Represented here by a tomato and a rope, ribosomes are central to all life on Earth because they help translate genetic information into proteins. Image: Dale Muzzey/UCSF |
A
hidden and never before recognized layer of information in the genetic code has
been uncovered by a team of scientists at the University of California, San
Francisco (UCSF) thanks to a technique developed at UCSF called ribosome
profiling, which enables the measurement of gene activity inside living cells—including
the speed with which proteins are made.
By measuring the rate of protein production in bacteria, the
team discovered that slight genetic alterations could have a dramatic effect.
This was true even for seemingly insignificant genetic changes known as “silent
mutations,” which swap out a single DNA letter without changing the ultimate
gene product. To their surprise, the scientists found these changes can slow
the protein production process to one-tenth of its normal speed or less.
As described in Nature,
the speed change is caused by information contained in what are known as
redundant codons—small pieces of DNA that form part of the genetic code. They
were called “redundant” because they were previously thought to contain
duplicative rather than unique instructions.
This new discovery challenges half a century of fundamental
assumptions in biology. It may also help speed up the industrial production of
proteins, which is crucial for making biofuels and biological drugs used to
treat many common diseases, ranging from diabetes to cancer.
“The genetic code has been thought to be redundant, but
redundant codons are clearly not identical,” said Jonathan Weissman, PhD, a
Howard Hughes Medical Institute Investigator in the UCSF School of Medicine
Department of Cellular and Molecular Pharmacology.
“We didn’t understand much about the rules,” he added, but the
new work suggests nature selects among redundant codons based on genetic speed
as well as genetic meaning.
Similarly, a person texting a message to a friend
might opt to type, “NP” instead of “No problem.” They both mean the same thing,
but one is faster to thumb than the other.
How ribosome
profiling works
The
work addresses an observation scientists have long made that the process
protein synthesis, so essential to all living organisms on Earth, is not smooth
and uniform, but rather proceeds in fits and starts. Some unknown mechanism
seemed to control the speed with which proteins are made, but nobody knew what
it was.
To find out, Weissman and UCSF postdoctoral researcher Gene-Wei
Li, PhD, drew upon a broader past effort by Weissman and his colleagues to
develop a novel laboratory technique called “ribosome profiling,” which allows
scientists to examine universally which genes are active in a cell and how fast
they are being translated into proteins.
Ribosome profiling takes account of gene activity by pilfering
from a cell all the molecular machines known as ribosomes. Typical bacterial
cells are filled with hundreds of thousands of these ribosomes, and human cells
have even more. They play a key role in life by translating genetic messages
into proteins. Isolating them and pulling out all their genetic material allows
scientists to see what proteins a cell is making and where they are in the
process.
Weissman and Li were able to use this technique to measure the
rate of protein synthesis by looking statistically at all the genes being
expressed in a bacterial cell.
They found that proteins made from genes containing particular
sequences (referred to technically as Shine-Dalgarno sequences) were produced
more slowly than identical proteins made from genes with different but
redundant codons. They showed that they could introduce pauses into protein
production by introducing such sequences into genes.
What the scientists hypothesize is that the pausing
exists as part of a regulatory mechanism that ensures proper checks—so that
cells don’t produce proteins at the wrong time or in the wrong abundance.
A primer on
DNA codons
All
life on earth relies on the storage of genetic information in DNA (or in the
case of some viruses, RNA) and the expression of that DNA into proteins to
build the components of cells and carry out all life’s genetic instructions.
Every living cell in every tissue inside every organism on Earth
is constantly expressing genes and translating them into proteins—from our
earliest to our dying days. A significant amount of the energy we burn fuels
nothing more than this fundamental process.
The genetic code is basically a universal set of instructions
for translating DNA into proteins. DNA genes are composed of four types of
molecules, known as bases or nucleotides (often represented by the four letters
A, G, T, and C). But proteins are strings of 20 different types of amino acids.
To code for all 20 amino acids, the genetic code calls for genes
to be expressed by reading groups of three letters of DNA at a time for every
one amino acid in a protein. These triplets of DNA letters are called codons.
But because there are 64 possible ways to arrange three bases of DNA together—and
only 20 amino acids used by life—the number of codons exceeds the demand. So
several of these 64 codons code for the same amino acid.
Scientists have known about this redundancy for 50 years, but in
recent years, as more and more genomes from creatures as diverse as domestic
dogs to wild rice have been decoded, scientists have come to appreciate that
not all redundant codons are equal.
Many organisms have a clear preference for one type
of codon over another, even though the end result is the same. This begged the
question the new research answered: if redundant codons do the same thing, why
would nature prefer one to the other?
