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The Molecular Basis of Mutation
A gene mutation is a permanent change in the DNA sequence. Gene mutations occur in two ways: they can
be inherited from a parent or acquired during a person’s lifetime. Mutations that are passed from parent to
child are called hereditary mutations or germline mutations (because they are present in the egg and sperm
cells, which are also called germ cells).
Acquired (or somatic) mutations occur in the DNA of individual cells at some time during a person’s life.
These changes can be caused by environmental factors such as ultraviolet radiation from the sun, or can
occur if a mistake is made as DNA copies itself during cell division. Acquired mutations in somatic cells
(cells other than sperm and egg cells) cannot be passed on to the next generation.
Some genetic changes are very rare; others are common in the population. Genetic changes that occur in
more than 1 percent of the population are called polymorphisms. They are common enough to be considered
a normal variation in the DNA. Polymorphisms are responsible for many of the normal differences between
people such as eye color, hair color, and blood type. Although many polymorphisms have no negative effects
on a person’s health, some of these variations may influence the risk of developing certain disorders.
To function correctly, each cell depends on thousands of proteins to do their jobs in the right places at the
right times. Sometimes, gene mutations prevent one or more of these proteins from working properly. By
changing a gene’s instructions for making a protein, a mutation can cause the protein to malfunction or to be
missing entirely. When a mutation alters a protein that plays a critical role in the body, it can disrupt normal
development or cause a medical condition. A condition caused by mutations in one or more genes is called a
genetic disorder.
It is important to note that genes themselves do not cause disease—genetic disorders are caused by mutations
that make a gene function improperly.
In gene mutation, one allele of a gene changes into a different allele. Because such a change takes place
within a single gene and maps to one chromosomal locus (“point”), a gene mutation is sometimes called a
point mutation. Nowadays, point mutations typically refer to alterations of single base pairs of DNA or of a
small number of adjacent base pairs.
It is always true that mutations reduce or eliminate gene function (loss-of-function mutations) are the most
abundant class. The reason is simple: it is much easier to break a machine than to alter the way that it works
by randomly changing or removing one of its components. For the same reason, mutations that increase or
alter the type of activity of the gene or where it is expressed (gain-of-function mutations) are much rarer.
At the DNA level, there are three main types of point mutational changes: base substitutions, base additions
or deletions and Frameshift mutation
1. Base substitutions are those mutations in which one base pair is replaced by another. Base substitutions
again can be divided into two subtypes: transitions and transversions.
A transition is the replacement of a base by the other base of the same chemical category (purine replaced
by purine: either A to G or G to A; pyrimidine replaced by pyrimidine: either C to T or T to C).
A transversion is the opposite—the replacement of a base of one chemical category by a base of the other
(pyrimidine replaced by purine: C to A, C to G, T to A, T to G; purine replaced by pyrimidine: A to C, A to
T, G to C, G to T). In describing the same changes at the double-stranded level of DNA, we must state both
members of a base pair: an example of a transition would be G·C → A·T; that of a transversion would be
G·C → T·A.
2. Addition or deletion mutations
The simplest of these mutations are single-base-pair additions or single-base-pair deletions. There are
examples in which mutations arise through simultaneous addition or deletion of multiple base pairs at once.
3. Frameshift mutation
This type of mutation occurs when the addition or loss of DNA bases changes a gene’s reading frame. A
reading frame consists of groups of 3 bases that each code for one amino acid. A frameshift mutation shifts
the grouping of these bases and changes the code for amino acids. The resulting protein is usually
nonfunctional. Insertions, deletions, and duplications can all be frameshift mutations.
Point mutations can also be categorized functionally:
1. Silent substitutions: the mutation changes one codon for an amino acid into another codon for that same
amino acid (code for the same or a different amino acid but without any functional change in the protein).
2. Missense mutations: the codon for one amino acid is replaced by a codon for another amino acid (code for a
different amino acid).
3. Nonsense mutations: the codon for one amino acid is replaced by a translation termination (stop) codon.
For example, sickle-cell disease is caused by a single point mutation (a missense mutation) in the betahemoglobin gene that converts a GAG codon into GTG, which encodes the amino acid valine rather than
glutamic acid.
Silent substitutions never alter the amino acid sequence of the polypeptide chain. The severity of the effect of
missense and nonsense mutations on the polypeptide will differ on a case-by-case basis.
For example, if a missense mutation causes the substitution of a chemically similar amino acid, referred to as
a synonymous substitution, then it is likely that the alteration will have a less-severe effect on the protein’s
structure and function. Alternatively, chemically different amino acid substitutions, called nonsynonymous
substitutions, are more likely to produce severe changes in protein structure and function. Nonsense
mutations will lead to the premature termination of translation.
New mutations are categorized as induced or spontaneous.
1. Induced mutations are defined as those that arise after purposeful treatment with mutagens, environmental
agents that are known to increase the rate of mutations.
2. Spontaneous mutations are those that arise in the absence of known mutagen treatment.
The frequency at which spontaneous mutations occur is low, generally in the range of one cell in 10 5 to 108.
Therefore, if a large number of mutants is required for genetic analysis, mutations must be induced. The
induction of mutations is accomplished by treating cells with mutagens. The mutagens most commonly used
are high-energy radiation or specific chemicals.
Induced Mutation
Mutagens act through at least three different mechanisms. They can replace a base in the DNA, alter a base
so that it specifically mispairs with another base, or damage a base so that it can no longer pair with any base
under normal conditions.
1. Base replacement
Some chemical compounds are sufficiently similar to the normal nitrogen bases of DNA that they are
occasionally incorporated into DNA in place of normal bases; such compounds are called base analogs.
Many of these analogs have pairing properties unlike those of the normal bases; thus they can produce
mutations by causing incorrect nucleotides to be inserted during replication.
2. Base alteration
Some mutagens are not incorporated into the DNA but instead alter a base, causing specific mispairing.
Certain alkylating agents, such as ethyl methanesulfonate (EMS) and the widely used nitrosoguanidine (NG).
3. Base damage
A large number of mutagens damage one or more bases, so no specific base pairing is possible. The result is
a replication block, because DNA synthesis will not proceed past a base that cannot specify its
complementary partner by hydrogen bonding.
Spontaneous mutations
It is known now that spontaneous mutations arise from a variety of sources, including errors in DNA
replication, spontaneous lesions, and transposable genetic elements.
 Errors in DNA replication
Mispairing in the course of replication is a source of spontaneous base substitution. Most mispairing
mutations are transitions. This is likely to be because an A·C or G·T mispair does not distort the DNA
double helix as much as A·G or C·T base pairs do.
 Spontaneous lesions
Naturally occurring damage to the DNA, called spontaneous lesions, also can generate mutations. Two of the
most frequent spontaneous lesions are depurination and deamination, the former being more common.
The deamination of cytosine yields uracil. Unrepaired uracil residues will pair with adenine in the
course of replication, resulting in the conversion of a G·C pair into an A·T pair (a G·C → A·T
transition).
Spontaneous mutations and human diseases
A number of these disorders are due to deletions or duplications of repeated sequences. For example,
mitochondrial encephalomyopathies are a group of disorders affecting the central nervous system or the
muscles. They are characterized by dysfunction of mitochondrial oxidative phosphorylation and by changes
in mitochondrial DNA structure. These disorders have been shown to result from deletions of DNA
sequences that lie between repeated sequences.
Fragile X syndrome is the most common form of inherited mental retardation, occurring in close to 1 of
1500 males and 1 of 2500 females. Fragile X syndrome results from changes in the number of a (CGG) n
repeat in the coding sequence of the FMR-1 gene.
Humans normally show a considerable variation in the number of CGG repeats in the FMR-1 gene, ranging
from 6 to 50.
Sometimes, unaffected parents and grandparents give rise from 50 to 200 several offspring with fragile X
syndrome the ancestors have been said to carry premutations. The repeats in these premutation alleles are
not sufficient to cause the disease phenotype, but they are much more unstable than normal alleles, and so
they lead to even greater expansion in their offspring.
The people with the symptoms of the disease have enormous repeat numbers, ranging from 200 to 1300
(mutated).
Myotonic dystrophy, the most common form of adult muscular dystrophy, is yet another example of
sequence expansion causing a human disease. Normal people possess, on average, five copies of the CTG
repeat; mildly affected people have approximately 50 copies; and severely affected people have more than
1000 repeats of the CTG triplet.