To Members and Friends of the Los Angeles Gerontology
Functional DNA at Oxford… — Steve Coles
“Just 8.2% of Our DNA Is
Friday, July 25; 2014;
(R&D) — Only 8.2 percent of human DNA is likely to be
doing something important -Â is “functional” Â- say Oxford University
researchers. This figure is very different from one given in 2012,
when some scientists involved in the ENCODE (Encyclopedia of DNA
Elements) project stated that 80 percent of our genome has some
That claim has been controversial, with many in
the field arguing that the biochemical definition of “function” was too
broadÂthat just because an activity on DNA occurs, it does not
necessarily have a consequence; for functionality you need to demonstrate
that an activity matters.
To reach their figure, the Oxford University
group took advantage of the ability of evolution to discern which
activities matter and which do not. They identified how much of our
genome has avoided accumulating changes over 100 million years of
mammalian evolution –Â a clear indication that this DNA matters, it has
some important function that needs to be retained.
“This is in large part a matter of different
definitions of what is ‘functional’ DNA,” says joint senior author Prof.
Chris Pointing of the MRC Functional Genomics Unit at Oxford University.
‘We don’t think our figure is actually too different from what you would
get looking at ENCODE’s bank of data using the same definition for
‘But this isn’t just an academic argument about the
nebulous word “function.” These definitions matter. When
sequencing the genomes of patients, if our DNA was largely functional,
we’d need to pay attention to every mutation. In contrast, with only 8%
being functional, we have to work out the 8% of the mutations detected
that might be important. From a medical point of view, this is essential
to interpreting the role of human genetic variation in disease.’
The researchers Chris Rands, Stephen Meader,
Chris Ponting and Gerton Lunter report their findings in the journal
PLOS Genetics. They were funded by the UK Medical Research Council
and the Wellcome Trust.
The researchers used a computational approach to
compare the complete DNA sequences of various mammals, from mice, guinea
pigs, and rabbits to dogs, horses, and humans.
Dr. Gerton Lunter from the Wellcome Trust Center
for Human Genetics at Oxford University, the other joint senior author,
explained: “Throughout the evolution of these species from their common
ancestors, mutations arise in the DNA and natural selection counteracts
these changes to keep useful DNA sequences intact.”
The scientists’ idea was to look at where
insertions and deletions of chunks of DNA appeared in the mammals’
genomes. These could be expected to fall approximately randomly in the
sequenceÂexcept where natural selection was acting to preserve functional
DNA, where insertions and deletions would then lie further
“We found that 8.2% of our human genome is
functional,” says Lunter. “We cannot tell where every bit of the 8.2% of
functional DNA is in our genomes, but our approach is largely free from
assumptions or hypotheses. For example, it is not dependent on what we
know about the genome or what particular experiments are used to identify
The rest of our genome is leftover evolutionary
material, parts of the genome that have undergone losses or gains in the
DNA codeÂoften called “junk” DNA.
“We tend to have the expectation that all of our
DNA must be doing something. In reality, only a small part of it is,”
says Dr. Chris Rands, first author of the study and a former DPhil
student in the MRC Functional Genomics Unit at Oxford
Not all of the 8.2 percent is equally important,
the researchers explain.
A little over one percent of human DNA accounts
for the proteins that carry out almost all of the critical biological
processes in the body. The other seven percent is thought to be
involved in the switching on and off of genes that encode proteins -Â at
different times, in response to various factors, and in different parts
of the body. These are the control and regulation elements, and there are
various different types.
“The proteins produced are virtually the same in
every cell in our body from when we are born to when we die,” says Rands.
“Which of them are switched on, where in the body and at what point in
time, needs to be controlled -Â and it is the seven percent that is doing
In comparing the genomes of different species,
the researchers found that while the protein-coding genes are very well
conserved across all mammals, there is a higher turnover of DNA sequence
in the regulatory regions as this sequence is lost and gained over
Mammals that are more closely related have a
greater proportion of their functional DNA in common.
But only 2.2% of human DNA is functional and
shared with mice, for example -Â because of the high turnover in the
regulatory DNA regions over the 80 million years of evolutionary
separation between the two species.
“Regulatory DNA evolves much more dynamically
that we thought,” says Lunter, “but even so, most of the changes in the
genome involve junk DNA and are irrelevant.”
He explains that although there is a lot of
functional DNA that isn’t shared between mice and humans, we can’t yet
tell what is novel and explains our differences as species, and which is
just a different gene-switching system that achieves the same
Ponting agrees: “There appears to be a lot of
redundancy in how our biological processes are controlled and kept in
check. It’s like having lots of different switches in a room to turn the
lights on. Perhaps you could do without some switches on one wall or
another, but it’s still the same electrical circuit.”
He adds: “The fact that we only have 2.2 percent
of DNA in common with mice does not show that we are so different. We are
not so special. Our fundamental biology is very similar. Every mammal has
approximately the same amount of functional DNA, and approximately the
same distribution of functional DNA that is highly important and less
important. Biologically, humans are pretty ordinary in the scheme of
things, I’m afraid.
“I’m definitely not of the opinion that mice are
bad model organisms for animal research. This study really doesn’t
address that issue,” he notes.
8.2% of the Human Genome Is Constrained: Variation in Rates of Turnover
across Functional Element Classes in the Human LineageSource: University of
R & D
Genomics & Proteomics
L. Stephen Coles, M.D., Ph.D., Cofounder
Los Angeles Gerontology Research GroupE-mail: firstname.lastname@example.orgE-mail: