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Rewriting Darwin: The new non-genetic inheritance
http://www.newscientist.com/article.ns?id=mg19926641.500&print=true
8.7.9

HALF a century before Charles Darwin published On the Origin of
Species, the French naturalist Jean-Baptiste Lamarck outlined his
own theory of evolution. A cornerstone of this was the idea that
characteristics acquired during an individual's lifetime can be
passed on to their offspring. In its day, Lamarck's theory was
generally ignored or lampooned. Then came Darwin, and Gregor
Mendel's discovery of genetics. In recent years, ideas along the
lines of Richard Dawkins's concept of the "selfish gene" have come
to dominate discussions about heritability, and with the exception
of a brief surge of interest in the late 19th and early 20th
centuries, "Lamarckism" has long been consigned to the theory
junkyard.

Now all that is changing. No one is arguing that Lamarck got
everything right, but over the past decade it has become
increasingly clear that environmental factors, such as diet or
stress, can have biological consequences that are transmitted to
offspring without a single change to gene sequences taking place. In
fact, some biologists are already starting to consider this process
as routine. However, fully accepting the idea, provocatively dubbed
the "new Lamarckism", would mean a radical rewrite of modern
evolutionary theory. Not surprisingly, there are some who see that
as heresy. "It means the demise of the selfish-gene theory," says
Eva Jablonka at Tel Aviv University, Israel. "The whole discourse
about heredity and evolution will change" (see "Rewriting Darwin and
Dawkins?").

That's not all. The implications for public health could also be
immense. Some researchers are talking about a paradigm shift in
understanding the causes of disease. For example, non-genetic
inheritance might help explain the current obesity epidemic, or why
there are family patterns for certain cancers and other disorders,
but no discernible genetic cause. "It's a whole new way of looking
at the inheritance and causes of various diseases, including
schizophrenia, bipolar disorder and diabetes, as well as cancer,"
says Robyn Ward of the cancer research centre at the University of
New South Wales in Sydney, Australia.

Lamarck's ideas about exactly how non-genetic inheritance might work
were woolly at best. He wrote, for example, of the giraffe's neck
becoming elongated over generations because of the animal's habit of
stretching up to feed on leaves in high treetops. The recent
research, by contrast, has a firm basis in biological mechanisms -
in so-called "epigenetic" change.

Epigenetics deals with how gene activity is regulated within a cell
- which genes are switched on or off, which are dimmed and how, and
when all this happens. For instance, while the cells in the liver
and skin of an individual contain exactly the same DNA, their
specific epigenetic settings mean the tissues look very different
and do a totally different job. Likewise, different genes may be
expressed in the same tissue at different stages of development and
throughout life. Researchers are a long way from knowing exactly
what mechanisms control all this, but they have made some headway.

Inside the nucleus, DNA is packaged around bundles of proteins
called histones, which have tails that stick out from the core. One
factor that affects gene expression is the pattern of chemical
modifications to these tails, such as the presence or absence of
acetyl and methyl groups. Genes can also be silenced directly via
enzymes that bind methyl groups onto the DNA. The so-called RNA
interference (RNAi) system can direct this activity, via small RNA
strands. As well as controlling DNA methylation and modifying
histones, these RNAi molecules target messenger RNA - much longer
strands that act as intermediaries between DNA sequences and the
proteins they code for. By breaking mRNA down into small segments,
the RNAi molecules ensure that a certain gene cannot be translated
into its protein. In short, RNAi creates the epigenetic "marks" that
control the activity of genes.

We know that genes - and possibly also non-coding DNA - control RNAi
and so are involved in determining an individual's epigenetic
settings. It is becoming increasingly apparent, though, that
environmental factors can have a direct impact too, with potentially
life-changing implications. The clearest example of this comes from
honeybees. All female honeybees develop from genetically identical
larvae, but those fed on royal jelly become fertile queens while the
rest are doomed to life as sterile workers. In March this year, an
Australian team led by Ryszard Maleszka at the Australian National
University in Canberra showed that epigenetic mechanisms account for
this. They used RNAi to silence a gene for DNA methyltransferase -
an enzyme necessary for adding methyl groups to DNA - in honeybee
larvae. Most of these larvae emerged as queens, without ever having
tasted royal jelly (Science, DOI: 10.1126/science.1153069).

For honeybees then, what they eat during early development creates
an epigenetic setting that has fundamental lifelong implications.
This is an extreme example, but researchers are starting to realise
that similar mechanisms are at play in other animals, and even in
humans. And, as for honeybees, it seems there is a critical early
period during which an individual's pattern of gene expression is
"programmed" to a large extent. Environmental factors can feed into
this programming, possibly with long-term health impacts.

In 2000, Randy Jirtle at Duke University in Durham, North Carolina,
led a ground-breaking experiment on a strain of genetically
identical mice. These mice carried the agouti gene, which makes them
fat and prone to diabetes and cancer. Jirtle and his student Robert
Waterland gave one group of females a diet rich in methyl groups
before conception and during pregnancy. They found that the
offspring were very different to their parents - they were slim and
lived to a ripe old age. Though the pups had inherited the damaging
agouti gene, the methyl groups had attached to the gene and dimmed
its expression.

Jirtle then tried supplementing the diets of pregnant agouti mice
with genistein, an oestrogen-like chemical found in soya. The dose
was designed to be comparable to the amount consumed by a person on
a high-soya diet, which is associated with a reduced risk of cancer
and less body fat. These mice were also more likely to give birth to
slim, healthy offspring which had less chance of becoming obese in
adulthood. This change was associated with increased methylation of
six DNA base-pair sites involved in regulating activity of the
agouti gene.

These and other animal studies strongly suggest that a pregnant
woman's diet can affect her child's epigenetic marks. So perhaps it
is not surprising that the effect of certain nutrients is being
called into question. Folate, for example, is a potent methyl donor.
It is routinely recommended during pregnancy and added to cereal
products in certain countries, including the US, because it reduces
the risk of spinal tube defects if eaten around the time of
conception. But Jirtle wonders whether it could also be inducing
as-yet-unknown, damaging epigenetic effects.

The legacy of stress

Diet is not the only environmental factor that can influence the
epigenetic setting of some genes. Michael Meaney at McGill
University in Montreal, Canada, and colleagues have found that
newborn mice neglected by their mothers are more fearful in
adulthood - and that these mice show much higher than normal levels
of methylation of certain genes involved in the stress response. On
a brighter note, these mice also point the way to a possible way to
reverse epigenetic changes (see "In sickness and in health").

In humans, too, there are troubling hints that damaging experiences
early in life, while the brain is still developing, can affect
epigenetic settings, perhaps with catastrophic consequences. In May,
Meaney and his colleagues reported a study of 13 men who had
committed suicide, all of whom had been victims of child abuse. They
showed clear epigenetic differences in their brains, compared with
the brains of men who had died of other causes. It is possible that
the changes in epigenetic marks were caused by the exposure to
childhood abuse, says the team. Could the changes have contributed
to their suicides too?

There is recent evidence that abnormal epigenetic patterns play a
role in mental health disorders. In March, Arturas Petronis at the
Centre for Addiction and Mental Health in Toronto, Canada, and
colleagues reported the first epigenome-wide scan of post-mortem
brain tissue from 35 people who had suffered from schizophrenia.
They found a distinctive epigenetic pattern, controlling the
expression of roughly 40 genes (The American Journal of Human
Genetics, vol 82, p 696). Several of the genes were related to
neurotransmitters, to brain development and to other processes
linked to schizophrenia. These findings lay the groundwork for a new
way of understanding mental illness, says Petronis, as a disease
with a significant epigenetic component.

As with the people who had committed suicide in Meaney's study,
these epigenetic marks may have arisen during development. Yet there
are also hints that the people with schizophrenia might instead have
inherited them from their parents - and that they in turn might pass
the marks on to their own children. In theory, epigenetic marks are
wiped clear between generations in mammals. Intriguingly, though,
the abnormalities in DNA methylation in Petronis's subjects were not
restricted to their frontal cortex: they were also present in their
sperm. "[This] suggests that it is possible that inherited
epigenetic abnormalities may be contributing to the familial nature
of schizophrenia and bipolar disorder," says team member Jonathan
Mill at the Institute of Psychiatry at King's College London.

This work is only suggestive, but when it comes to cancer, the
evidence is stronger. Some colorectal cancers are known to develop
when a key DNA-repair gene called MHL1 becomes coated in methyl
groups, preventing it from working. In 2007, Ward and her colleagues
published a study of a woman with this type of cancer and her three
children. The MHL1 gene was active in two of the children, but one
son had a heavily methylated, silenced gene like his mother (The New
England Journal of Medicine, vol 356, p 697).

The paper caused a sensation among cancer researchers because it
suggested an entirely new way in which disease risk might be
inherited. Of course the finding could have been a coincidence, or
the son might have inherited a genetic propensity to methylation of
this gene, rather than the epigenetic mark itself. Since the paper
came out, though, direct inheritance is starting to look more
likely. Other teams have identified similar families, and in all
cases the effect seems to be transmitted down the maternal line via
the egg. The MHL1 gene in the sperm of affected men appears normal.

Some epigenetic marks may also be inherited from fathers, however.
In a now classic study published in 2005, Matthew Anway at the
University of Idaho in Moscow and colleagues showed that male rats
exposed to the common crop fungicide vinclozolin in the womb were
less fertile and had a higher than normal risk of developing cancer
and kidney defects. Not only were these effects transmitted to their
offspring, they were passed from father to son through the three
following generations as well (Science, vol 308, p 1466). The team
found no DNA changes, only altered DNA methylation patterns in the
sperm of these rats, suggesting that epigenetic factors were to
blame.

The following year, a team at the University of Maryland in
Baltimore found that male mice that had inhaled cocaine passed
memory problems onto their pups. Again, their sperm showed no
apparent DNA damage, but in the seminiferous tubules, where sperm
are produced, the researchers found changes in the levels of two
enzymes involved in methylating DNA.

In people, too, there is evidence that environmental impacts on
fathers and mothers can produce changes in their children. This has
led some researchers to consider a startling possibility. Could the
current epidemic of type II diabetes and obesity in developed
countries be related to what our parents and our grandparents ate?

Nutrition does seem to have some lasting effect, according to a
study by Marcus Pembrey of the Institute of Child Health at
University College London and his colleagues. They analysed records
from the isolated community of Överkalix in northern Sweden and
found that men whose paternal grandfathers had suffered a shortage
of food between the ages of 9 and 12 lived longer than their peers
(European Journal of Human Genetics, vol 14, p 159). A similar
maternal-line effect existed for women, but in this case by far the
biggest effect on longevity of the granddaughters occurred when food
was limited while grandmothers were in the womb or were infants. It
would appear that humans thrive on relatively meagre rations, and
the team concluded that under these conditions some sort of key
information - perhaps epigenetic in nature - was being captured at
the crucial stages of sperm and egg formation, then passed down
generations.

Pembrey's team also looked at more recent records from the UK,
collected for the Avon Longitudinal Study of Parents and Children.
They identified 166 fathers who reported starting smoking before the
age of 11 and found that their sons - but not their daughters - had
a significantly higher than average body mass index at the age of 9.

Also in 2006, Tony Hsiu-Hsi Chen at the National Taiwan University
in Taipei and colleagues reported that the offspring of men who
regularly chewed betel nuts had twice the normal risk of developing
metabolic syndrome during childhood. Betel nuts are also associated
with several symptoms of metabolic syndrome in chewers including
increased heart rate, blood pressure, waist size and body weight.

The mother's nutrition might affect a child's risk of obesity, too.
Women in the Netherlands who were in the first two trimesters of
pregnancy during a famine in 1944 and 1945 gave birth to boys who,
at 19, were much more likely to be obese.

All these results raise an important question. Why should factors
like food intake or smoking around the time sperm or eggs are
created, or at the embryo stage, have such an influence on a child's
metabolism and weight?

Extended periods of too much or too little food might trigger a
switch to a pattern of gene expression that results in earlier
puberty and so earlier mortality, says Pembrey - and this might be
heritable. "The reason why some people gain weight more easily is
because their metabolic genes are used differently," says Reinhard
Stöeger at the University of Washington in Seattle. He suggests that
long before the emergence of modern humans, a network of metabolic
genes evolved that was honed for a relative scarcity of food, but
not feast or famine. "These genes have become epigenetically
programmed during the early stages of life in response to adverse
environmental conditions - such as feast. This might explain the
current epidemic of type II diabetes and obesity in the west, where
food is plentiful." Prolonged epigenetic silencing in response to
the environment might also lead to a DNA change that "locks in"
epigenetic marks, Stöeger suggests.

Out of the melting pot of recent findings, a host of fundamental
questions are now being thrown up. If what we eat could affect our
grandchildren, should we be more careful? If so, in what ways?
Should we be more concerned about the long-term impact of war or
child abuse? Could we choose a diet to reduce our own cancer risk,
and that of our children? We are only starting to get an inkling
about how to answer these, but one thing is clear: genes are only
part of the story.

Evolution - Learn more about the struggle to survive in our
comprehensive special report.

Genetics - Keep up with the pace in our continually updated special
report.

Rewriting Darwin and Dawkins?

The realisation that individuals can acquire characteristics through
interaction with their environment and then pass these on to their
offspring may force us to rethink evolutionary theory. While
examples of this "transgenerational epigenetic inheritance" are only
just emerging in mammals, there is long-standing and widespread
evidence for it in plants and fungi. That may explain why botanists
are much more ready to acknowledge and promote the idea that
epigenetic inheritance has a significant role in evolution, whereas
zoologists are generally reluctant to do so, says Eva Jablonka from
Tel Aviv University, Israel.

That looks set to change. "There was a trickle of findings of
epigenetic inheritance in animals through the 20th century, and it
is turning into a flood about now," says Russell Bonduriansky, at
the University of New South Wales in Sydney, Australia. One of his
favourite recent examples involves the water flea, daphnia. When
predators are around, the fleas develop large, defensive spines. If
they then reproduce, their offspring also develop these spines -
even when not exposed to predators.

For Bonduriansky, this suggests a possible adaptive function of
epigenetic inheritance - the fine-tuning of an individual to
short-term variations in its environment. "There's no lag time for
the offspring to respond to the environment on their own," he says.

The idea that epigenetic variation could be adaptive - rather than a
form of random, non-directed variation - is very controversial,
harking back as it does to the discredited theory of Lamarckian
evolution. Nevertheless, this has not deterred some researchers from
exploring the full implications of epigenetic inheritance.

For example, there is evidence that epigenetic changes can affect
mate preference. Last year, David Crews and Andrea Gore at the
University of Texas at Austin published a study of male rats whose
great-grandfathers had been exposed to the fungicide vinclozalin.
Previous research has revealed that such exposure leads to increased
infertility and higher risks of cancer even four generations later.
Crews and Gore found that female rats tended to avoid these males.
They could sense something was wrong, says Gore. The females seemed
to select mates on the basis of an epigenetic pattern, as opposed to
a genetic difference, she adds.

Back to the future

For Bonduriansky the accumulating evidence calls for a radical
rethink of how evolution works. Jablonka, too, believes that
"Lamarckian" mechanisms should now be integrated into evolutionary
theory, which should focus on mechanisms, rather than units, of
inheritance. "This would be very significant," she says. "It would
reintroduce development, in a very direct and strong sense, into
heredity and hence evolution. It would mean the pre-synthesis view
of evolution, which was very diverse and very rich, can return, but
with molecular mechanisms attached."

That needn't necessarily mean an end to the idea of the gene as the
basic unit of inheritance, or Richard Dawkins's selfish gene,
according to some. "I don't think it violates the basic concept that
Dawkins articulated," says Eric Richards, at Washington University
in St Louis, Missouri. "Epigenetic marks can also be viewed as part
of that basic unit in a more inclusive definition of a gene," he
says.

What does Dawkins himself think? "The 'transgenerational' effects
now being described are mildly interesting, but they cast no doubt
whatsoever on the theory of the selfish gene," he says. He suggests,
though, that the word "gene" should be replaced with "replicator".
This selfish replicator, acting as the unit of selection, does not
have to be a gene, but it does have to be replicated accurately, the
occasional mutation aside. "Whether [epigenetic marks] will
eventually be deemed to qualify as 'selfish replicators' will depend
upon whether they are genuinely high-fidelity replicators with the
capacity to go on for ever. This is important because otherwise
there will be no interesting differences between those that are
successful in natural selection and those that are not." If all the
effects fade out within the first few generations, they cannot be
said to be positively selected, Dawkins points out.

In sickness and in health

Epigenetic abnormalities have been found in nearly every type of
cancer and in other diseases, such as cardiovascular disease. But
the discovery that diseases can be caused by environmental factors
influencing the expression of genes has an upside. "The beauty of
any epigenetic modification is that it is reversible by drugs," says
Robyn Ward from the University of New South Wales in Sydney,
Australia.

Take the epigenetic marks acquired by mice as a result of maternal
neglect during infancy. Here, methyl groups become attached to genes
involved in the stress response, resulting in heightened anxiety.
But, using drugs, Michael Meaney at McGill University in Montreal,
Canada, and his team have reversed the methylation of these genes
and their associated behavioural responses in adulthood (Journal of
Neuroscience, vol 25, p 11045). They injected the drugs directly
into the brain although it is possible that a special diet could do
the same trick, Meaney says.

NEW ROLE FOR OLD DRUGS

Other drugs that influence methylation are now in early-stage
anti-cancer trials. Some of them are not new, but are being
reassessed in the light of new knowledge about how they work.
Azacytidine, for example, which was used years ago with limited
success to treat a range of bone-marrow stem-cell disorders, is
undergoing trials again on these very same disorders. Now that it
has become clear the drug induces epigenetic changes, researchers
are altering doses and redesigning trials with the aim of activating
tumour-suppressor genes that have been silenced by methylation.

This approach does have a major drawback - epigenetic drugs are not
specific. Side effects, such as nausea and diarrhoea, are probably
down to their broad range of action, says Ward. It might be possible
to target drugs more specifically, but that is a very long way off.
Still, the fact that it offers a whole new way of treating disease
leads many to consider the epigenetics approach to be very
promising.

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Weblinks

Human Epigenome Project, Wellcome Trust
http://www.genome.wellcome.ac.uk/doc_wtx036556.html
MethylGene
http://www.methylgene.com/
Richard Dawkins
http://www.richarddawkins.net
Eva Jablonka
http://www.tau.ac.il/humanities/cohn/staff/eva-jablonka.htm