Will
new revelations about RNA force us to rethink how our past affects future
evolution?
by PHILIP BALL ¥ Posted January 14, 2008
09:15 AM
Illustration
by Jacob Magraw
In the campus gardens of the Cold Spring Harbor
Laboratory, the center for genetics research on Long Island, stands a 15-foot
molecule. Made by the architect Charles Jencks, it is an aluminum sculpture of
DNA whose structure James Watson, the laboratory's president, deduced with
Francis Crick in 1953. Its twinned spiral strands have now come to represent
nothing less than life itself: Within these helices, so we are told, lie all the
instructions for making an organism, passed from one generation to the next by
copying the DNA blueprint.
But over the past year or so, it has begun to
look increasingly as though biologists may need to reconsider the role of their
favorite molecule. For nearly 50 years, the central dogma of biology has been
that genetic information is contained within DNA and is passed by rote
transcription through RNA to make proteins. Tiny changes in the information
content of the underlying DNA are what then drive evolution. But this
information may not be the sole determinant of biological identity. Indeed,
it's becoming clear that we do not even know what 'genetic information' means
any more—certainly it's not a simple, linear sequence of biochemical
'characters' that define a gene. Even evolution might not be driven solely by
the appearance of random mutations in DNA that are inherited by subsequent
generations, essentially as Darwin supposed. The central dogma is being eroded,
and it now appears as if DNA's cousin, the humble intermediary RNA, plays at
least an equal role in genetics and the evolution of the species.
Who says so? Consider the work of Minoo
Rassoulzadegan at the French National Institute for Health and Medical
Research's laboratory in Nice. Last year she showed that mice could inherit
white patches on their tails—normally the result of a mutation in a gene
called Kit—even if they lacked the
mutant gene for this trait. The white patches appeared because RNA molecules,
which passed from parent to offspring after accumulating in sperm cells,
overrode the demands of DNA.
Or take the work of David Haussler and his
colleagues at the University of California, Santa Cruz. They have shown that a
gene called HAR1F, which is probably
responsible for some key differences between human and chimpanzee brains,
doesn't even make a protein, only an RNA molecule. In other words, the human
brain may have evolved through the guidance of RNA.
These and a host of other recent findings are
rewriting the textbooks of molecular biology. They are beginning to show not
only that RNA is more fundamental to genetics than once believed, but also that
it can directly affect evolution and elucidate the differences between species.
The result is a story that looks a lot messier, but potentially a lot more
interesting, than anyone ever guessed.
The old genetic picture seemed so beautifully
simple—indeed, probably too beautiful to be true. It began with the
identification by the Austro-Hungarian monk Gregor Mendel of discrete,
particle-like units that are responsible for the inheritance of traits from one
generation to the next. In Mendel's scheme, you either picked up a trait from
one parent or you didn't; there was no blending or averaging from both parents.
These units became known as genes, and were found to reside on the chromosomes.
In 1944 Oswald Avery and his coworkers found that genes are made of DNA. Nine
years later Watson and Crick discovered that genes encode information as a
sequence of the four different chemical building blocks of DNA, strung along
the double strands like beads. From this the central dogma was born.
But we've slowly learned that genetics is not
so simple. For one thing, decoding the human genome—the sum total genetic
material in the chromosomes—showed that most (98 percent) of our DNA
doesn't consist of protein-encoding genes at all. Some of this non-coding DNA
comprises regulatory sequences, to which proteins or RNA bind to control gene
transcription, ultimately determining which RNA and proteins are produced. Most
is a complete mystery.
That itself didn't seem to challenge the
central dogma or the notion that genetics is all about DNA. Rather, this cozy
picture has been altered gradually by a series of recent discoveries, beginning
with that of so-called microRNAs. Some RNA is not transcribed as a mere
messenger for protein synthesis—it's the RNA molecule itself that is the
end product, and that plays a key role in controlling events in the cell. In
other words, some nominally non-coding DNA does encode important actors in cell
biology—those made from RNA, not protein.
HAR1 is an example. This snippet of primate DNA was
discovered by comparing the genome sequences of humans and chimpanzees to look
for regions that have diverged significantly since we shared a common ancestor.
Haussler and his colleagues showed last year that HAR1 appears in a gene (HAR1F) expressed in neurons during
a crucial period of 'brain wiring' in the neocortex, which makes it look as
though it might be one of the key genetic factors that distinguish human brains
from those of other primates. Yet because HAR1 does not make any proteins, the implication is that
it's the RNA transcript that somehow controls brain development. Geneticist
Gerton Lunter of the University of Oxford thinks that to understand the
molecular basis of evolution, "we should stop looking at proteins and
start looking at non-coding DNA."
Ronald Plasterk of the University of Utrecht
seems to agree. He and his team have scanned the RNA extracted from brain cells
of both humans and chimps and have found around 450 new microRNAs, more than
doubling the number previously
known. Some of these microRNAs are found
in other organisms too, but many are not, suggesting that they have arisen
relatively recently in evolutionary history. If they have roles in gene
regulation, then it may be that the differences between human and chimp brains
aren't so much a matter of differences in genes but in the ways the genes are
expressed. Plasterk and colleagues think that organisms might keep a pool of
microRNAs on hand as an evolutionary 'playground,' enabling differences between
species to be established without having to alter the genomes.
Whatever their function, humans can't do
without microRNAs. These molecules can interfere with the processing of DNA by
binding to complementary RNA transcripts of genes, preventing the transcripts
from being turned into proteins. This is called RNA interference, and it
provides a way of turning genes off when they are not required. Such gene
'silencing' isn't necessarily confined to the cell that contains the
interfering RNA—it can spread to other cells by transfer of RNA, and can
even pass down through generations when it accumulates in sperm and eggs.
RNAs that control genes are one thing; but RNAs
that rewrite inheritance—as in the work of Rassoulzadegan—are quite
another. Yet, in 2005 Robert Pruitt and his coworkers at Purdue University
discovered another example of RNA editing the putative 'book of life.' They
found that plants of the cress Arabidopsis could carry the non-mutant form of a gene called HOTHEAD (which causes some plant
organs to fuse together) even if both parent plants had the mutant gene. It was as though Arabidopsis had found a way to correct
the mistakes of the previous generation. Pruitt suspects that the non-mutant
gene may be maintained by mutant plants and passed to offspring in the form of
RNA, which can then be 'reverse-transcribed' back into the genome. This kind of
inheritance is quite different from that described by Mendel, and seemingly
contradicts our straightforward notion of Darwinian evolution.
Pruitt argues that it might be useful for
organisms to carry a cache of non-chromosomal genetic information 'remembered'
from past generations in order to offset the problems associated with the
accumulation of bad genes through inbreeding. The unexplained build-up of RNA
in human sperm suggests that we might inherit genetic controls outside of the
chromosomes, too. RNA may be guiding our future evolution, through our past.
Another deep insight into the importance of RNA
came late last year, when the first results were announced of an international
project called the Encyclopedia of DNA Elements (ENCODE), which set out to look
in detail at just one percent of the entire human genome (a total of about 30
million DNA bases). It is widely thought that much of our genome is non-coding
junk acquired over the course of evolution that no longer serves any useful
purpose, like so many dead files forgotten and never consulted on a computer
hard drive.
ENCODE showed otherwise. Nearly all of the
human genome is transcribed into DNA—it is all, in this sense, active
information. We just don't know what it all does. Some of the non-coding
transcripts, such as gene-silencing microRNA, have well defined functions, but
many—simply called transcripts of unknown function (TUFs)—do not
fall cleanly into the categories of coding or non-coding. They may contain bits
of protein sequences, and it is possible that they do indeed serve as templates
for small proteins. It's not yet clear just how well these TUFs are conserved
from one species to another, as one might expect them to be if they have an
important role in cellular processes. The fact is that TUFs are
baffling—a clue that there's something profoundly lacking in our current
picture of genomics, and that somehow RNA is involved.
The ENCODE project also showed that many genes
don't seem to be transcribed as expected, linearly from start to finish. About
1-in-20 of the products transcribed are fused from more than one gene, while
some transcripts seem to pick up bits and pieces from widely separated parts of
the genome. If DNA were a book, it would be unreadable: words would run into
one another or be fragmented throughout the text. It is as if our
classifications of the genome in terms of genes,
protein-coding
sequences, junk, and so on, are simply ignored by the transcription
machinery—in other words, it's as if we've misinterpreted the language of
inheritance to start with.
One of the consequences of this new view of
genetics is that it is forcing some rethinking of what a 'gene' actually is. At
the very least, it seems to be a fuzzy-edged entity, and not the sharply
defined 'particle' that Mendel's work implied. But the implications go deeper
than that, because they erode the primacy of DNA itself. The development and
evolution of all organisms must be regarded as an intricate collaboration
between both of the cell's nucleic acids—DNA and RNA. If that's so, it is
time to stop talking of the RNA World as something that happened billions of
years ago on Earth, when RNA is believed to have been required to perform some
of the functions of both DNA and proteins, serving as both information carriers
and proto-enzymes. We are living in that world now.
Even
this picture of a dual role for RNA, though, perhaps imposes a modern prejudice
on the whole issue, which says that biomolecules are either data banks or
machines. To judge from what we know now, both the implicit hierarchy of the
central dogma and the prescriptive rhetoric of a DNA 'book of life' may be
misplaced. The time has come for a new definition of the gene that includes a
more fundamental role for RNA. Tidy ideas are useful in science, but we need to
know when to abandon them, as when both Newtonian mechanics and the
solar-system model of the atom were replaced by the subtler world of quantum
physics. Molecular and evolutionary biology appears to be poised for a
revolution of that order.
http://www.seedmagazine.com/news/2008/01/redefining_genes.php?page=all&p=y