1) Identical twins have the same DNA sequence but can become increasingly different over time with subtle differences in personalities, appearances, behaviors, and disease susceptibilities. 2) This is due to differences in their "epigenome" or how they use their DNA through epigenetic modifications like DNA methylation and histone modifications rather than changes to the DNA sequence. 3) A study of 512 adolescent twins found differences in DNA methylation profiles of imprinted genes between genetically identical twins, supporting the role of environment in influencing epigenetics and contributing to differences between twins.

1. A
bout once every 80 live
births, a twin pair is
born. The majority of
these twins are fraternal,
meaning they are
derived from two separate fertilisations
andareassimilargeneticallyasbrothers
or sisters.
It is only once in every 250 deliv-
eries that a single embryo splits after
fertilisation. This event
results in the formation of
“identical” twins. As these
twins are derived from the
same fertilisation, they have
identical genomes. Yet,
somehow identical twins
becomeincreasinglydifferent
overtime,withsubtlediffer-
encesintheirpersonalities,
how they look, how they
act and even in their
susceptibility to getting a
certain disease, such as
autism spectrum disorders,
schizophrenia,bipolardisorder,
epilepsy and diabetes.
The cause of this has to do with their
“epigenome”,orhowdifferentlytheyuse
their DNA. But let’s start with some
background.
Thegeneticsequenceofanindividual
is more or less static over time. Still, the
genome has the remarkable ability to
dynamicallyrespondtoitsenvironment.
ThisisbecauseDNAisonlyhalfthestory.
Every living cell contains about
2 metres of DNA. To fit this DNA
neatlyintothetinynucleus,itiswrapped
around proteins called histones. Both
these histones and the DNA itself can
harbour chemical modifications that
can activate or repress the underlying
DNA sequence.
26 | | APRIL 2012
Identical twins essentially
have the same DNA sequence,
but the way they use their
DNA can be vastly different.
Identical Genes,
IndividualTwins
BY MARCEL COOLEN
Photo:FotostudioEnjoy,IngridvanHeteren(NL)

2. This additional layer of structure is called epigenetics, which
is often defined as “changes in the functioning of the genome
that occur without a change in DNA sequence”. It can be
thought of as the interpreter of a poem that helps us to under-
stand its meaning, but there is often more than one way to look
at the text.
Epigenetics is the mechanism that the cell employs to help
understand and interpret the DNA code in the correct space
and time. For example, it makes heart and brain cells act very
differentlyeventhoughtheyhavethesamegeneticinformation.
Moreover, epigenetic marks can respond to environmental
signals, such as stress, diet, toxins and physical activity, and
hence these external factors can influence gene expression. My
research with Prof Susan Clark at the Garvan Institute of
Medical Research has now shown that these epigenetic marks
can be vastly different between identical twins.
Twin or no twin, each newly formed embryo contains two
copies of every chromosome – except for the sex chromosomes
in male embryos – one inherited from its father and one from
its mother. For most genes both the paternal and maternal
chromosomes are used by the cells to make protein products.
However, a small set of about 80 genes behave differently and
are predetermined to only use the copy passed down from either
the father or the mother. This process is known as imprinting.
Imprinted genes are somehow stamped with a memory
making it possible to tell which copy came from the mother
and which copy was inherited from the father. This stamp is an
epigenetic modification, where the DNA is methylated on only
one of the chromosome copies.
APRIL 2012 | | 27
WHAT IS EPIGENETICS?
Epigenetics is the study of changes in gene expression that are
not caused by changes in the DNA sequence. Different cell types
in a human body have different epigenetic profiles even though
their DNA is the same. These epigenetic profiles are like a memory
system for a cell, telling it what to do and which part of its DNA to
use without the need for external signals to tell it how to act.
Several levels of epigenetic regulation exist:
• DNA methylation: DNA is built using four nucleotides:
adenosine, cytosine, guanine and thymine. Cytosine can
become chemically modified (methylated) if it is immediately
followed in the DNA sequence by guanine, and this turns the
gene’s activity off.
• Histone modification: DNA in the cell is wrapped around
histone proteins that can be chemically modified in many
ways (e.g. acetylated or methylated). These chemical
modifications inform the cell how tightly to wrap the DNA
around the histones. Different modifications can have
activating and repressing roles on the DNA. To date, more than
100 different histone modifications have been identified,
making this a complex level of gene regulation.
• Higher order chromatin structure: linear DNA is wrapped
around histones and further folded and condensed to varying
degrees, forming higher order chromatin structures. Inactive
regions are tightly packed and no longer accessible for gene
transcription, whereas active chromatin is more loosely
packed. The position inside the nucleus is also informative on
the activity of larger chromosomal regions.
Identical twins show a higher joint incidence of many diseases
than fraternal twins, indicating that genetic components are
important in these traits. None of the traits have a joint
incidence of 100% in identical twins, revealing that it is more
than just the DNA sequence that determines a trait.
Height
Reading Disability
Autism
Alzheimer’s
Schizophrenia
Alcoholism
Hypertension
Bipolar Disorder
Diabetes
Multiple Sclerosis
Breast Cancer
Crohn’s Disease
Stroke
Rheumatoid Arthritis
% of twin pairs with the same trait
0% 100%

3. It is not clear why imprinting exists,
but it is evident that imprinting is essen-
tial for normal development. Improper
imprinting can lead to severe develop-
mental abnormalities, cancer and other
health problems. It is also associated with
an increased risk for developing colon
cancer later in life.
We have just completed a large study
intwinsthatfocusedontheDNAmethy-
lation profiles of imprinted genes that are
importantinthecontrolofgrowthduring
early development. The study involved a
detailed analysis of 512 adolescent twins
(128identicaltwinpairsand128fraternal
twin pairs), making it one of the largest
studies ever undertaken of this sort.
Our analysis aimed to determine what
role genetics plays in determining who
we are versus the role of environmental
factors. By comparing genetically related
people with genetically identical people,
we could examine how closely their
methylation patterns matched.
We were able to find differences in
the DNA methylation profiles of
imprinted genes in genetically identical
twins. It is these changes that probably
give rise to the differences observed in
identical twins. These findings support
the hypothesis that changes in DNA
methylation reflect the interplay between
the environment and genetics.
We also found that methylation
patterns are exquisitely inherited, so the
methylation patterns of identical twins
are very similar to each other. This
demonstrated that the DNA sequence
does instruct the methylation pattern.
When that methylation pattern changes,
however, it gives rise to potential changes
that determine who we are. The overall
variability of DNA methylation patterns
weobservedinthisstudycouldberespon-
sible for some of these differences
between identical twins.
Wenowhaveevidencethatchangesin
methylation patterns occur in genetically
identical people, and therefore these
changes can potentially change disease
susceptibility. The next step will be to
examine twins that are discordant for a
particulardisease,suchasType2diabetes.
Inthesecaseswewillbelookingfordiscor-
dance in the methylation of key genes.
The impact of epigenetics on cancer
and other diseases offers a golden oppor-
tunity to develop new treatments. While
it is virtually impossible to change an
inaccurate DNA sequence, it is poten-
tially possible to change the epigenetic
packaging of the DNA, allowing a proper
interpretation of the genetic code.
In fact, clinical trials of epigenetic
drugs are already underway. These drugs
have been approved for use in critically ill
patientsandarehavingpositiveoutcomes,
although we are still at that early stage
where they are not specific for the cancer.
But they can change gene expression, and
hopefully that will be enough for the
cancer cell to resume normal cellular
death processes.
The research described here was performed by Dr Marcel Coolen
at the Garvan Institute of Medical Research’s Epigenetics group
headed by Professor Susan Clark. Dr Coolen is currently group
leader at the Department of Human Genetics, Radboud University
Nijmegen Medical Centre, The Netherlands.
28 | | APRIL 2012
Even though identical twins have the same DNA sequence, they are unique individuals
with different personalities, traits and disease susceptibilities. Epigenetics is a
regulatory layer that allows for variation in how the same DNA sequence is interpreted.
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