MUTATIONS
1
What Are Mutations?
• Changes in the
nucleotide sequence of
DNA
• May occur in somatic
cells (aren’t passed to
offspring)
• May occur in gametes
(eggs & sperm) and be
passed to offspring
Are Mutations Helpful or Harmful?
• Some type of skin
cancers and leukemia
result from somatic
mutations
• Some mutations may
improve an organism’s
survival (beneficial)
Types of Mutations
– Chromosome mutations
• Changes in chromosome structure
– Genome mutations
• Changes in chromosome number
– Single-gene mutations
• Relatively small changes in DNA structure
• Occur within a particular gene
Chromosome Mutations
• May Involve:
– Changing the
structure of a
chromosome
– The loss or gain
of part of a
chromosome
Chromosome Mutations
• Five types exist:
–Deletion
–Inversion
–Translocation
–Nondisjunction
–Duplication
Deletion
• Due to breakage
• A piece of a
chromosome is lost
Inversion
• Chromosome segment
breaks off
• Segment flips around
backwards
• Segment reattaches
Duplication
• Occurs when a gene
sequence is
repeated
Translocation
• Involves two
chromosomes that
aren’t homologous
• Part of one
chromosome is
transferred to
another
chromosomes
Nondisjunction
• Failure of chromosomes to separate
during meiosis
• Causes gamete to have too many or too
few chromosomes
• Disorders:
– Down Syndrome – t(hree 21st chromosomes
– Turner Syndrome – single X chromosome
– Klinefelter’s Syndrome – XXY chromosomes
Chromosome Mutation
Animation
Gene Mutations
• Change in the
nucleotide sequence of
a gene
• May only involve a single
nucleotide
• May be due to copying
errors, chemicals,
viruses, etc.
Types of Gene Mutations
• Include:
–Point Mutations
–Substitutions
–Insertions
–Deletions
–Frameshift
Point Mutation
• Change of a single
nucleotide
• Includes the deletion,
insertion, or substitution
of ONE nucleotide in a
gene
Point Mutation
• Sickle Cell disease is
the result of one
nucleotide substitution
(GAA GTA )
• Valine is replaced with
Glutamic Acid
• Occurs in the
hemoglobin gene
Base Pair Substitutions :
Silent
Missense – new protein (Amino Acid Substitutions)
Nonsense – stop codon
1. Silent mutation
5’ ATG GGA GCT CTA TTA ACC TAA 3’
met gly ala leu leu thr stop
Silent mutation
5’ ATG GGA GCT CTA TTG ACC TAA 3’
met gly ala leu leu thr stop
2. Missense mutation
5’ ATG GGA GCT CTA TTA ACC TAA 3’
met gly ala leu leu thr stop
Missense mutation
5’ ATG GGA GCT CTA TTT ACC TAA 3’
met gly ala leu phe thr stop
3. Nonsense mutation
5’ ATG GGA GCT CTA TTA ACC TAA 3’
met gly ala leu leu thr stop
Nonsense mutation
5’ ATG GGA GCT CTA TGA ACC TAA 3’
met gly ala leu stop
Frameshift Mutation
• Inserting or deleting one
or more nucleotides
• Changes the “reading
frame” like changing a
sentence
• Proteins built incorrectly
Frameshift Mutation
• Original:
–The fat cat ate the wee rat.
• Frame Shift (“a” deleted):
– The fat cta tet hew eer at.
Amino Acid Sequence
Changed
Gene Mutation Animation
Normal Male
2n = 46
Normal Female
2n = 46
Male, Trisomy 21 (Down’s)
2n = 47
Female Down’s Syndrome
2n = 47
29
Klinefelter’s Syndrome
2n = 47
Turner’s Syndrome
2n = 45
31
CAUSES OF MUTATIONS
• Chemical
agents
and
physical
agents
MECHANISM of MUTAGENs
• Deamination of DNA structure
– Nitrous acid (HNO2) replaces amino groups of base
with keto groups
• -NH2  =O
• Can change cytosine
to uracil
– Pairs with A, not G
• Can change adenine
to hypoxanthine
– Pairs with C, not T
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MECHANISM of MUTAGENs
• Alkylation of DNA structure
– Alkylating agents covalently attach methyl or ethyl
groups to bases
• e.g., Nitrogen mustards, ethyl
methanesulfonate (EMS)
– Appropriate base pairing is disrupted
Effect of EMS
MECHANISM of MUTAGENs
• Interfere with the DNA replication process
– e.g., Acridine dyes such as proflavin
• Flat, planar structures interchelate into the double helix
– Sandwich between adjacent base pairs
• Helical structure is distorted
• Single-nucleotide additions and deletions can result
MECHANISM of MUTAGENs
• Base analog
– Some mutagens are base analogs
• e.g., 2-aminopurine
• e.g., 5-bromouracil (5BU)
• Become incorporated into
daughter strands during
DNA replication
Effect of BU
MECHANISM of MUTAGENs
• Effect of Radiation
– Ionizing radiation such as X rays and gamma rays
– Short wavelength and high energy
– Can penetrate deeply into biological materials
– Creates “free radicals”
» Chemically reactive molecules
– Free radicals alter DNA structure in a variety of ways
» Deletions, single nicks, cross-linking, chromosomal breaks
MECHANISM of MUTAGENs
– Nonionizing radiation such as
UV light
– Contains less energy
– Penetrates only the surface of material
such as the skin
– Causes the formation of thymine dimers
– May be repaired through one of numerous
repair systems
– May cause a mutation when that DNA
strand is replicated
DETERMINING OF MUTAGENS
• Ames test is commonly used
• Developed by Bruce Ames
– Uses his- strains of Salmonella typhimurium
• Mutation is due to a point mutation rendering an
enzyme inactive
– Reversions can restore his+ phenotype
• Ames test monitors rate of reversion mutations
• Ames test
– Suspected mutagen is mixed with rat liver extract
and his- Salmonella typhimurium
• Rat liver extract provides cellular
enzymes that may be required to
activate a mutagen
– Bacteria are plated on minimal
media
• his+ revertants can be detected
• Mutation frequency calculated
– Compared to control