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Mechanisms of genetic change
You can think of DNA changes, and hence for RNA and protein too, as arising from one of
four general ways: from recombination events where DNA strands exchange; as a
consequence of damage to DNA; from errors in the replication of DNA at cell division;
and by the action of mobile genetic elements, like viruses and transposons. We will
introduce these points separately.
Recombination is the shuffling of large sections of DNA (i.e. many bases at a time) as a
result of crossover between two different sections of DNA double helix. Two regions of
DNA come together and, in a controlled way, the two double helices are broken and joined
back together, in an exchanged manner so that the new DNA molecules are made of two
regions from different origins. There are two notable situations where this occurs, for
deliberate biological reasons. The first is during meiosis, the cell division that gives rise to
gametes (egg and sperm cells). This kind of recombination usually occurs between sister
chromosomes (i.e. the two copies of a given kind) where they share significant similarity,
just before the chromosomes separate to form eggs or sperm, which carry only one copy
of each kind of chromosome. The end result is that offspring have chromosomes that are
not identical to their parents’, but rather versions that are a spliced combination of the
originals. This is an important means of generating genetic variation within a species and,
because recombination occasionally occurs at the wrong spot with an offset between the
chromosomes, is a means by which entire genes get duplicated. The second notable
occurrence of recombination involves genes of antibodies, i.e. for the immune system. In
this instance the recombination is used to form a diverse array of immune cells each
producing different antibodies. This is part of the way that the immune response adapts to
the potentially limitless variety of invading organisms. The antibody genes contain many
alternative coding regions (i.e. exons) in different groups and the splicing brought about
by recombination effectively selects a different coding region from within each group, to
create different final exon combinations in each cell, so that it makes antibodies that bind a
different target.
DNA is a relatively inert biological molecule, which is important for its role as the store
and transmitter of inherited information. Nevertheless, there are still means by which the
chemical structure of DNA can be disrupted. This can be as a result of various things
including: high energy radiation (X-rays, gamma rays); ultraviolet light; highly reactive
free-radical compounds, including those generated as a natural consequence of breathing
oxygen; high temperatures and chemical toxins. DNA damage is a constant part of life and
as such many repair mechanisms have evolved to fix things. Usually the damage can be
fixed directly by repair enzymes, but if it gets too bad a cell will often commit suicide.
Sometimes, however, the repair may not reproduce the original chemical structure or the
damage may escape being fixed, so that when the DNA is replicated the base-pair
matching at that position goes awry and the sequence changes. Because DNA damage is a
somewhat random process and localised to small areas the sequence changes it creates
mostly involve only a single base pair; a single-nucleotide polymorphism. However, larger
changes are possible, for example, when there are double-stranded DNA breaks that are
joined back together in the wrong way, as can be seen in some cancer cell lines.
As hinted at in the discussion of DNA damage, the replication of DNA strands is a time
when variations become consolidated. However, it is also a time when variations can
initially occur because DNA replication itself is slightly error-prone. This is important
because it allows the changes to feed evolutionary processes, but they are mistakes
nonetheless; DNA is produced where the occasional base pair doesn’t match. The reason
for this kind of mistake is because of the chemical structure of the DNA bases themselves.
The bases are in a state of structural flux; there is an exchange between the normal form
and another chemical structure. In chemical structure terms there is tautomerism, an
equilibrium between different double-bonded forms (the double bond can switch from
C=C to C=N by the movement of a hydrogen). While the standard chemical form is far
more common, the occasional brief occurrence of the alternative form version results in a
structure where different base pairs can form, compared to the normal Crick-Watson
pairing (G:C, A:T). If the alternative form appears during replication the wrong base may
be incorporated into the new strand, thus giving a base-pair mismatch. In many organisms,
including humans, once the newly added base reverts to its normal form the pair mismatch
can be detected and immediately removed by the proof-reading apparatus of the DNA
replication machinery.
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Occasionally, however, the mismatch still escapes, and although
this is a very rare event (maybe of the order of 1 in 10
10
for mammal genomes), given a
large number of total bases (6×10
9
in a human cell), a large number of cell division events
and all the individuals of a population it will undoubtedly happen from time to time. An
escaped base-pair mismatch may still be repaired by enzymes, but as either of the two
bases could be replaced, to give a matching pair, the fix may either regenerate the original
sequence or consolidate a change, to give a single-nucleotide polymorphism.
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