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X rays, gamma rays, and cosmic rays
have even short wavelengths and are more energetic than UV radiation.
They penetrate deep into tissues, causing ionization (loss of electrons)
of molecules which become reactive free radicals which can cause physical damage to DNA.
Exposure to ionizing radiation has been shown to be directly related to the induction of mutations.
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Ethylmethane sulfonate (EMS, a mustard gas) is an alkylating
agent
that can donate an alkyl group (C2H5) to a keto group in guanine.
The resulting 6-ethylguanine acts as an analog of adenine and pairs with thymine,
leading to transition mutations.
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Bacterial transposons (Tn elements)
are larger than IS elements and contain protein-coding genes
in addition to that for transposase.
A transposon inserted into a plasmid contains inverted repeats (IR) that can form a
heteroduplex.
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The IR segments can reanneal after the original duplex has been separated, forming
heteroduplex loops that can be seen under an electron microscope.
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5-bromouracil (5-BU) ia a derivative of uracil and behaves as a
thymine analog,
which increases the probability of a tautomeric shift
from the normal keto form to the enol form,
mis-pairing with guanine instead of adenine.
After one round of replication, an A - T to G - C transition mutation results.
video
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Base excision repair (BER) in E. coli.
AP) site.
AP site.
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Each copia element consists an inverted terminal repeat (ITR) within
a long direct terminal repeat (DTR) sequence at each end.
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Chemical mutagens such as nitrous acid (HNO2) may cause nucleotide
deamination: conversion of an amino group to a keto group.
Thus cytosine and adenine are converted to uracil (which base pairs with adenine) and
hypoxanthine (which base pairs with cytosine), respectively.
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Visible light is a form of radiation energy constituting part of the electromagnetic spectrum.
Radiation with shorter wavelength than visible light, such as ultraviolet (UV) light,
possesses more energy, and has a disruptive
impact on organic molecules.
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Insertion sequence (IS)
elements contain a gene that encodes an enzyme called transposase, which can
make staggered cuts in DNA.
The ends of IS elements contain inverted terminal repeats (ITRs),
which act as recognition sites for the binding of transposase.
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Acridine dyes such as Proflavin and Acridine orange
are about the same dimensions as nitrogenous base pairs and intercalate, or wedge,
between the purines and pyrimidines of intact DNA.
Intercalation introduces contortions in the DNA helix and causes deletions and insertions
that create frameshift mutations.
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Barbara McClintock
(Nobel 1983)
studied two mutations in maize,
Dissociation (Ds) and Activator (Ac),
now known as transposable elements (
transposons
).
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The Ames test
exposes auxotrophic strains of Salmonella (his–) to a chemical compound to assess its
mutagenicity.
Liver extract is added, since metabolic modification of these compounds in the liver may make them mutagenic.
The mutagenicity of a chemical is reflected in the frequency of reverse mutation,
which yields wild-type (his+) bacteria.
video
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Point mutations are base substitutions
in which one base pair is altered.
Insertions or deletions can lead to
frameshift
mutations where all subsequent downstream amino acids are changed.
Frameshifts involving multiples of three nucleotides can restore the initial reading frame.
video
nucleotide_excision_repair.html: 15_17-nucleotide_excision_repair.jpg
Nucleotide excision repair (NER).
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A cataract is clouding of the crystalline lens of the eye and has a genetic component in its cause.
It is inherited as an autosomal dominant mutation; about 50% of the offspring of a heterozygous individual
are expected to show the trait.
This pedigree is consistent with an autosomal dominant mode of inheritance, but does not prove it.
The presence of an unaffected daughter in generation IV argues against X-linkage,
since she received her X chromosome from her affected father.
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Hemophilia exhibits X-linked
inheritance,
where affected fathers pass the trait to all of their daughters, who are usually heterozygous carriers.
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Photoreactivation repair.
In E. coli, the photoreactivation enzyme (PRE) can cleave the bonds between thymine dimers,
energized by a photon of blue light.
The reaction reverses the effect of UV radiation on DNA.
video
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DNA danage (such as a thymine dimer)
may cause a gap on the newly synthesized strand during replication.
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The RecA protein catalyzes a recombinational exchange, gilling the gap opposite the dimer.
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The new gap is filled by DNA polymerase and DNA ligase.
This postreplication repair is also referred to as homologous recombination repair.
video
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Spontaneous mutations happen naturally and randomly and are usually linked to normal biological or chemical processes in
the organism. Induced mutations result from the influence of an extraneous factor, either natural or artificial.
The Luria-Delbrück fluctuation test demonstrated that mutations are not adaptive but occur spontaneously.
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Nucleotides can exist in tautomeric forms (structural isomers) by a position change of a
proton
(tautomeric shift).
The less common, transient tautomers can form hydrogen bonds with noncomplementary bases.
The anomalous pairing is always between a pyrimidine and a purine,
as shown in the T - G and C - A pairs.
thymine_dimer.html: 15_09-thymine_dimer.jpg
Exposure to ultraviolet (UV) radiation can result in the creation of pyrimidine
(thymine and cytosine) dimers in DNA,
particularly those involving two thymine residues.
The dimers distort the DNA conformation and result in higher error rates during DNA
replication.
video
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Transition mutation.
A rare tautomer in the template strand pairs with a noncomplementary base during DNA replication.
next
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In the next round of replication, the "mismatched" members of the base pair are separated;
the tautomer usually shifts back to its normal isomer.
Replication of the two strands by normal base pairing results in a point mutation called a
transition mutation,
where a purine substitutes for a purine, or a pyrimidine substitutes for a
pyrimidine.
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In absence of Ac, Ds does not have any effect on
expression of the aleurone-color gene W, resulting in production of anthocyanin pigments
and purple kernels.
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When Ac is present, Ds may be transposed
to a region adjacent to W. Ds can induce chromosome breakage,
leading to loss of function of the W gene.
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If Ds is transposed into the W gene, W gene is inhibited,
producing mutant effect.
Subsequently, Ds can jump out of the W gene, and wild-type expression of W is
restored.
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The Ac sequence contains oncoding regions (Nc) and an open reading frames (ORF)
which encodes a transposase enzyme and enables the sequence to "jump".
Ds elements are similar to Ac but contain a deletion within the transposase gene,
making them dependent on the Ac element for transposition.
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Abnormal amounts of
trinucleotide repeat sequences can cause human genetic disorders such as
fragile X syndrome, Huntington disease, myotonic dystrophy,
and spinobulbar muscular atrophy.
The number of repeats may increase in each subsequent generation,
a phenomenon known as genetic anticipation.
xeroderma_pigmentosum.html: 15_18-xeroderma_pigmentosum.jpg
The recessive genetic disorder
xeroderma pigmentosum results in defective
NER and cannot repair the thymine dimers from UV damage.
The 4-year-old boy shows marked skin lesions, including two cancers on his nose.
The 18-year-old girl on the right has been carefully protected from sunlight since her diagnosis of
XP in infancy; several cancers have been removed.