CHAPTER 13 GENE REGULATION 1

2 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

3 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

4 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. CG C A A G kink thymine dimer Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. T T

5 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

CHROMOSOME MUTATIONS 6 AN EXAMPLE: Translocation has been pinpointed as the cause of chronic myeloid leukemia, a type of cancer (of the white blood cells)

7 GENE MUTATIONS Point Mutations (Substitutions) Missense Nonsense Silent Frameshift Mutations Insertion Deletion 27

8 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

Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings The molecular basis of sickle-cell disease: a point mutation In the DNA, the mutant template strand 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 Normal hemoglobinSickle-cell hemoglobin Glu Val C TT C AT G AA G UA 33 55 33 55 55 33 55 33

Sickle Cell 10

Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Base-pair substitution

Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Base-pair insertion or deletion mRNA Protein Wild type A U G AAGUUUGGCUAA 55 MetLysPhe Gly Amino end Carboxyl end Stop Base-pair insertion or deletion Frameshift causing immediate nonsense A U G UAAGUUUGGCUA A U G AAGUUGGCUAA A U G UUUGGCUAA Met Stop U MetLys Leu Ala MetPheGly Stop Missing AAG Extra U Frameshift causing extensive missense Insertion or deletion of 3 nucleotides: no frameshift but extra or missing amino acid 33

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). 13

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 14

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 15

16 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