of an imprinted gene copy, however, depends only on which parent it was
inherited from. For some imprinted genes, the cell only uses the copy from the
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Backgrounder: Epigenetics and Imprinted Genes Page 2 of 4
mother to make proteins, and for others only that from the father.
Then, in the mid 1980s, scientists studying mice discovered that inheritance of
genetic material from both a male and a female parent was required for normal
development. The experiments also revealed that the resulting abnormalities
changed depending on whether the inherited genetic material was all male in origin
or all female.
Around the same time, others discovered that the effects of some transgenes in
mice differed when they were passed from the male or female parent. The first
naturally occurring example of an imprinted gene was the discovery of imprinting in
the IGF-2 gene in mice in 1991, and currently about 50 imprinted genes have been
identified in mice and humans.
The "battle of the sexes" hypothesis is partly based on studies in animals that
suggest growth-promoting imprinted genes help ensure the continuation of the
father's genes, a particularly important issue for species in which more than one
male can contribute to a single litter of offspring. The mother, however, is more
interested in maintaining her own health, biologically speaking, and hence her
genes "fight" the paternal genes and limit the size of the embryo or fetus.
In cancer, some tumor suppressor genes are actually maternally expressed genes
that are mistakenly turned off, preventing the growth-limiting protein from being
made. Likewise, many oncogenes -- growth-promoting genes -- are paternally
expressed genes for which a single dose of the protein is just right for normal cell
proliferation. However, if the maternal copy of the oncogene loses its epigenetic
marks and is turned on as well, uncontrolled cell growth can result.
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There's also evidence in mice that some imprinted genes may play a role in
behavior, particularly in nurturing and social situations.
For example, researchers are still trying to understand the process by which cells
maintain or change their gene's imprinting marks. In sperm and egg, for instance,
imprinted gene copies have to be re-imprinted. Imagine one copy of a paternally
imprinted gene passed from a father to his daughter (the copy is paternally
inherited and will be "on") and then to her child (it's now a maternally inherited copy
and will be "off").
To find answers to these and other questions, imprinting in early stage embryos will
need to be studied. Hopkins researchers recently created a mouse model in which
the paternal and maternal gene copies are easily distinguished in order to help
answer these questions. The true test will be one day evaluating the questions in
humans, although such experiments are not currently permitted.
-- JHMI --
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