1. CHAPTER 12 GENE MUTATION GENETICS SPRING 2016

2. I. INTRODUCTION A. Vocabulary 1. Mutation- a change in a gene’s nucleotide base sequence a. mutation refers to genotype b. mutant refers to phenotype 2. Intron- non-coding part of a gene 3. Exon- part of a gene that encodes amino acids

3. B. Effects of a mutation may vary 1. Proteins a. stop or slow production b. overproduce c. impair function through alterations i. secretion Ii. Location Iii. Interactions 2. not all mutations are harmful

4. C. presence of mutations 1. somatic mutations 2. germline mutations

5. II. MUTATIONS CAN ALTER PROTEINS- 3 EXAMPLES A. The Beta Globin Gene 1. sickle cell disease Difference in hemoglobin protein complex Specifically, beta globin

6. 2. Composition of hemoglobin a. two alpha polypeptide subunits b. two beta subunits 3. Mutation a. substitution of valine for glutamine at the 6 th amino acid in beta chain b. substitution came from single base substitution from CTC to CAC i. RNA codons GAG to GUG

7. 4. Results a. forms sickle-shaped blood cells b. lodge in blood bessels i. oxygen level falls Ii. Great pain in blocked body parts

8. B. Disorders of orderly collagen 1. collagen is a major component of connective tissue a. mutations lead to a variety of medical issues 2. Ehlers-Danlos Syndrome (stretchy skin) a. collagen molecules cannot assemble b. lack the strength to keep skin from becoming too stretchy

9. 3. Aortic aneurysm a. the aorta weakens and can suddenly burst b. detection of the mutations before symptoms arise can be life saving c. if aortic weakening is detected early enough, it can be treated surgically

10. C. Early-onset Alzheimers Disease 1. autosomal dominant form a. gene located on chromosome 14 b. gene encodes a protein called Presenilin 1

11. 2. Presenilin 1 normally monitors beta amyloid a. substance accumulates in the brains of people with Alzheimer’s 3. Mutation causes elevated levels of Presenilin 1 in blood stream a. somehow disrupts amyloid production, folding or function

13. D. Multiple mutations cause confusion 1. Mutations have varying effects a. different mutations in one gene may cause differing degrees of the same syndrome b. different mutations in other genes may cause distinct disorders

14. 2. Genetic heterogeneity a. the same symptoms are can be caused by different mutations b. causes confusion when assigning mutations to specific medical conditions

15. EXIT SLIP 2 things you learned/found interesting 1 question you still have 1 fun thing you did over spring break

16. LET’S REVIEW What is one way that mutations can affect proteins? Sickle cell disease is caused by a mutation in which subunit(s) of the hemoglobin protein complex? What is one example of a collagen disorder?

17. III CAUSES OF MUTATION A. Spontaneous Mutation 1. What is it? a. not caused by a mutagen b. originates as an error in DNA i. tautomers

19. 2. Spontanous Mutation Rate a. varies for different genes b. estimated that each human gene has about a 1 in 100,000 chance of mutating i. mitochondrial genes mutate at a higher rate Ii. They cannot repair DNA

20. c. rate for autosomal genes is estimated by a formula i. De novo cases/ 2X ii. De novo = new mutation iii. X = number of individuals examined

21. 3. Mutational Hot Spots a. mutations are more likely to occur in “hot spots” i. places where base sequences are repetitive ii. Replication molecules may become “confused” Ex. She went to the store to pick up some banananas but was disapppointed to find that they all looked rotten.

22. b. DNA strand may pair with itself i. DNA locally unwinds Ii. Symmetrical or repeated sequences pair with each other instead of a new strand

24. c. base additions or deletions are likely to occur near palindromes i. complementary strand sequences that read the same in a 5’ to 3’ direction

25. BEFORE WE MOVE ON…. What is a mutagen? What are some examples of mutagens? How often are we exposed to mutagens?

26. B. Induced Mutation 1. intentional use of mutagens a. alkylating agents remove a DNA base b. acridine dyes add or remove a single DNA base c. X-Rays delete a few bases or break chromosomes

27. d. there are several ways to test the mutagenicity of a substance i. The Ames test assesses how likely a substance is to harm the DNA in a rapidly growing bacteria ii. Site-directed mutagenesis changes a gene in a desired way

28. 2. Accidental Exposures to mutagens a. exposures can happen in many ways i. workplace contact ii. Industrial accidents iii. Medical treatments iv. Weapons that emit radiation

29. POP QUIZ! April Fools!

30. C Natural Exposure to Mutagens 1. Natural sources of radiation a. Cosmic rays b. sunlight c. radioactive minerals i. found in earth’s crust ii. Ex. Radon

31. 2. Radiation is measured in millirems a. Average annual exposure is 360 millirems 3. Most mutagenic radiation is ionizing a. It is able to remove electrons from atoms b. breaks the backbone of DNA c. 3 major types i. Alpha ii. Beta iii. Gamma

32. IV. TYPES OF MUTATIONS A. Point Mutations 1. A change in a single DNA base 2. Two types of point mutations a. transition i. Purine replaces purine ii. Pyrimidine replaces pyrimidine b. Transversion i. Purine replaces pyrimidine or vice versa

33. B Missense and Nonsense Mutations 1. Missense Mutation a. caused by point mutation b. Codon encodes for a different amino acid 2. Nonsense Mutation a. caused by point mutation b. changes the codon into a “stop” codon

34. C. Deletions and Insertions can shift the reading frame 1. Frameshift mutation a. changes that alter the reading frame i. reading frame - nucleotide position where protein encoding begins b. if deletions or insertions occur in groups of 3, mutation does not cause frameshift

35. 2. Deletion mutation a. removes genetic material b. ranges from one to thousands of bases or more 3. Insertion mutation a. adds genetic material b. may repeat part of a gene’s sequence Called tandem duplication

37. D. Expanding Repeats 1. 1992- Myotonic dystrophy was puzzling scientists a. worsened and began at earlier age as it passed to each generation b. phenomenon called “anticipation” c. originally thought to be psychological

38. 2. Disease progression isn’t psychological a. found that the gene expanded with each generation b. repeat of the triplet CTG was discovered c. expanding triplet repeats are associated with more than 15 human disorders

39. 3. Repeats cause extra-long proteins a. proteins function differently b. these functions may shut down a cell

40. E. Splice Site Mutations 1. Changes that affect introns and exons a. intron may not be removed when it should be i. causes the protein to be too long b. exons may be “skipped” and cause the protein to be too short

41. 2. These mutations may only occur in certain cells a. Some cells don’t “skip” exons b. currently looking for a way to coax the cells to produce the missing protein

42. V. THE IMPORTANCE OF POSITION A. Globin Variants 1. Hundreds of globin gene mutations a. can cause anemia with or without sickling b. can cause cyanosis i. poor oxygen binding

43. 2. Hemoglobin S vs. Hemoglobin C a. both occur at the 6 th amino acid of the beta globin b. S mutation causes sickle cells but C mutations are healthy c. both are resistant to malaria

44. 3. Hemoglobin M a. Mutation in either alpha or beta globin chain b. mutation changes the iron in hemoglobin c. change in iron causes cyanosis

45. VI. FACTORS THAT LESSEN THE EFFECTS OF MUTATION A. Mutation is natural 1. DNA is flexible a. i.e. able to change 2. Essential for evolution a. mutations may better equip a species for survival

46. B. DNA has built-in protection against mutation 1. Mutations in the 3 rd codon are often “silent” a. the amino acid does not change 2. Mutations in the 2 nd codon give similar products a. the amino acid may change, but it has a similar conformation b. does not disrupt the protein too much

48. C. Conditional Mutations 1. phenotype is only affected under certain conditions a. person should avoid symptom “triggers”

49. 2. Ex G6PD deficiency a. this enzyme normally helps cells extract energy from glucose i. 100 million people have this deficiency b. can cause hemolytic anemia c. deficient people should avoid the following: i. fava beans ii. Some antimalarial drugs iii. Pollen in certain areas

50. VII. DNA REPAIR A. Types of DNA Repair 1. Photoractivation a. Enables ultraviolet-damaged DNA to be recovered when exposed to sunlight b. Unfortunately, humans do not have this type of repair i. Fungi do

51. 2. Excision repair a. Enzymes cut out (excise) the mutated DNA i. DNA polymerase fills in the correct DNA b. Nucleotide excision repair i. Replaces up to 30 nucleotides c. Base excision repair i. only replaces up to 5 nucleotides at a time ii. Corrects specific errors

52. 3. Mismatch repair a. enzymes “proofread” newly replicated DNA b. replace mismatched bases with correct ones c. different from excision in the cause of the error

53. B. DNA Repair Disorders 1. Trichothiodystrophy a. Symptoms i. dwarfism ii. Mental retardation iii. Failure to develop iv. Brittle hair

54. b. causes i. at least 5 different genes can cause disorder ii. Low sulfur content iii. Faulty nucleotide and/or base excision repair

55. 2. Inherited Colon Cancer a. hereditary nonpolyposis form b. Causes i. faulty mismatch repair ii. Causative gene found on Chromosome 2 c. very common i. affects 1 in 200 people

56. 3. Xeroderma Pigmentosum (XP) a. Symptoms i. ultra sensitive to sunlight ii. 10,000-fold increase risk of developing skin cancer b. Causes i. malfunction of nucleotide excision repair ii. Deficient DNA polymerase

58. 4. Ataxia Telangiectasis (AT) a. Symptoms i. extremely high risk of cancer development ii. Poor balance iii. Red marks on the face iv. Delayed puberty b. Causes i. Deficit in kinase that functions as cell cycle checkpoint ii. Cells go through division without checking new DNA

59. c. Most populations have carriers of this mutation i. carriers are at an increased risk of developing cancer ii. More sensitive to radiation