[asa] Encyclopedia Of DNA: New Findings Challenge Established Views On Human Genome

From: Rich Blinne <rich.blinne@gmail.com>
Date: Thu Jun 14 2007 - 00:27:35 EDT

Here's what I quoted from Nature in an NIH press release via Science
Daily. Note the Francis Collins quote inter alia.

Encyclopedia Of DNA: New Findings Challenge Established Views On
Human Genome

Science Daily An international research consortium just published a
set of papers that promise to reshape our understanding of how the
human genome functions. The findings challenge the traditional view
of our genetic blueprint as a tidy collection of independent genes,
pointing instead to a complex network in which genes, along with
regulatory elements and other types of DNA sequences that do not code
for proteins, interact in overlapping ways not yet fully understood.

In a group paper published in the June 14 issue of Nature and in 28
companion papers published in the June issue of Genome Research, the
ENCyclopedia Of DNA Elements (ENCODE) consortium, which is organized
by the National Human Genome Research Institute (NHGRI), part of the
National Institutes of Health (NIH), reported results of its
exhaustive, four-year effort to build a parts list of all
biologically functional elements in 1 percent of the human genome.
Carried out by 35 groups from 80 organizations around the world, the
research served as a pilot to test the feasibility of a full-scale
initiative to produce a comprehensive catalog of all components of
the human genome crucial for biological function.
"This impressive effort has uncovered many exciting surprises and
blazed the way for future efforts to explore the functional landscape
of the entire human genome," said NHGRI Director Francis S. Collins,
M.D., Ph.D. "Because of the hard work and keen insights of the ENCODE
consortium, the scientific community will need to rethink some long-
held views about what genes are and what they do, as well as how the
genome's functional elements have evolved. This could have
significant implications for efforts to identify the DNA sequences
involved in many human diseases."

The completion of the Human Genome Project in April 2003 was a major
achievement, but the sequencing of the genome marked just the first
step toward the goal of using such information to diagnose, treat and
prevent disease. Having the human genome sequence is similar to
having all the pages of an instruction manual needed to make the
human body. Researchers still must learn how to read the manual's
language so they can identify every part and understand how the parts
work together to contribute to health and disease.

In recent years, researchers have made major strides in using DNA
sequence data to identify genes, which are traditionally defined as
the parts of the genome that code for proteins. The protein-coding
component of these genes makes up just a small fraction of the human
genome -- 1.5 percent to 2 percent. Evidence exists that other parts
of the genome also have important functions.
However, until now, most studies have concentrated on functional
elements associated with specific genes and have not provided
insights about functional elements throughout the genome. The ENCODE
project represents the first systematic effort to determine where all
types of functional elements are located and how they are organized.

In the pilot phase, ENCODE researchers devised and tested high-
throughput approaches for identifying functional elements in the
genome. Those elements included genes that code for proteins; genes
that do not code for proteins; regulatory elements that control the
transcription of genes; and elements that maintain the structure of
chromosomes and mediate the dynamics of their replication.

The collaborative study focused on 44 targets, which together cover
about 1 percent of the human genome sequence, or about 30 million DNA
base pairs. The targets were strategically selected to provide a
representative cross section of the entire human genome. All told,
the ENCODE consortium generated more than 200 datasets and analyzed
more than 600 million data points.

"Our results reveal important principles about the organization of
functional elements in the human genome, providing new perspectives
on everything from DNA transcription to mammalian evolution. In
particular, we gained significant insight into DNA sequences that do
not encode proteins, which we knew very little about before," said
Ewan Birney, Ph.D., head of genome annotation at the European
Molecular Biology Laboratory's European Bioinformatics Institute
(EBI) in Hinxton, England, who led ENCODE's massive data integration
and analysis effort.
The ENCODE consortium's major findings include the discovery that the
majority of DNA in the human genome is transcribed into functional
molecules, called RNA, and that these transcripts extensively overlap
one another. This broad pattern of transcription challenges the long-
standing view that the human genome consists of a relatively small
set of discrete genes, along with a vast amount of so-called junk DNA
that is not biologically active.

The new data indicate the genome contains very little unused
sequences and, in fact, is a complex, interwoven network. In this
network, genes are just one of many types of DNA sequences that have
a functional impact. "Our perspective of transcription and genes may
have to evolve," the researchers state in their Nature paper, noting
the network model of the genome "poses some interesting mechanistic
questions" that have yet to be answered.

Other surprises in the ENCODE data have major implications for our
understanding of the evolution of genomes, particularly mammalian
genomes. Until recently, researchers had thought that most of the DNA
sequences important for biological function would be in areas of the
genome most subject to evolutionary constraint -- that is, most
likely to be conserved as species evolve. However, the ENCODE effort
found about half of functional elements in the human genome do not
appear to have been obviously constrained during evolution, at least
when examined by current methods used by computational biologists.

According to ENCODE researchers, this lack of evolutionary constraint
may indicate that many species' genomes contain a pool of functional
elements, including RNA transcripts, that provide no specific
benefits in terms of survival or reproduction. As this pool turns
over during evolutionary time, researchers speculate it may serve as
a "warehouse for natural selection" by acting as a source of
functional elements unique to each species and of elements that
perform the similar functions among species despite having sequences
that appear dissimilar.

Other highlights of the ENCODE work include:
Identification of numerous previously unrecognized start sites for
DNA transcription.
Evidence that, contrary to traditional views, regulatory sequences
are just as likely to be located downstream of a transcription start
site on a DNA strand as upstream.
Identification of specific signatures of change in histones, which
are the proteins that organize DNA, and correlation of these
signatures with different genomic functions.
Deeper understanding of how DNA replication is coordinated by
modifications in histones.
"Teamwork was essential to the success of this effort. No single
experimental approach can be used to identify all functional elements
in the genome. So, it was necessary to conduct multiple, diverse
experiments and then analyze them using multiple computational
methods," said Elise A. Feingold, Ph.D., program director for ENCODE
in NHGRI's Division of Extramural Research, which provided most of
the funding for the pilot project.

Note: This story has been adapted from a news release issued by NIH/
National Human Genome Research Institute.

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Received on Thu Jun 14 00:27:55 2007

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