CHAPTER 13

GENE REGULATION

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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 togetherThymine dimers.

C G

C

A

A

G

kink

thyminedimer

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T

T

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Causes of Mutations

Usually, these dimers are removed by DNA repair enzymesDeficient DNA repair enzymes leave the skin

cells vulnerable to the mutagenic effects of ultraviolet light

Accumulation of mutationHigh incidence of cancer

CHROMOSOME MUTATIONS

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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)MissenseNonsenseSilent

Frameshift Mutations InsertionDeletion

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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 : THE CAT ATE THE RAT After deletion: THE ATA TET HER AT After insertion: THE CCA TAT ETH ERA T

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 The molecular basis of sickle-cell disease: a point mutation

In the DNA, themutant templatestrand has an A where the wild-type template has a T.

The mutant mRNA has a U instead of an A in one codon.

The mutant (sickle-cell) hemoglobin has a valine (Val) instead of a glutamic acid (Glu).

Mutant hemoglobin DNAWild-type hemoglobin DNA

mRNA mRNA

Normal hemoglobin Sickle-cell hemoglobin

Glu Val

C T T C A T

G A A G U A

3′ 5′ 3′ 5′

5′ 3′5′ 3′

Sickle Cell

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Base-pair substitution

Wild type

A U G A A G U U U G G C U A AmRNA 5′Protein Met Lys Phe Gly Stop

Carboxyl endAmino end

3′

A U G A A G U U U G G U U A A

Met Lys Phe Gly

Base-pair substitutionNo effect on amino acid sequence

U instead of C

Stop

A U G A A G U U U A G U U A A

Met Lys Phe Ser Stop

A U G U A G U U U G G C U A A

Met Stop

Missense A instead of G

NonsenseU instead of A

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Base-pair insertion or deletion

mRNA

Protein

Wild type

A U G A A G U U U G G C U A A5′

Met Lys Phe Gly

Amino end Carboxyl end

Stop

Base-pair insertion or deletionFrameshift causing immediate nonsense

A U G U A A G U U U G G C U A

A U G A A G U U G G C U A A

A U G U U U G G C U A A

Met Stop

U

Met Lys Leu Ala

Met Phe GlyStop

MissingA A G

Missing

Extra U

Frameshift causing extensive missense

Insertion or deletion of 3 nucleotides:no frameshift but extra or missing amino acid

3′

Tay-Sachs DiseaseFrameshift 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 DiseaseFrameshift 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 FibrosisFrameshift 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