MicroRNAs shape evolution of most
genes
CAMBRIDGE, Mass. (November 29, 2005) — RNA continues
to shed its reputation as DNA's faithful sidekick. Now,
researchers in the lab of Whitehead Institute Member
David
Bartel have found that a class of small RNAs called
microRNAs influence the evolution of genes far more
widely than previous research had indicated.
"MicroRNAs are affecting the majority of protein-coding
genes, either at a functional level or an evolutionary
level," says Andrew Grimson, a post-doctoral fellow
in Bartel's lab.
In order to make a protein, a gene codes for a specific
molecule called messenger RNA, or mRNA. Each mRNA molecule
contains a blueprint for making a protein. A microRNA
can bind to a short sequence on a targeted mRNA and
suppress protein production.
In a paper published last January in the journal Cell,
Bartel's lab, in collaboration with Chris Burge's lab
at MIT, presented evidence that one third of human genes
are regulated by microRNAs. In this new study, published
online Nov. 24 in Science, the researchers
demonstrate that microRNAs affect the expression or
evolution of the majority of human genes.
Nearly all genes, the authors explain, contain short
sequences that match portions of microRNAs. Some of
these potential microRNA target sites are evolutionarily
"conserved," meaning that they show up in
the same spot on the same gene across species as disparate
as the mouse and the chicken. The authors of last January's
Cell paper showed that thousands of human genes
contain microRNA sites that are conserved in this way.
To the extent that evolution has preserved these sites
more than would be expected by chance, scientists have
regarded them as sites that microRNAs target.
But is a matching sequence all that's required for microRNA
targeting and gene regulation, and do nonconserved sites
also have the potential to disrupt protein production?
In the new study, scientists in the Bartel lab designed
an experiment that zeroed in on these nonconserved targets.
Grimson took mRNAs whose target sequences were not conserved
and exposed them to microRNAs, which latched on without
a problem. The experiment proved that a matching sequence
is generally sufficient to disrupt mRNA's ability to
make protein.
But while Grimson showed that, at least in the lab,
microRNAs could regulate mRNAs with nonconserved sites,
the researchers still didn't know the extent to which
nonconserved mRNAs coexisted with their matching microRNAs
in the natural cell environment. To answer this question,
the researchers turned to gene expression patterns of
different types of mouse cells.
Kyle Kai-How Farh, a graduate student in Bartel's lab,
found that mRNAs with nonconserved sites were generally
absent in cells with corresponding microRNAs—more
absent than statistical models suggested. The researchers
concluded that over the course of evolution many mRNAs,
in order to maintain their functions and ensure fitness
of the organism, have quickly lost sites that pair up
with microRNAs.
In addition to the thousands of cases where genes have
avoided microRNA targeting, Farh also investigated the
opposite extreme, cases where genes have maintained
microRNA target sites over the course of evolution.
He found that as immature muscle cells stop dividing
and become mature muscle cells, microRNAs are activated
and suppress genes that are no longer needed at such
high levels in the mature muscle. "Many of these
evolutionarily conserved microRNA targets are known
to be active in the processes of cell proliferation,
development, and cancer," says Farh. "Our
genomes have good reason to maintain the microRNA targeting
sites necessary for turning down these genes at the
appropriate place and time."
An emerging idea is that microRNAs often act to reduce
the quantity of protein a gene produces without shutting
it off all together. "We think the microRNAs are
sometimes having what you can call a dampening effect,"
says Bartel, who is also a Howard Hughes Medical Institute
investigator and MIT professor of biology. "They
appear to be helping cells achieve optimal levels of
proteins."
"MicroRNAs are leaving an evolutionary footprint
on the majority of the mammalian genome," says
Grimson. "Some genes are trying to preserve beneficial
microRNA sites and others are evolving in order to avoid
developing harmful ones."
This study was funded by the National Institutes of
Health and the Howard Hughes Medical Institute.
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