When it was recognized that changes (mutations)
in genes occur spontaneously (T. H. Morgan,
1910) and can be induced by X-rays (H. J.
Muller, 1927), the mutation theory of heredity
became a cornerstone of early genetics. Genes
were defined asmutable units, but the question
what genes and mutations are remained. Today
we know that mutations are changes in the
structure of DNA and their functional consequences.
The study of mutations is important
for several reasons. Mutations cause diseases,
including all forms of cancer. They can be induced
by chemicals and by irradiation. Thus,
they represent a link between heredity and environment.
And without mutations, well-organized
forms of life would not have evolved.
The following two plates summarize the chemical
nature of mutations.
A. Error in replication
The synthesis of a new strand of DNA occurs by
semiconservative replication based on complementary
base pairing (see DNA replication).
Errors in replication occur at a rate of about 1 in
105. This rate is reduced to about 1 in 107 to 109
by proofreading mechanisms. When an error in
replication occurs before the next cell division
(here referred to as the first division after the
mutation), e.g., a cytosine (C) might be incorporated
instead of an adenine (A) at the fifth
base pair as shown here, the resulting mismatch
will be recognized and eliminated by
mismatch repair (see DNA repair) in most cases.
However, if the error is undetected and allowed
to stand, the next (second) divisionwill result in
a mutant molecule containing a CG instead of
an AT pair at this position. This mutationwill be
perpetuated in all daughter cells. Depending on
its location within or outside of the coding region
of a gene, functional consequences due to a
change in a codon could result.
B. Mutagenic alteration of a nucleotide
A mutation may result when a structural
change of a nucleotide affects its base-pairing
capability. The altered nucleotide is usually
present in one strand of the parent molecule. If
this leads to incorporation of awrong base, such
as a C instead of a T in the fifth base pair as
shown here, the next (second) round of replication
will result in two mutant molecules.
C. Replication slippage
A different class of mutations does not involve
an alteration of individual nucleotides, but results
from incorrect alignment between allelic
or nonallelic DNA sequences during replication.
When the template strand contains short tandem
repeats, e.g., CA repeats as in microsatellites
(see DNA polymorphism and Part II,
Genomics), the newly replicated strand and the
template strand may shift their positions relative
to each other. With replication or polymerase
slippage, leading to incorrect pairing of
repeats, some repeats are copied twice or not at
all, depending on the direction of the shift. One
can distinguish forward slippage (shown here)
and backward slippage with respect to the
newly replicated strand. If the newly synthesized
DNA strand slips forward, a region of nonpairing
remains in the parental strand. Forward
slippage results in an insertion. Backward slippage
of the new strand results in deletion.
Microsatellite instability is a characteristic feature
of hereditary nonpolyposis cancer of the
colon (HNPCC). HNPCC genes are localized on
human chromosomes at 2p15–22 and 3p21.3.
About 15% of all colorectal, gastric, and endometrial
carcinomas show microsatellite instability.
Replication slippage must be distinguished
from unequal crossing-over during
meiosis. This is the result of recombination between
adjacent, but not allelic, sequences on
nonsister chromatids of homologous chromosomes
(Figures redrawn from Brown, 1999).
Brown, T.A.: Genomes. Bios Scientific Publ., Oxford,
Dover, G.A.: Slippery DNA runs on and on and
on ... Nature Genet. 10:254–256, 1995.
Lewin, B.: Genes VII. Oxford University Press,
Rubinstein, D.C., et al.: Microsatellite evolution
and evidence for directionality and variation
in rate between species. Nature Genet.
Strachan, T.A., Read, A.P.: Human Molecular
Genetics. 2nd ed. Bios Scientific Publ., Oxford,
Vogel, F., Rathenberg, R.: Spontaneous mutation
in man. Adv. Hum. Genet. 5:223–318, 1975.