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CHAPTER 13
GENE REGULATION
1
Mutation

Mutation is a permanent change in the
sequence of bases in DNA.

Protein is completely inactivated
Germ-line mutations occur in sex cells
 Somatic mutations occur in body cells

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Causes of Mutations

Spontaneous mutation


DNA can undergo a chemical change
Replication Errors


1 in 1,000,000,000 replications
DNA polymerase



Proofreads new strands
Generally corrects errors
Induced mutation:



Mutagens such as radiation, organic chemicals
Many mutagens are also carcinogens (cancer causing)
Environmental Mutagens


Ultraviolet Radiation
Tobacco Smoke
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Causes of Mutations
Ultraviolet (UV) radiation is easily absorbed
by the pyrimidines in DNA.
 Cause neighboring thymine molecules next
to one another to bond together


Thymine dimers.
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C G
kink
T
A
T
A
thymine
dimer
C G
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Causes of Mutations

Usually, these dimers are removed by DNA
repair enzymes

Deficient DNA repair enzymes leave the skin
cells vulnerable to the mutagenic effects of
ultraviolet light
Accumulation of mutation
 High incidence of cancer

5
CHROMOSOME MUTATIONS
AN EXAMPLE: Translocation has been pinpointed
as the cause of chronic myeloid leukemia, a type of
cancer (of the white blood cells)
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GENE MUTATIONS

Point Mutations (Substitutions)
Missense
 Nonsense
 Silent


Frameshift Mutations
Insertion
 Deletion

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7
GENE MUTATIONS: Effect of Mutations
on Protein Activity

Point Mutations



Involve change in a single DNA nucleotide
Changes one codon to a different codon
Affects on protein vary:




Nonfunctional
Reduced functionality
Unaffected
Frameshift Mutations


One or two nucleotides are either inserted or deleted
from DNA
Protein always rendered nonfunctional



Normal :
After deletion:
After insertion:
THE CAT ATE THE RAT
THE ATA TET HER AT
THE CCA TAT ETH ERA T
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The molecular basis of sickle-cell
disease: a point mutation
Wild-type hemoglobin DNA
3
Mutant hemoglobin DNA
5
C
T
T
In the DNA, the
5 mutant template
strand has an A where
the wild-type template
has a T.
A
The mutant mRNA has
a U instead of an A in
one codon.
3
T
C
mRNA
A
mRNA
G
A
A
5
G
3
U
5
Normal hemoglobin
Glu
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3
Sickle-cell hemoglobin
Val
The mutant (sickle-cell)
hemoglobin has a valine
(Val) instead of a glutamic
acid (Glu).
Sickle Cell
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Base-pair substitution
Wild type
mRNA
A U G A A G U U U G G C U A A
5
Protein
Met
Lys
Phe
Gly
3
Stop
Amino end
Carboxyl end
Base-pair substitution
No effect on amino acid sequence
U instead of C
A U G A A G U U U G G U U A A
Met
Lys
Missense
Phe
Gly
Stop
A instead of G
A U G A A G U U U A G U U A A
Met
Lys
Phe
Ser
Stop
Nonsense
U instead of A
A U G U A G U U U G G C U A A
Met
Stop
Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings
Base-pair insertion or deletion
Wild type
mRNA 5
Protein
A U G A A G U U U G G C U A A
Met
Lys
Gly
Phe
3
Stop
Amino end
Carboxyl end
Base-pair insertion or deletion
Frameshift causing immediate nonsense
Extra U
A U G U A A G U U U G G C U A
Met
Stop
Frameshift causing
extensive missense
U Missing
A U G A A G U U G G C U A A
Met
Lys
Leu
Ala
Insertion or deletion of 3 nucleotides:
no frameshift but extra or missing amino acid
A A G Missing
A U G U U U G G C U A A
Met
Phe
Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings
Gly
Stop
Tay-Sachs Disease
Frameshift Mutation:
•
•
•
Caused by 4 bp INSERTION in exon 11 of
the HEXA gene on chromosome 15
This causes a stop codon in the wrong
location
Deficient hexosaminidase (hex A).
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Crohn’s Disease
Frameshift Mutation
Inflammation of the digestive tract….usually
small intestine affected the most
 Originally thought to have been caused by
environmental factors
 In 2001 it was determined that an
INSERTION of cytosine into the NOD2
gene of DNA

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Cystic Fibrosis
Frameshift Mutation
Caused by a DELETION of three base
pairs on the CFTR gene.
 phenylalanine not located at position 508 in
the protein
 mutation is often called F508

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Carcinogenesis

Development of cancer involves a series of
mutations

Proto-oncogenes – Stimulate cell cycle

Tumor suppressor genes – inhibit cell cycle

Mutation in oncogene and tumor suppressor
gene:

Stimulates cell cycle uncontrollably

Leads to tumor formation
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