Consider the neutral mutations which rendered the drug Tamiflu useless against seasonal flu (reading pasted below). Do you think this kind of cryptic variation is important to study for

Consider the neutral mutations which rendered the drug Tamiflu useless against seasonal flu (reading pasted below).
Do you think this kind of cryptic variation is important to study for its potential impact on human health? Why or why not?
When Jesse Bloom hear in 2009 that TAM IFLU, once the
world’s best treatment for flu, had inexplicably lost its punch,
he thought he knew why. Sitting in his lab at the California
Institute of Technology, the biologist listened to a spokesper
son from the World Health Organization recount the tale of
the drug’s fall from grace. Introduced in 1999, the compound
was the first line of defense against the various strains of flu
virus that circulate around the world every year. It did not just treat symptoms; it slowed the
replication of the virus in the body, and it did its job well for a time. But in 2007 strains world
wide started shrugging off the drug. Within a year Tamiflu was almost completely useless
against seasonal influenza.! The WHO spokesperson explained that the sweeping resistance
came about through the tiniest of changes in the flu’s genetic material. All flu viruses have a
protein on their surface called neuraminidase?the “N” in such designations as HlNl?which
helps the viruses to break out of one cell and infect another. Tamiflu is meant to stick to this
protein and gum it up, trapping the viruses and curtailing
their spread. But flu viruses can escape the drug’s attention
through a single change in the gene encoding the neuramin
idase protein. A mutation called H274Y subtly alters neur
aminidase’s shape and prevents Tamiflu from sticking to it.
Most public health experts had assumed that flu viruses would
eventually evolve resistance to Tamiflu. But no one anticipated
it would happen via H274Y, a mutation first identified in 1999
and originally thought to be of little concern. Although it allows
flu viruses to evade Tamiflu, it also hampers their ability to in
fect other cells. Based on studies in mice and ferrets, scientists
concluded that the mutation was “unlikely to be of clinical con
sequence.” They were very wrong. The global spread of viruses
bearing H274Y proved as much.
That spread “sounded alarm bells to me,” Bloom says. Something
else had changed to let the virus use the mutant neuraminidase
without losing the ability to spread efficiently. He soon found
that certain strains of HlNl had two other mutations that com
pensated for H274Y’s debilitating effects on the virus’s ability to
spread from cell to cell. Neither of the pair had any effect on their
own. In the lingo of biologists they were “neutral.” But viruses
that carried both of them could pick up H274Y, gaining resis
tance to Tamiflu without losing their infectivity. Both mutations
looked innocuous individually, but together they made the virus
more adaptable in the face of a challenge. To put it another way,
they made it better at evolving.
Such neutral mutations are also known collectively as hidden
or cryptic variation. They were long ignored by most researchers,
but thanks to technological advances, scientists are starting to
see that they are a major driving force in evolution?including
the evolution of microorganisms that make us sick. By studying
cryptic variation, scientists are finding new ways of safeguarding
Once effective medicines,
like Tamiflu, for
instance, are losing their power to fight
the flu virus, and other agents of disease.
All flu viruses
have a protein on their
surface called neuraminidase?the ” N” in
such designations as H IN l-w hich helps
the viruses to break out of one cell and
infect another. Tamiflu formerly gummed
up the process, but a seemingly innocuous
mutation in the virus changed that.
Researchers have found
that in many
cases of disease agents, innocuous
mutations are pairing up. Such “cryptic
mutations” are giving rise to valuable
changes, making diseases more potent.
IN BRIEF
COURTESY PARDIS SABETI
our health and discovering fuller answers to one of evolution’s
most fundamental questions: Where do new adaptive traits come
from? As Joshua Plotkin from the University of Pennsylvania puts
it: “This is the forefront of modern evolutionary biology.”
HOW IT WORKS
As the flu example shows, one way that cryptic mutations can en
hance adaptation is by collaborating with other mutations to pro
duce a whole that is greater than the sum of its parts. Imagine that
someone gave you a triangular metal frame or a pair of wheels.
Both parts would be useless on their own, but put them together
and you get a working bicycle. If you have either component, you
have nothing immediately useful but you are primed to reap the
benefits of the second one. In the same way cryptic variation can
lay the groundwork for future adaptations.
Some cryptic mutations can also prove useful on their own,
essentially keeping quiet until circumstances arise where they
come in handy. And, by building up a lot of cryptic variation,
organisms can increase their ability to adapt. Imagine that some
thing goes badly wrong in your house. If you have a bunch of tools
you never needed before stashed away in a cupboard, one of them
might end up being good for the job or could be modified. In the
same way, a storehouse of cryptic variation increases the chances
that living things will be preadapted to cope with new challenges.
These ideas fit well with Darwin’s theory of natural selection, in
which beneficial traits that boost an organism’s reproductive suc
cess are passed down to future generations, or “selected”to continue
on. Biologists, however, are increasingly realizing that some muta
tions are important not because they provide immediate benefits
but because they enable adaptations to occur in the future. These
INNOVATOR
Pardis Sabeti
tackles the interaction of
infectious disease and the modern human
body?and how both evolve as a result
Why take on the study of how infectious diseases?and the
human body’s responses to them?evolve?
I remember as a child loving math and loving nature. Genetics
is biology as mathematical information, which suits me so well.
And in graduate and medical school, I just gravitated toward
infectious disease. Microbes are fascinating. They have had
such a major impact on our evolution, and they themselves
evolve over time. I wanted to understand these interactions
and find a novel way to have an impact on human health.
What do you consider your “Aha!” moment?
While finishing my Ph.D. while in medical school, I had spent
many months on an algorithmic idea to find evidence of
evolution in the human genome. I had been working through
the math and implementing it. It finally came together one
night at 3 a.m. Sitting in my dorm room, I pressed the button
and saw a signal of evolution on a trait protective from malaria.
It was beautiful. At that moment I knew a little something
about the world?about our origins?that no one else in the
world knew.
How important is infectious disease to our human evolution?
We and all other organisms are in a constant struggle for
survival on this earth. Sometimes we cooperate. Sometimes we
fight. At each step we evolve, often in response to each other.
It would be wonderful to get to a place where we could live in
a harmony.
Is our human response to infectious disease still evolving?
If so, at what rate?
The rate of mutations in our gepomes are relatively constant,
but the forces that drive our evolution are everchanging. I
would imagine between the many infectious diseases and
the big cultural and environmental changes, there is a lot going on
right now in terms of human evolution. We may not even know how
many hidden forces we are contending with.
What’s the next question we need to be asking?
One big one is: How is it that in the 21st century we can a get a cold
or other infectious illness and have no idea what bug is making us
sick? We have an opportunity to develop technologies so that the
next time you get sick, you know just what is causing it and even
how you got it. Diagnosis is only a first step toward treatments, but
with the information, we will have the power to act.
?
Johnna Rizzo
A fruit fly,
Drosophila
meiahogaster,
exhibits
an ectopic eye on
?’its wing, a mutation
unleashed by the
‘ absence of_Hsp90. /
Right: The secondary
structure of Hsp90.
FROM LEFT: EYE OF SC1ENCE/SCIENCE SOURCE; MATTI HAPPY
mutations can build up because
natural selection does not re
move genetic alterations that
have no obvious effects on our
proteins, cells or bodies.
The notion that cryptic mu
tations can be useful has a long
history. In the 1930s Sewall
Wright, one of the founding
fathers of evolutionary theory,
recognized that initially unim
portant genetic changes could
later give rise to valuable ones.
Theodosius Dobzhansky, an
other central figure, said that
species need to have “a store
of concealed, potential, vari
ability.” Even so, until very
recently scientists managed to
document only a few arcane
examples of hidden mutations
affecting the wings or hairs of
flies without any proof these
changes
benefited
the
ani
mals. “We didn’t have the tools
to take it further, and the
topic languished,” says Joanna
Masel from the University of
Arizona in Tucson. With pow
erful
sequencing technology
and mathematical models on
hand, scientists have now been
able
to
show
that
cryptic
variation is a powerful and widespread force in evolution. In
everything from flu viruses to flowers to fungi, they have found
tangible case studies where useful adaptations arose from seem
ingly neutral mutations.
EVIDENCE
One of the clearest examples comes from Andreas Wagner at
the University of Zurich and involves molecules called ribo-
zymes, which consist of RNA (genetic material related to DNA)
and function in the body as catalysts. They speed up chemical
reactions involving other RNA molecules but are picky about
the ones they interact with. To react with a new target, they
need to alter their shapes. And to do that, they need the se
quence of their building blocks to change. In test-tube studies
Wagner found that ribozymes could adapt to deal with a new
target six times faster if they had previously built up lots of
cryptic variation. Just as in the Tamiflu-resistant flu viruses,
these mutations made no difference on their own; they merely
brought some of the ribozymes a step closer to achieving the
changes they needed. “They had a leg up in the evolutionary
process,” Wagner says.
Another example comes from studies of heat-shock proteins,
which help nascent proteins to fold properly into their func
tional forms and also protect them from losing their function
in response to various stresses, such as excess heat. In 1998
Suzanne Rutherford andSusanLindquistfromtheMassachusetts
Institute of Technology showed that a heat-shock protein called
Hsp90 can both hide cryptic variation and unleash it, depend
ing on circumstances.
By helping proteins to fold correctly, Hsp90 allows them to
tolerate genetic mutations that might otherwise catastrophically
distort their shapes. It can thus allow proteins to build up such
mutations, along with neutral ones. If conditions become more
challenging?such as a significant rise in temperature?the
Hsp90 molecules may be in such demand that they cannot aid
all the proteins that need them. Suddenly, proteins have to fold
without Hsp90’s help, and all their cryptic mutations become
exposed to natural selection. Some of these mutations would
have beneficial effects in the challenging conditions and would
thus pass to the next generation.
Rutherford and Lindquist first demonstrated what Hsp90
does in fruit flies. When they depleted the protein by exposing
flies to heat or chemicals, the insects grew up with all sorts
of weird features, from subtle, unimportant things like extra
hairs to severe deformities like misshapen eyes. None of these
changes were caused by fresh mutations but rather by existing
dormant ones that had been hidden by Hsp
90
and unmasked
by its absence. For good reason, Lindquist has described Hsp90
as an evolutionary “capacitor,” after the devices that store elec
trical charge and release it when needed. It stores cryptic vari
ation, unleashing it in demanding environments, just when it
is most needed.
Hsp
90
is ancient and found in plants and fungi as well as
animals?signs that it is one of life’s critical molecules. One of
Lindquist’s lab members, Daniel Jarosz,
discovered that a fifth of all the varia
tion in the yeast genome is concealed by
Hsp90?a huge reservoir just waiting to
be released. By exposing so much vari
ation in one fell swoop, Hsp90’s behav
ior provides a possible answer to one of
evolution’s most puzzling questions?the
origin of complex combinations of traits.
“Sometimes it’s hard to envision how new forms or func
tions could emerge if they require multiple mutations, none of
which are individually beneficial. The frequency of it should be
exceedingly rare,” Jarosz says. It is a dilemma that opponents
of evolutionary theory often seize on. But heat-shock proteins,
and cryptic variation more broadly, provide a possible solution.
When environments change, they allow organisms to make use
of mutations that were sitting quietly in the wings but that in
combination suddenly offer a solution to some challenge to sur
vival. They act as evolutionary rocket fuel. “Hsp90 can help us
to understand how complex traits could ever be achieved in very
rapid fashion,” Jarosz says. For those in the field, it is an exciting
time. “We’re really at the cusp of making big discoveries in the
most fundamental question in evolutionary biology: ‘How does
life bring about new things?'” Wagner says.
Beyond
offering new
insight into the
underpinnings
of evolution,
research into
cryptic
mutations is
suggesting new
ways to look
at and combat
disease.
THE DISEASE CONNECTION
Beyond offering new insight into the underpinnings of evolu
tion, research into cryptic mutations is suggesting new ways to
look at and combat disease. It has been very hard to decipher
the genetic underpinnings of many human traits or diseases,
from height to schizophrenia. Even though they run strongly
in families, scientists have found only a small number of genes
associated with them. Plotkin wonders if cryptic variation
might help to solve the puzzle of this “missing heritability.” Per
haps we should be looking for mutations that have no effect on
their own but rather influence the risk of diseases in combina
tion. “This is just wild speculation on my part, but it sounds
reasonable to me,” he says.
The same thinking is being applied to other disorders. We
continually provide bacteria, fungi and viruses with new chal
lenges by attacking them with our immune system or hitting
them with waves of toxic drugs. One of their chief defences is
the ability to evolve resistance, and cryp
tic variation helps them to do t faster.
Lindquist, for example, has shown that
Candida albicans,
the fungus responsible
for thrush, needs lots of Hsp
90
to evolve
resistance to antifungal drugs. When she
blocked Hsp90, the fungi stayed vul
nerable. Cancer cells also benefit from
Hsp90, because they need help in fold
ing their wide array of unstable mutant
proteins. Many scientists are now testing
chemicals that block Hsp90 as potential
treatments for cancer or ways of prevent
ing fungi and bacteria from developing
drug-resistance.
Others are trying to predict how cryp
tic variation fuels the evolution of viruses.
Plotkin and Bloom are focusing on in
fluenza. “The flu virus is evolving all the
time to escape all the antibodies that it
has stimulated in the human population,”
Plotkin says. “This is why we have to up
date the vaccine every year.” Last year he
analyzed the genomes of flu viruses col
lected over four decades. He found hun
dreds of pairs of mutations, where one
swiftly appeared after the other. In many
cases the first of the pair was neutral?it did nothing except to
pave the way for the second mutation. By identifying these hid
den mutations, which predate more serious ones, we could find
strains that are primed for resistance and cut them off with the
right vaccines. “We could, to some extent, predict the evolution
of flu,” Plotkin says.
Plotkin also envisages focusing on cryptic mutations for a dif
ferent end: making new molecules useful for the biotechnology
industry. Many scientists are trying to artificially evolve designer
proteins that will do specific tasks. Typically they look for mu
tations that overtly alter proteins in ways that enhance their
ability to do the chosen task. But it may be useful to look for
the hidden neutral mutations that could make proteins more
likely to acquire useful mutations. “Understanding the role of
cryptic mutations in an evolving protein could help to improve some already
very useful techniques for engineering enzymes,” Plotkin says.
Applications like these are just the beginning. In many ways

the study of cryptic variation has been a metaphor for itself.

Knowledge and interest in the field has been building up under

the surface for a long time, largely hidden from view, only to be

released by the influx of new technology. “We’re really at the tip

of the iceberg,” Plotkin says.

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