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The importance of epigenetics in Prader-Willi
syndrome
Each cell of the human body contains genetic material in its nucleus. This genetic material, made up of two
strands of DNA linked together as a 'double helix', are arranged into what are referred to as chromosomes in humans there are 23 pairs of chromosomes, with one in each pair inherited from the father and one
from the mother. Men and women have a similar arrangement of chromosomes for 22 of these pairs, but
one pair differs (numbered as pair 23), with men having one X and one Y chromosome and women having
two X chromosomes but no Y chromosome.
DNA includes approximately 40,000 genes that code for individual proteins, which are the building blocks
of the body. Other parts of the DNA that are not coding for genes have important regulatory functions. The
sequence of DNA is identical in all cells of any given person but quite normally varies between individuals
(except for identical twins) as, in the formation of sperm and ova, there is a process whereby the
combination of genes that are passed on at fertilization varies. It is this variation that partly or largely
accounts for the difference in physical and other characteristics that make each of us unique.
Major abnormalities of specific genes can lead to specific disorders or illnesses - this is often as a result of a
fault or 'mutation' in the gene that can then no longer function normally.
DNA therefore is the fundamental genetic code that is unique to each of us.
The term 'epigenetics' refers to processes that then follow in the decoding of the DNA and which accounts
for observed differences, for example, between organs of the body or between individuals where such
differences are not as a result of differences in the DNA code of individuals - rather, these differences are
due to some other process that has modified the way that genes are 'expressed' and function.
The most obvious example of this is the fact that all organs (heart, liver, brain etc) in an individual person's
body contain the same DNA code but the genes that are 'expressed' in the liver as opposed to the brain, for
example, are very different - thus leading to the development of a specialist organ able to carry out specific
functions. This is an example of 'epigenesis' - the modifying of gene expression by some mechanism other
than by altering the underlying DNA code.
The expression of the gene or genes (as yet not fully identified) located in the region referred to as q11-13
on chromosome 15 that are implicated in PWS are subject to an unusual and relatively rare 'epigenetic'
modification. Normally the two copies or 'alleles' of any given gene (one from mother and one from father)
are equally expressed, but for a small proportion of genes this is not so. It is the case with some genes that
only the copy inherited from the father or only the copy inherited from the mother is expressed. The other
copy is silenced due to being 'imprinted'. In the case of PWS, the suspect genes located on chromosome 15
at q11-13 are like this. It is only the copy or allele that is inherited from the father that is normally
expressed. The maternal copy is quite normally 'imprinted' and not active. Under normal circumstances
having just this one active copy from the father is sufficient but when a person has a deletion at q11-13 on
the paternal copy of chromosome 15 and the only active copy of the relevant gene or genes are deleted
and are lost, PWS ensues.
Similarly when both copies of chromosome 15 are abnormally inherited from the mother, and the father's
chromosome 15 is not present (disomy or UPD), neither copy of the relevant genes are active, as both
copies are switched off, as both are inherited from the mother, rather than one from the father and one
from the mother.
The importance of epigenetics in Prader-Willi syndrome
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Although rare (accounting for 1% or 2% of people PWS), a mutation of the imprinting centre on
chromosome 15 also results in PWS, further underlining the importance of epigenetics. In these cases there
is no loss or physical change in the relevant genes; simply their epigenetic control has been disrupted,
resulting in no expression from the copy inherited from the father.
It is becoming increasingly apparent that these unusual genes, whereby the gender of the parent of origin
can effect whether they are expressed or not, are very important in human development, and there are
complex theories put forward as to why such genes have developed during evolution. In the case of PWS it
is clear that the relevant genes must be epigenetically modified in the way described above. In addition,
the observation that certain forms of mental illness are more common in those with the UPD form of PWS,
compared to those with PWS due to a deletion, suggests that there are other genes on chromosome 15
that have the opposite 'imprint' to that observed in PWS - only the copy of this presumed, but unidentified
gene, that is inherited from the mother is expressed and the copy from the father is switched off. These
other genes are not directly relevant to the core features of PWS, but they may be important in
understanding the reasons for this excess of specific mental illnesses in those with UPD.
As knowledge about imprinted genes increases, and what they do and where in the body they are most
actively expressed is established, then it is likely to become possible to understand what goes wrong when
these crucial genes are not working. This is where studies using mice whose genes have been modified to
be like that which occurs in PWS become very important, as such 'mouse models' provide the means for
investigating the brain abnormalities that might explain the over-eating behaviour etc.
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The importance of epigenetics in Prader-Willi syndrome
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