Most people understand genes to be specific segments of
DNA that determine traits or diseases that are inherited. Textbooks
suggest that genes are copied ("transcribed") into RNA molecules, which
are then used as templates for making protein - the highly diverse set
of molecules that act as building blocks and engines of our cells. The
truth, it now appears, is not so simple.
As part of a huge collaborative effort called ENCODE (Encyclopedia
of DNA Elements),
a research team led by Cold Spring Harbor Laboratory (CSHL) Professor
Thomas Gingeras, Ph.D., today publishes a genome-wide analysis of RNA
messages, called transcripts, produced within human cells.
Their analysis - one component of a massive release of research results
by ENCODE teams from 32 institutes in 5 countries, with 30 papers
appearing today in 3 different high-level scientific journals-- shows
that three-quarters of the genome is capable of being transcribed. This
figure is important because it indicates that nearly all of our genome
is dynamic and active. It stands in marked contrast to consensus views
prior to ENCODE's comprehensive research efforts, which suggested that
only the small protein-encoding fraction of the genome was transcribed,
and therefore important.
The vast amount of data generated with advanced technologies by
Gingeras' group and others in the ENCODE project is likely to radically
change the prevailing understanding of what defines a gene, the unit we
routinely use, for instance, to speak of inheritable traits like eye
color or to explain the causes of and susceptibility to most diseases,
running the gamut from cancer to schizophrenia to heart disease.
In 2003 the ENCODE project consortium was set up by the U.S.
government's National Human Genome Research Institute (NHGRI) to examine
the newly minted sequence of the human genome in greater depth. At the
time, the genome was thought of as a linear molecule of DNA with "genes"
being contained within isolated sections that make up just 1%-2% of its
total length. The long stretches of DNA between these gene islands were
once thought to be mostly functionless spacers, padding, or even "junk
Through the work of Gingeras and others in this latest phase of the
ENCODE project consortium, we now know that most of the DNA around
protein-encoding genes is also capable of being transcribed into RNA -
another way of saying that it has the potential of performing useful
functions in cells.
In preliminary ENCODE results published in 2007, the researchers closely
examined about 1% of the human genome. The initial results showed that
much more of our DNA could be transcribed than previously thought. Far
from being padding, many of these RNA messages appeared to be functional.
The Gingeras lab discovered potentially new classes of functional RNAs
in this preliminary work. The additional knowledge that parts of one
gene or functional RNA can reside within another were surprising, and
suggested a picture of the architecture of our genome that was much more
complex than previously thought.
What the new ENCODE data reveals
Two of the 30 papers published by Gingeras and other ENCODE colleagues,
including CSHL Professor and HHMI Investigator Gregory Hannon, Ph.D.,
who is also a co-author in this study, today mark the culmination of
project's second phase. What distinguishes the data analyzed in this
phase is comprehensiveness. The initial observations of 2007 are now
extended to cover the entire human genome - a tour-de-force effort in
which the transcribed RNA from different sub-cellular compartments of 15
human cell lines was analyzed
Although the results vary between cell lines, a consensus picture is
emerging. In addition to showing that up to three-quarters of our DNA
may be transcribed into RNA, the data strongly suggests, according to
Gingeras, that a large percent of non-protein-coding RNAs are localized
within cells in a manner consistent with their having functional roles.
The current outstanding question concerns the nature and range of those
functions. It is thought that these "non-coding" RNA transcripts act
something like components of a giant, complex switchboard, controlling a
network of many events in the cell by regulating the processes of
replication, transcription and translation - that is, the copying of DNA
and the making of proteins based on information carried by messenger
With the understanding that so much of our DNA can be transcribed into
RNA comes the realization that there is much less space between what we
previously thought of as genes, Gingeras points out.
"We see the boundaries of what were assumed to be the regions between
genes shrinking in length," he says, "and genic regions making many
overlapping RNAs." It appears, he continues, that the boundaries of
conventionally described genes are melding together, challenging the
notion that a gene is a discrete, localized region of a genome separated
by inert DNA. "New definitions of a gene are needed," Gingeras says.
What are the practical implications? According to Gingeras, they include
being able to identify possible causes for natural traits such as height
or hair loss and disease states such as cancer. Many genetic variations
associated with a trait often map to what were formally believed to be
"With our increasingly deeper understanding that such regions are
related to the neighboring or "distal" protein coding regions - via the
creation of non-coding RNAs - we will now seek underlying explanations
of the association of the genetic variation and traits of interest."
This topic is explored in a second paper published today that summarizes
the finding of all the consortium groups participating in the current
phase of the ENCODE project: The ENCODE Project Consortium. 2012. An
integrated encyclopedia of DNA elements in the human genome. Nature
"Exploration of the genome is akin to our efforts at exploring our
physical universe," Gingeras says. "We expect to be amazed and excited
by our future efforts to map and explore our personal genetic universes."
"Landscape of transcription in human cells" is published online in Nature
on September 5, 2012. The authors are: Sarah Djebali, Carrie A. Davis
and 83 others. The paper can be obtained online at doi:10.1038/nature11233.
Other new ENCODE results can be found in the following journals: Nature
(6 papers); Genome
Research (18 papers); and Genome
Biology (6 papers).
Cold Spring Harbor Laboratory