DNA can undergo spontaneous changes in its chemistry that result in both
deletions and substitutions. DNA naturally loses purine bases at times in a
process called apurination. Most often, a purine’s lost when the bond
between adenine and the sugar, deoxyribose, is broken. (See Chapter 6 for a
reminder of what a nucleotide looks like.) When a purine is lost, replication
treats the spot occupied by the orphaned sugar as if it never contained a
base at all, resulting in a deletion.
Tuesday, April 14, 2009
Deamination
Deamination is another chemical change that occurs naturally in DNA. It’s
what happens when an amino group (composed of a nitrogen atom and two
hydrogens, NH2) is lost from a base. Figure 13-4 shows the before and after
stages of deamination. When cytosine loses its amino group, it’s converted to
uracil. Uracil normally isn’t found in DNA at all because it’s a component of
RNA. If uracil appears in a DNA strand, replication replaces the uracil with a
thymine, creating a substitution error. Until it’s snipped out and replaced
during repair (see “Evaluating Options for DNA Repair” later in this chapter),
uracil acts as a template during replication and pairs with adenine.
Ultimately, what was a C-G pair transitions into an A-T pair instead.
what happens when an amino group (composed of a nitrogen atom and two
hydrogens, NH2) is lost from a base. Figure 13-4 shows the before and after
stages of deamination. When cytosine loses its amino group, it’s converted to
uracil. Uracil normally isn’t found in DNA at all because it’s a component of
RNA. If uracil appears in a DNA strand, replication replaces the uracil with a
thymine, creating a substitution error. Until it’s snipped out and replaced
during repair (see “Evaluating Options for DNA Repair” later in this chapter),
uracil acts as a template during replication and pairs with adenine.
Ultimately, what was a C-G pair transitions into an A-T pair instead.
Induced mutations
Induced mutations result from exposure to some outside agent such as chemicals
or radiation. It probably comes as no surprise to you to find out that
many chemicals can cause DNA to mutate. Carcinogens (chemicals that cause
cancers) aren’t uncommon; the chemicals in cigarette smoke are probably
the biggest offenders. In addition to chemicals that cause mutations, sources
of radiation, from X-rays to sunlight, are also mutagenic. A mutagen is any
factor that causes an increase in mutation rate. Mutagens may or may not
have phenotypic effects — it depends on what part of the DNA is affected.
The following sections cover two major categories of mutagens: chemicals
and radiation. Each causes different damage to DNA.
or radiation. It probably comes as no surprise to you to find out that
many chemicals can cause DNA to mutate. Carcinogens (chemicals that cause
cancers) aren’t uncommon; the chemicals in cigarette smoke are probably
the biggest offenders. In addition to chemicals that cause mutations, sources
of radiation, from X-rays to sunlight, are also mutagenic. A mutagen is any
factor that causes an increase in mutation rate. Mutagens may or may not
have phenotypic effects — it depends on what part of the DNA is affected.
The following sections cover two major categories of mutagens: chemicals
and radiation. Each causes different damage to DNA.
Chemical mutagens
The ability of chemicals to cause permanent changes in the DNA of organisms
was discovered by Charlotte Auerbach in the 1940s (see the sidebar “The
chemistry of mutation” for the full story). There are many types of mutagenic
chemicals; the following sections address four of the most common.
was discovered by Charlotte Auerbach in the 1940s (see the sidebar “The
chemistry of mutation” for the full story). There are many types of mutagenic
chemicals; the following sections address four of the most common.
Base analogs
Base analogs are chemicals that are structurally very similar to the bases
normally found in DNA. Base analogs can get incorporated into DNA during
replication because of their structural similarity to normal bases. One base
analog, 5-Bromouracil, is almost identical to the base thymine. Most often,
5-bromouracil (also known as 5BU), which is pictured in Figure 13-5, gets
incorporated as a substitute for thymine and as such is paired with adenine.
The problem arises when DNA replicates again with 5-bromouracil as part of
the template strand; 5BU’s mistaken for a cytosine and gets mispaired with
guanine. The series of events looks like this: 5-bromouracil is incorporated
where thymine used to be, so T-A becomes 5BU-A. After one round of replication,
the pair is 5BU-G because 5BU is prone to chemical changes that make
it a mimic of cytosine, the base normally paired with guanine. After a second
of replication, the pair ends up as C-G because 5BU isn’t found in normal DNA.
Thus, an A-T ends up as a C-G pair.
normally found in DNA. Base analogs can get incorporated into DNA during
replication because of their structural similarity to normal bases. One base
analog, 5-Bromouracil, is almost identical to the base thymine. Most often,
5-bromouracil (also known as 5BU), which is pictured in Figure 13-5, gets
incorporated as a substitute for thymine and as such is paired with adenine.
The problem arises when DNA replicates again with 5-bromouracil as part of
the template strand; 5BU’s mistaken for a cytosine and gets mispaired with
guanine. The series of events looks like this: 5-bromouracil is incorporated
where thymine used to be, so T-A becomes 5BU-A. After one round of replication,
the pair is 5BU-G because 5BU is prone to chemical changes that make
it a mimic of cytosine, the base normally paired with guanine. After a second
of replication, the pair ends up as C-G because 5BU isn’t found in normal DNA.
Thus, an A-T ends up as a C-G pair.
Alkylating agents
Like base analogs, alkylating agents induce mispairings between bases.
Alkylating agents, such as the chemical weapon mustard gas, add chemical
groups to the existing bases that make up DNA. As a consequence, the
altered bases pair with the wrong complement, thus introducing the mutation.
Surprisingly, alkylating agents are often used to fight cancer as part
of chemotherapy; therapeutic versions of alkylating agents may inhibit
cancer growth by interfering with the replication of DNA in rapidly dividing
cancer cells.
Alkylating agents, such as the chemical weapon mustard gas, add chemical
groups to the existing bases that make up DNA. As a consequence, the
altered bases pair with the wrong complement, thus introducing the mutation.
Surprisingly, alkylating agents are often used to fight cancer as part
of chemotherapy; therapeutic versions of alkylating agents may inhibit
cancer growth by interfering with the replication of DNA in rapidly dividing
cancer cells.
Unusually reactive forms of oxygen
Some forms of oxygen, called free radicals, are unusually reactive, meaning
they react readily with other chemicals. These oxygens can damage DNA
directly (by causing strand breaks) or can convert bases into new unwanted
chemicals that, like most other chemical mutagens, then cause mispairing
during replication. Free radicals of oxygen occur normally in your body as a
product of metabolism, but most of the time, they don’t cause any problems.
Certain activities, such as cigarette smoking and high exposure to radiation,
pollution, and weed killers, increase the number of free radicals in your
system to dangerous levels.
they react readily with other chemicals. These oxygens can damage DNA
directly (by causing strand breaks) or can convert bases into new unwanted
chemicals that, like most other chemical mutagens, then cause mispairing
during replication. Free radicals of oxygen occur normally in your body as a
product of metabolism, but most of the time, they don’t cause any problems.
Certain activities, such as cigarette smoking and high exposure to radiation,
pollution, and weed killers, increase the number of free radicals in your
system to dangerous levels.
Intercalating agents
Many different kinds of chemicals wedge themselves between the stacks of
bases that form the double helix itself, disrupting the shape of the double
helix. Chemicals with flat ring structures, such as dyes, are prone to fitting
themselves between bases in a process called intercalation.
bases that form the double helix itself, disrupting the shape of the double
helix. Chemicals with flat ring structures, such as dyes, are prone to fitting
themselves between bases in a process called intercalation.
Radiation
Radiation damages DNA in a couple of different ways. First, radiation can
break the strands of the double helix by knocking out bonds between sugars
and phosphates (see Chapter 6 for a review of how the strands are put
together). If only one strand is broken, the damage is easily repaired. But
when two strands are broken, large parts of the chromosome can be lost;
these kinds of losses can affect cancer cells (see Chapter 14) and cause birth
defects
break the strands of the double helix by knocking out bonds between sugars
and phosphates (see Chapter 6 for a review of how the strands are put
together). If only one strand is broken, the damage is easily repaired. But
when two strands are broken, large parts of the chromosome can be lost;
these kinds of losses can affect cancer cells (see Chapter 14) and cause birth
defects
Charlotte Auerbach.
If ever anyone had an excuse to give up, it’s
Charlotte Auerbach. Born in Germany in 1899,
Auerbach was part of a lively and highly educated
Jewish family. In spite of her deep interest
in biology, she became a teacher, convinced
that higher education would be closed to her
because of her religious heritage. As anti-
Jewish sentiment in Germany grew, Auerbach
lost her teaching job in 1933 when every Jewish
secondary-school teacher in the country was
fired. As a result, she emigrated to Britain
Charlotte Auerbach. Born in Germany in 1899,
Auerbach was part of a lively and highly educated
Jewish family. In spite of her deep interest
in biology, she became a teacher, convinced
that higher education would be closed to her
because of her religious heritage. As anti-
Jewish sentiment in Germany grew, Auerbach
lost her teaching job in 1933 when every Jewish
secondary-school teacher in the country was
fired. As a result, she emigrated to Britain
Charlotte’s experiments
What Charlotte’s experiments did do was show
that mustard gas was an alkylating agent, a
mutagen that causes substitution mutations.
Shortly after the end of World War II and after
persevering through burns caused by hot mustard
gas, Auerbach published her findings. At
last, she received the recognition and respect
her work warranted. Charlotte Auerbach went
on to have a long and highly successful career
in genetics. She stopped working only after old
age robbed her of her sight. She died in
Edinburgh, Scotland, in 1994 at the age of 95.
that mustard gas was an alkylating agent, a
mutagen that causes substitution mutations.
Shortly after the end of World War II and after
persevering through burns caused by hot mustard
gas, Auerbach published her findings. At
last, she received the recognition and respect
her work warranted. Charlotte Auerbach went
on to have a long and highly successful career
in genetics. She stopped working only after old
age robbed her of her sight. She died in
Edinburgh, Scotland, in 1994 at the age of 95.
Facing the Consequences of Mutation
When a gene mutates and that mutation is passed along to the next generation,
the new, mutated version of the gene is considered a new allele. Alleles are
simply alternative forms of genes. For most genes, many alleles exist. The
effects of mutations that create new alleles are compared with the mutation’s
physical (phenotypic) effects. If the mutation has no effect, it’s considered silent.
Most silent mutations result from the redundancy of the genetic code. The code
is redundant in the sense that multiple combinations of bases have identical
meanings
the new, mutated version of the gene is considered a new allele. Alleles are
simply alternative forms of genes. For most genes, many alleles exist. The
effects of mutations that create new alleles are compared with the mutation’s
physical (phenotypic) effects. If the mutation has no effect, it’s considered silent.
Most silent mutations result from the redundancy of the genetic code. The code
is redundant in the sense that multiple combinations of bases have identical
meanings
mutations
Sometimes, mutations cause a completely different amino acid to be put in
during translation. Mutations that actually alter the code are called missense
mutations. A nonsense mutation occurs when a message to stop translation
(called a stop codon) is introduced into the middle of the sequence (see
Chapter 9 for more on translation). The introduction of the stop codon
usually means the gene stops functioning altogether.
Mutations are often divided into two types:
Neutral: When the amino acid produced from the mutated gene still creates
a fully functional, normal protein
during translation. Mutations that actually alter the code are called missense
mutations. A nonsense mutation occurs when a message to stop translation
(called a stop codon) is introduced into the middle of the sequence (see
Chapter 9 for more on translation). The introduction of the stop codon
usually means the gene stops functioning altogether.
Mutations are often divided into two types:
Neutral: When the amino acid produced from the mutated gene still creates
a fully functional, normal protein
Functional change:
When a new protein is created, representing a change
in function of the gene. Changes in function caused by mutations can be
either gains or losses. A gain-of-function mutation creates an entirely new
trait or phenotype. Sometimes, the new trait is harmless, like a new eye
color. In other cases, the gain is decidedly harmful and usually autosomal
dominant (flip to Chapter 12 for more on autosomal dominant traits)
because the gene is producing a new protein that actually does something
(the gain-of-function part). Even though there’s only one copy of the new
allele, its effect is noticeable and thus considered dominant over the original,
unmutated allele.
in function of the gene. Changes in function caused by mutations can be
either gains or losses. A gain-of-function mutation creates an entirely new
trait or phenotype. Sometimes, the new trait is harmless, like a new eye
color. In other cases, the gain is decidedly harmful and usually autosomal
dominant (flip to Chapter 12 for more on autosomal dominant traits)
because the gene is producing a new protein that actually does something
(the gain-of-function part). Even though there’s only one copy of the new
allele, its effect is noticeable and thus considered dominant over the original,
unmutated allele.
mutation
If a mutation causes the gene to stop functioning altogether or vastly
alters normal function, it’s considered a loss-of-function mutation. All nonsense
mutations are loss-of-function mutations, but not all loss-of-function
mutations are the result of nonsense mutations. The usefulness of the protein
made from a particular gene can be lost even when no stop codon
has been added prematurely. Insertions and deletions are often loss-offunction
mutations because they cause frameshifts (Chapter 9 explains
how the genetic code is read in frames). Frameshifts cause an entirely
new set of amino acids to be put together from the new set of instructions.
Most of the time, these new proteins are useless and nonfunctional.
Loss-of-function mutations are usually recessive because the normal,
unmutated allele is still producing product, usually enough to compensate
for the mutated allele. Loss-of-function mutations are only detected when
a person is homozygous for the mutation and is making no functional gene
product at all.
alters normal function, it’s considered a loss-of-function mutation. All nonsense
mutations are loss-of-function mutations, but not all loss-of-function
mutations are the result of nonsense mutations. The usefulness of the protein
made from a particular gene can be lost even when no stop codon
has been added prematurely. Insertions and deletions are often loss-offunction
mutations because they cause frameshifts (Chapter 9 explains
how the genetic code is read in frames). Frameshifts cause an entirely
new set of amino acids to be put together from the new set of instructions.
Most of the time, these new proteins are useless and nonfunctional.
Loss-of-function mutations are usually recessive because the normal,
unmutated allele is still producing product, usually enough to compensate
for the mutated allele. Loss-of-function mutations are only detected when
a person is homozygous for the mutation and is making no functional gene
product at all.
Evaluating Options for DNA Repair
Mutations in your DNA can be repaired in four major ways:
Mismatch repair: Incorrect bases are found, removed, and replaced with
the correct, complementary base. Most of the time, DNA polymerase,
the enzyme that helps make new DNA, immediately detects mismatched
bases put in by mistake during replication. DNA polymerase can back up
and correct the error without missing a beat. But if a mismatched base
Mismatch repair: Incorrect bases are found, removed, and replaced with
the correct, complementary base. Most of the time, DNA polymerase,
the enzyme that helps make new DNA, immediately detects mismatched
bases put in by mistake during replication. DNA polymerase can back up
and correct the error without missing a beat. But if a mismatched base
Direct repair:
Bases that are modified in some way (like when oxidation
converts a base to some new form) are converted back to their original
states. Direct repair enzymes look for bases that have been converted
to some new chemical, usually by the addition of some unwanted group of
atoms. Instead of using a cut-and-paste mechanism, the enzymes clip off
the atoms that don’t belong, converting the base back to its original form.
converts a base to some new form) are converted back to their original
states. Direct repair enzymes look for bases that have been converted
to some new chemical, usually by the addition of some unwanted group of
atoms. Instead of using a cut-and-paste mechanism, the enzymes clip off
the atoms that don’t belong, converting the base back to its original form.
Base-excision repairs:
Base-excisions and nucleotide-excisions (check
out the next bullet) work in much the same way. Base-excisions occur
when an unwanted base (such as uracil; see the section “Spontaneous
chemical changes” earlier in this chapter) is found. Specialized enzymes
recognize the damage, and the base is snipped out and replaced with
the correct one.
out the next bullet) work in much the same way. Base-excisions occur
when an unwanted base (such as uracil; see the section “Spontaneous
chemical changes” earlier in this chapter) is found. Specialized enzymes
recognize the damage, and the base is snipped out and replaced with
the correct one.
Nucleotide-excision repair:
Nucleotide-excision means that the entire
nucleotide (and sometimes several surrounding nucleotides as well)
gets removed all at once. When intercalating agents or dimers distort
the double helix, nucleotide-excision repair mechanisms step in to snip
part of the strand, remove the
nucleotide (and sometimes several surrounding nucleotides as well)
gets removed all at once. When intercalating agents or dimers distort
the double helix, nucleotide-excision repair mechanisms step in to snip
part of the strand, remove the
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