A new class of mutations, involving duplications instead of deletion or 'misspelling'and displaying queer patterns of transmission, might be behind a host of genetic and neurological disorders that afflict humankind
THE entire DNA (deoxyribonucleic acid)
content in a cell can be compared to a
book containing instructions for making the plant or animal of which that cell
is a part. The four bases that make up
the DNA code - A, T, G and c - are like
the letters in the book. Within a given
individual, the book is present in many
identical 'copies'; two occur in each cell.
The copies in a cell are actually versions that are not exactly the same. The
process of copying occurs at different
levels. Firstly, there is the analogue of a Xerox, or better still, an old-fashioned
typeset copy. This act of copying takes
place each time a cell divides into two, as
happens anywhere from 30 to 50 times
during the p rogression from a newly
fertilised egg to an adult.
More importantly, there is another
form of copying which accompanies the
process of sexual reproduction. This
involves what might be called copying
with shuffling. Exactly one copy of what
the child gets comes from the father,
and the other copy from. the mother.
Each of these copies consists of a single
book of instructions created by shuffling the pages in the two books present
in either parent.
As with any copying process,
mistakes, known as mutations, can
occur. The probability that a mutation
occurs is on the whole a random event,
meaning that it is the same from one
individual to another and from one
generation to another. A mutation is a
single-step affair. If a mutation has any
effect at all, it is because an instruction is
missing, or is misleading. In terms of
our analogy of a book, an error in copying could cause Go to point five to
become Go to joint five, or Go to xoint
five, both the distortions here would be
classed as mutations.
Mutations have been implicated in
human diseases, which are therefore
known as genetic diseases. Over the last
five years, an entirely new class of mutations, also with a role in human diseases, has been discovered. A recent article by
G R Sutherland and R I Richards of the
Women's and Children's Hospital in
Adelaide, Australia, brings us up-to-
date on the progress in the field
(Proceedings of the us National Academy
of Sciences, Vol 92, 1995).
These new kinds of mutations do
not involve deletions or misspellings
within a putative message, but consist of
duplications instead. Also, they exhibit
unusual patterns of transmission. The
most striking feature is that within a
family at risk, the chances of a member
being affected seem to increase from
one generation to the next. In other
words, there is an element of anticipation exhibited by the phenomenon.
The genetics of transmission is curious too: 'men appear to pass on an,
increased risk through their daughters,
but not through their sons. For these
reasons, the concerned mutations have
been called 'dynamic' mutations. The
best studied case of a dynamic mutation
leading to genetic disease is that of the
fragile-x syndrome. This is the most
common cause of familial mental retardation in Caucasians and is associated
with an amplification of the triplet
sequence ccc (c and G are two of the
four bases present in a DNA helix) lying
in the neighbourhood of a gene known
as FMR1 on the human x-chromosome.
Normal individuals contain anywhere
from six to about 50 copies Of CCG
repeated in tandem - meaning one
after the other.
Typically, there are one or two
imperfections within the repeat. After
the CCG copy number exceeds 50, it
tends to increase steadily from generation to generation until a critical figure
of about 230 is reached. Until this point,
there is no visible effect of the increase
in copy number. Once the number
reaches 230, it can increase to above 230
in a single generation. At that stage, it is
said to become a full mutation, and the
consequence of this is that the instructions encoded in the FMR1 gene are no
longer expressed. The affected individual - most likely to be a
male, since females can have a second,
normal x-chromosome - tends to be
mentally retarded. Also, the chromosome itself is likely to be 'fragile': it can
break at the region of the amplified
repeats.
However, it is unknown how the
absence of the message in the FMR1 gene
leads to the syndrome. An understand-
ing of the genetics of the fragile-x syndrome has begun to emerge. The pat-
tern of transition from pre-mutation to
full mutation (more than 230 repeats) is
such that mothers with a pre-matation
carry a risk of having affected sons, but
fathers with a pfe-mutation do not tend
to have affected daughters (the fathers
cannot have affected sons; the male
x-chromosome comes from th e mother,
not ftom the father). The reason for this
appears to be that the process of meiosis
- the shuffling and consequent
reduction of genetic material that is a
prerequisite for reproduction - is very
different in the two sexes.
Besides the fragile-x syndrome, a
host of human neurological disorders
have turned out to be due to dynamic
mutations of a different trinucleotide
repeat, the AGC. in some cases the
repeats are in the neighbourhood of the
affected gene (as in fragile-x), but in
other cases they are found within the
coding region of the gene. AS AGC codes
for the amino acid glutamine, when
there are AGc repeats in the DNA, the
decoded message includes a long stretch
of repeats of glutamine.
Theories have been proposed to
explain why poly-glutamine stretches
might cause the cellular machinery to
malfunction. One genetic disease,
hereditary nonpolyposis colon cancer
(HNPCC), is caused by a dinucleotide
repeat (iG). In all these cases ', changes in
the repeat copy number are believed to
be on account of 'slippages' during the
process of gene shuffling. Genes that are
similar insequence to HNpcc have been
found in yeast and bacteria, and they
encode enzymes whose responsibility is
to repair copying errors that could lead
to mismatches between the parental and
copied strands.
This is extremely interesting. The
effect of damaging genes which are
responsible for correcting copying
errors will be a general increase in the
mutation rate. But how an increase in
mutation rates might bring about the
disease is yet to be explained.
Nevertheless, it is clear that we are in the midst of a phase of anticipation our-
selves - an anticipation that a deeper
understanding of this unusualclass of
genetic diseases might lead to methods
for clinical intervention.
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