Genotypes and Epigenotypes
From: Michael Ragland (ragland37_at_webtv.net)
Date: 08/25/04
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Date: Wed, 25 Aug 2004 04:41:38 +0000 (UTC)
"Just as geneticists are probing samples to identify genotypes and
haplotypes [lengthy genetic sequences that are inherited in blocks], we
need to examine multiple samples from different tissues and different
people to establish 'epigenotypes,'" says Feinberg. "Only by
superimposing genetic and epigenetic information will we get a complete
picture of how genes' functions are affected in healthy people and in
those with particular diseases."
Andrew Feinberg, M.D.
Life Sciences / Chemistry
Johns Hopkins Medical Institutions28.07.2004
Scientists suggest framework for epigenetics in common disease
Scientists at Johns Hopkins are calling for simultaneous evaluation of
both genetic and epigenetic information in the search to understand
contributors to such common diseases as cancer, heart disease and
diabetes. Writing in the August issue of Trends in Genetics, available
now online, the scientists provide a framework for systematically
incorporating epigenetic information into traditional genetic studies,
something they say will be necessary to understand the genetic and
environmental factors behind common diseases. "Epigenetics doesn't
underlie all human disease, but we definitely need to develop the
technology to figure out when and where epigenetic changes do influence
health and disease," says Andrew Feinberg, M.D., King Fahd Professor of
Medicine.
Much as the genetic sequence is passed from parent to child, epigenetic
"marks" that sit on our genes are also inherited. These "marks," usually
small methyl groups, are attached to genes' backbones and convey
information, such as identifying which parent the gene came from. The
marks also normally turn genes on or off. But just as changes in DNA
sequences can cause diseases such as cancer, gain or loss of epigenetic
marks can, too.
To date, only small, targeted regions of DNA have been analyzed for
accompanying epigenetic marks. But the Hopkins researchers say now is
the time to begin studying epigenetics on the same mammoth scale used to
probe the sequence of creatures' genetic building blocks.
But to establish what's "normal," epigenetically speaking, for the
entire genome, Feinberg says scientists will need new technologies to
quickly, accurately and inexpensively determine which epigenetic marks
are present and where they are, much as "high-throughput" technology
revolutionized genetics.
"That kind of power is needed to create comprehensive epigenetic
information, but right now the technology doesn't exist," says Feinberg,
who pioneered the study of epigenetics in cancer. "Developing that
technology, and the necessary statistical approaches to analyze the
data, will require a major collaborative effort and should be first on
the to-do list."
A first step toward these goals is the new, multi-institutional Center
for the Epigenetics of Common Human Disease, which Feinberg is
directing. With a $5 million, five-year grant from the National Human
Genome Research Institute and the National Institute of Mental Health,
Center researchers will develop the tools they need and then begin
systematically examining the epigenetics of autism and bipolar disorder.
But a broader effort will be necessary, Feinberg says.
"Just as geneticists are probing samples to identify genotypes and
haplotypes [lengthy genetic sequences that are inherited in blocks], we
need to examine multiple samples from different tissues and different
people to establish 'epigenotypes,'" says Feinberg. "Only by
superimposing genetic and epigenetic information will we get a complete
picture of how genes' functions are affected in healthy people and in
those with particular diseases."
Feinberg and co-authors Hans Bjornsson and epidemiologist Daniele Fallin
say current attempts to establish genetic contributors to common
diseases will fall short without equivalent epigenetic information.
It's widely believed that common, complex diseases like cancer, diabetes
and heart disease stem from collections of changes in a number of
as-yet-unknown genes because of the wide variation in severity, age of
onset, ease of treatment, rate of progression and other factors.
But the Hopkins scientists point out that epigenetic variation adds
another layer of complexity that also could contribute broadly to
diseases' variability. How much epigenetic marks vary normally is still
unknown, but faulty epigenetics are already known to be at work in
cancer and relatively rare Beckwith-Wiedemann syndrome, among others
conditions.
"The epigenetic marks a person has could influence disease directly, but
they also could affect whether an underlying genetic mutation or genetic
variation can actually result in biologic or physiologic changes," says
Bjornsson, a physician from Iceland who is pursuing his Ph.D. in human
genetics at Hopkins. "We think the latter is going to be very important
in explaining the variability of the most common diseases."
For example, if a disease-causing mutation is present in a gene turned
"off" by its epigenetic marks, then the mutation can't cause disease.
More subtly, alteration of epigenetic marks could "tune" gene expression
to cause a full spectrum of effects. Epigenetic variation is also likely
to help relate environment and age to disease incidence and risk, the
researchers say.
"Common complex diseases occur more often as people age, and genetics
alone hasn't fully been able to account for that by accumulation of
mutations," says Feinberg. "But epigenetic marks might more easily
change as cells and people age or be more easily influenced by
environmental factors than the actual DNA sequence is. We need to look
at those possibilities."
The researchers were supported by grants from the National Human Genome
Research Institute, the National Cancer Institute, and by a Fulbright
Scholarship to Bjornsson.
More information:www.jhmi.edu
"It's uncertain whether intelligence has any long term survival value.
Bacteria do quite well without it."
Stephen Hawking
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