MUTATIONS

Changes in DNA that affect genetic information

Most mutations are the result of errors in the replication
process. Exposure of a cell or virus to radiation or to certain
chemicals increases the likelihood of mutations.
 Types of DNA Change
• The simplest mutations are base changes, where one base is
converted to another. These can be classified as either:
– --“transitions”, where one purine is changed to another purine (A -> G,
for example), or one pyrimidine is changed to another pyrimidine (T ->
C, for example).
– “transversions”, where a purine is substituted for a pyrimidine, or a
pyrimidine is substituted for a purine. For example, A -> C.

• Another simple type of mutation is the gain or loss f one or a

few bases.
• Larger mutations include insertion of whole new sequences,
often due to movements of transposable elements in the DNA
or to chromosome changes such as inversions or
translocations.
• Deletions of large segments of DNA also occurs.
Different forms and origins of Mutations
 Mutations – changes in the DNA
• Silent mutation – alters a base but does not
change the amino acid
• Missense mutation – causes change in a single
amino acid
• Sense mutation- converts a stop codon into an
amino acid codon.
• Nonsense mutation – changes a normal codon
into a stop codon

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 Types of Mutation

• Mutations can be classified according to their effects

on the protein (or mRNA) produced by the gene that
is mutated.

• 1. Silent mutations (synonymous mutations). Since

the genetic code is degenerate, several codons
produce the same amino acid.
Especially, third base changes often have no
effect on the amino acid sequence of the protein.
These mutations affect the DNA but not the protein.
Therefore they have no effect on the organism’s
phenotype.
 Types of Mutation
• 2. missense mutations. Missense mutations substitute one
amino acid for another. Some missense mutations have very
large effects, while others have minimal or no effect. It
depends on where the mutation occurs in the protein’s
structure, and how big a change in the type of amino acid it
is.
•
– Example: HbS, sickle cell hemoglobin, is a change in the
beta-globin gene, where a GAG codon is converted to
GUG. GAG codes for glutamic acid, which is a hydrophilic
amino acid that carries a -1 charge, and GUG codes for
valine, a hydrophobic amino acid. This amino acid is on
the surface of the globin molecule, exposed to water.
Under low oxygen conditions, valine’s affinity for
hydrophobic environments causes the hemoglobin to
crystallize out of solution.

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 More Types of Mutation
• 3. Nonsense mutations convert an amino acid into a stop
codon. The effect is to shorten the resulting protein.
Sometimes this has only a little effect, as the ends of proteins
are often relatively unimportant to function. However, often
nonsense mutations result in completely non-functional
proteins.

– an example: Hb-β McKees Rock. Normal beta-globin is 146

amino acids long. In this mutation, codon 145 UAU (codes
for tyrosine) is mutated to UAA (stop). The final protein is
thus 143 amino acids long. The clinical effect is to cause
overproduction of red blood cells, resulting in thick blood
subject to abnormal clotting and bleeding.
 More Types of Mutation
• 4. Sense mutations are the opposite of nonsense mutations.
Here, a stop codon is converted into an amino acid codon.
Since DNA outside of protein-coding regions contains an
average of 3 stop codons per 64, the translation process
usually stops after producing a slightly longer protein.

– Example: Hb-α Constant Spring. alpha-globin is normally

141 amino acids long. In this mutation, the stop codon
UAA is converted to CAA (glutamine). The resulting
protein gains 31 additional amino acids before it reaches
the next stop codon. This results in thalassemia, a severe
form of anemia.

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 More types of mutations

•Normal THE ONE BIG FLY HAD ONE RED EYE

•Missense THQ ONE BIG FLY HAD ONE RED EYE
•Nonsense THE ONE BIG ***
•Frameshift THE ONE QBI GFL YHA DON ERE DEY
•Deletion THE ONE BIG HAD ONE RED EYE
•Insertion THE ONE BIG WET FLY HAD ONE RED EYE
•Duplication THE ONE BIG FLY FLY HAD ONE RED EYE
•Expanding Mutation
–Generation 1 THE ONE BIG FLY HAD ONE RED EYE
–Generation 2 THE ONE BIG FLY FLY HAD ONE RED EYE
–Generation 3 THE ONE BIG FLY FLY FLY HAD ONE RED EYE
 Gene Mutations

• Point Mutations – changes in

one or a few nucleotides
– Substitution
• THE FAT CAT ATE THE RAT
• THE FAT HAT ATE THE RAT
 Gene Mutations
• Frameshift Mutations – shifts
the reading frame of the genetic
message so that the protein may
not be able to perform its
function.
– Insertion
• THE FAT CAT ATE THE RAT
• THE FAT HCA TAT ETH ERA T

– Deletion
H
• THE FAT CAT ATE THE RAT
• TEF ATC ATA TET GER AT

H
 Chromosome Mutations
• Changes in number and structure of entire
chromosomes
• Original Chromosome ABC * DEF
• Deletion AC * DEF
• Duplication ABBC * DEF
• Inversion AED * CBF
• Translocation ABC * JKL
GHI * DEF
 Significance of Mutations
• Most are neutral
• Eye color
• Birth marks
• Some are harmful
• Sickle Cell Anemia
• Down Syndrome
• Some are beneficial
• Sickle Cell Anemia to Malaria
• Immunity to HIV
 What Causes Mutations?
• There are two ways in which DNA can
become mutated:
– Mutations can be inherited.
• Parent to child
– Mutations can be acquired.
• Environmental damage
• Mistakes when DNA is copied
 Different Causes of mutation
1. Tautomeric Shifts: spontaneous
2. Base Analogues: chemical
3. Alkylating Agents: chemical
4. Intercalating Dyes: chemical
5. Deamination: chemical
6. UV Radiation and Thymine Dimers
7. High-Energy Radiation (X rays, gamma rays,
cosmic rays)
 1. Tautomeric Shifts Cause
Spontaneous Mutations
• Can’t be avoided - inherent in the chemistry of bases.

• Always a transition: changing one purine (G or A) to the

other purine, or one pyrimidine (C or T) to the other
pyrimidine.

• DNA proofreading minimizes the mutation rate due to

tautomeric shifts. This involves 3’-5’ exonuclease activity
in DNA polymerase.
 Keto-Enol Tautomeric Shifts in T and G

common rare
 Amino-imino Tautomeric Shifts in C and A

common
rare
Mispairing Due to Tautomeric Shifts
 Formation of a TA to CG Transition
During DNA Replication

Transition is a purine replaced by different purine or pyrimidine

replaced by different pyrimidine.
 2. Base Analogues: DNA can
Incorporate 5-BU in place of Thymine

common rare
Changes T-A pair > C-G pair. T > C, and A > G are both Transitions
3. Alkylating Agents: Ethylmethane
Sulfonate (EMS) Alkylates Guanine

Note: changes a G-C pair into an A-T pair

(G > A is a transition, C > T is a transition)
Another example: mustard gases first used in WWI.
4. Intercalating Dyes Cause Frameshifts

Intercalate themselves into the DNA double helix, distorting it,

and causing insertion or deletion during DNA replication or
recombination. Other examples: Ethidium Bromide, DAPI.
5. Deamination is Caused by Nitrous Acid

(a) Causes: C -> T transition (and G -> A transition)

(b) Causes: A -> G transition (and T -> C transition). All.
Deamination can be spontaneous as well.
6. Ultraviolet Radiation Cause
Thymine Dimers
260 nanometer
wavelength
7. High-Energy (Ionizing) Radiation
Effects of Ionizing Radiation

• Causes either point mutations or breaks in

phosphodiester bonds of DNA backbone.

• If both strands broken, there can sometimes be repair in

mammals through the double-strand break repair (DSB)
system.

• Dividing cells are more susceptible to therapeutic X-rays

than non-dividing cells (radiation therapy for cancer).
 Chromosome Mutations
• Down Syndrome
– Chromosome 21 does not
separate correctly.
– They have 47 chromosomes
in stead of 46.
– Children with Down
Syndrome develop slower,
may have heart and
stomach illnesses and vary
greatly in their degree of
inteligence.
 Chromosome Mutations

• Cri-du-chat
– Deletion of material on 5th
chromosome
– Characterized by the cat-like
cry made by cri-du-chat babies
– Varied levels of metal
handicaps
 Sex Chromosome Abnormalities

• Klinefelter’s Syndrome
– XXY, XXYY, XXXY
– Male
– Sterility
– Small testicles
– Breast enlargement
Sex Chromosome Abnormalities
• XYY Syndrome
– Normal male traits
– Often tall and thin
– Associated with antisocial and behavioral problems
 Sex Chromosome Mutations
• Turner’s Syndrome
–X
– Female
– sex organs don't mature
at adolescence
– sterility
– short stature
 Sex Chromosome Mutations
• XXX
• Triple X syndrome or 47,XXX, is a genetic
condition that occurs when a female has an
extra copy of the X chromosome
– Trisomy X
– Female
– Little or no visible differences
– tall stature
– learning disabilities
– limited fertility
 Mutations Among Humans
Achromatopsi
Acoustic neuroma Thousands of distinct diseases have
Adenosice deaminase deficiency
Adenylosuccinate lyase deficiency
been ascribed to mutations that
Aicardi syndrome result in deficiencies of critical
Albinism
Albright’s syndrome
enzymes.
Alkaptonuria
Alpers syndrome
Antitrypins deficiency
All known mutations, in humans and
Alpha-mannosidosis otherwise, are the result of something
Alport syndrome
Alzheimer’s disease
that once worked either no longer
Amyotrophic lateral sclerosis working (such as blindness) or working
Androgen insensitivity syndrome
Angelman syndrome
in the wrong place (such as extra fingers
Anencephely or toes).
Hereditary angioedema (HAE)
Hereditary ataxias
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