MicroRNAs and RNA Interference
he human genome provides blueprints
for building a human body, and it also
includes instructions for how to use the
blueprints. Those instructions are so small—RNA
molecules 21 or 22 bases long—that for many
years researchers unwittingly threw them out.
Today an entire industry is forming to adapt these
natural controllers of gene expression, called
microRNAs, into diagnostic tests and even new
types of treatments for disease.
MicroRNAs belong to a class of RNA mole-
cules called noncoding RNAs, so-named because
they were not among the F
rst three major classes
of RNA described (mRNA, tRNA, and rRNA). The
human genome probably has close to 1,000
microRNAs, about half of which have been discov-
ered. The DNA sequences that encode microRNAs
are found in parts of the genome accessed to pro-
duce proteins and also in the vast regions that do
not encode protein and are less well understood.
Each microRNA binds to parts of the initial
control regions (corresponding to DNA promot-
ers) of a particular set of mRNAs, by comple-
mentary base pairing. When a microRNA binds
a “target” mRNA, it turns o±
transcription. In this
way, a single type of microRNA controls speciF
sets of genes. In turn, a single type of mRNA
can bind several different microRNAs. To ana-
lyze these complex interactions, researchers use
experiments as well as computational tools (bio-
Within the patterns of microRNA function
may lie clues to developing new ways to F
ght dis-
ease, because these controls of gene expression
have stood the test of evolutionary time. The F
applications are in cancer, as certain microRNAs
are either more or less abundant in cancer cells
than in healthy cells of the same type from which
the cancer cells formed. Restoring the levels of
microRNAs that normally suppress the too-rapid
cell cycling of cancer, or blocking production of
microRNAs too abundant in cancer, could help to
return cells to normal. The F
rst microRNA-based
diagnostic tests became available in 2008 and
are used to distinguish types of lung cancer and
for cancer that has spread and the original tumor
cannot be identiF
ed by other means.
In a related technology called RNA interfer-
ence (RNAi), small, synthetic RNA molecules are
introduced into cells. They block gene expres-
sion in the same manner as the naturally occur-
ring microRNAs. Many companies are developing
RNAi-based drugs. The technological challenge is
in directing
where they a±
ect the genome.
Mutations occur in two general ways—spontaneously or
induced. They may happen spontaneously due to the chemi-
cal tendency of free nitrogenous bases to exist in two slightly
different structures. For extremely short times, a base can be
in an unstable form. If, by chance, such an unstable base is
inserted into newly forming DNA, an error in sequence will
be generated and perpetuated when the strand replicates.
Another replication error that can cause mutation is when the
existing (parental) DNA strand slips, adding nucleotides to or
deleting nucleotides from the sequence.
In contrast to spontaneous mutations are induced muta-
tions, a response to exposure to certain chemicals or radia-
tion. Anything that causes mutation is termed a
tah-jen). A familiar mutagen is ultraviolet radiation,
part of sunlight. Prolonged exposure to ultraviolet radiation
can form an extra bond between two adjacent thymine DNA
bases that are part of the same DNA strand in a skin cell. This
extra bond kinks the double helix, causing an incorrect base
to be inserted during replication. The cell harboring such a
mutation may not be affected, may be so damaged that it
dies and peels off, or it may become cancerous. This is how
too much sun exposure can cause skin cancer. Mutagens are
also found in hair dye, food additives, smoked meats, and
ame retardants.
Disease may result from a mutation, whether spon-
taneous or induced. If the mutation alters the amino acid
sequence of the encoded protein so that it malfunctions or
isn’t produced at all, and health is impaired. For example,
If the change affects the person in a noticeable or detectable
way and occurs in less than one percent of the population, it
is considered a mutation. If there is no detectable change from
what is considered normal and the change is seen in more
than one percent of the population, it is considered a SNP.
These designations, however, are subjective. They depend
upon what we can identify and what we consider normal. A
more general and traditional use of the term “mutation” is as
the mechanism of change in a DNA sequence.
The human genome has millions of SNPs. Association studies look at
SNP combinations in populations and attempt to identify patterns
found almost exclusively in people with a particular disorder. The cor-
relations between SNP patterns and elevated disease risks can be used
to guide clinical decision-making—for example, suggesting which
patients might respond to one drug but not another. However, some-
times the associations are statistical ²
ukes that vanish when more data
are included. Still, several companies promote SNP-based tests direct-
to-consumers on the Internet. These should be approached with cau-
tion, because the accuracy of using population-level data to diagnose
disease in an individual has not been well-studied.
Another way that people differ in their DNA sequences
is by the number of repeats of particular sequences, called
copy number variants. Such a repeated sequence may range
from only a few DNA bases to millions.
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