1. Human Genetic Mutations

2. What is a mutation? Mutations are changes made to an organism’s genetic material. These changes may be due to errors in replication, errors during transcription, radiation, viruses and many other things. Mutations can occur within a specific gene (small scale), as well as to the chromosome as a whole (large scale).

3. Are mutations always bad? Favorable mutations present organisms with an advantage over others and ensure their survival. These mutations will accumulate in a population. Less favorable mutations are removed from the gene pool through natural selection. –Organisms with these mutations will not survive.

4. Gene Mutations Small scale: one gene is affected Any change to the DNA sequence of a gene: Nucleotides/Bases may be added, missing, or changed

5. Causes of Mutations spontaneous occur during DNA replication Caused by MUTAGENS physical, ex: radiation from UV rays, X-rays or extreme heat or chemical (molecules that misplace base pairs or disrupt the helical shape of DNA).

6. Gene Mutations: 2 Types Point Mutation Frameshift Mutation

7. Point Mutation- One Base Change One base (A, T, C, or G) is substituted for another Example: Sickle-cell anemia 3 Possible Consequences: –nonsense mutations: code for a stop, which can translate the protein –missense mutations: code for a different amino acid –silent mutations: code for the same amino acid

8. What does it look like? THE BIG RED DOG RAN OUT. THE BIG RAD DOG RAN OUT. THE BIG RED. THE BGR EDD OGR ANO…. THE BIG RED DOO GRA NOU THE BIG DOG RAN OUT. THE BIG BIG BIG BIG BIG RED DOG RAN OUT. Normal Missense Nonsense Frameshift (1 bp deletion) Frameshift (1 bp insertion) Frameshift (3bp deletion) Triplet repeat expansion

9. Example: Sickle Cell Anemia Normal Red Blood Cell Red blood cells shaped like a disc Hemoglobin (protien) carries oxygen to all parts of the body Sickle Red Blood Cell Red blood cells form an abnormal crescent shape Hemoglobin (protein) is abnormally shaped don't move easily through your blood vessels form clumps and get stuck in the blood vessels

10. Sickle Cell Anemia Blood smear (normal) Image Credit: http://lifesci.rutgers.edu/~babiarz/http://lifesci.rutgers.edu/~babiarz/ Sickle cell anemia Image Credit: http://explore.ecb.org/http://explore.ecb.org/

11. Mutations: Substitutions Substitution mutation GGTCACCTCACGCCA ↓ CCAGUGGAGUGCGGU ↓ Pro-Arg-Glu-Cys-Gly Substitutions will only affect a single codon Their effects may not be serious unless they affect an amino acid that is essential for the structure and function of the finished protein molecule (e.g. sickle cell anemia) Normal gene GGTCTCCTCACGCCA ↓ CCAGAGGAGUGCGGU Codons ↓ Pro-Glu-Glu-Cys-Gly Amino acids © 2010 Paul Billiet ODWSODWS

12. Mutations: Inversion Normal gene GGTCTCCTCACGCCA ↓ CCAGAGGAGUGCGGU Codons ↓ Pro-Glu-Glu-Cys-Gly Amino acids Inversion mutation GGTCCTCTCACGCCA ↓ CCAGGAGAGUGCGGU ↓ Pro-Gly-Glu-Cys-Gly Inversion mutations, also, only affect a small part of the gene © 2010 Paul Billiet ODWSODWS

13. Mutations: Additions Normal gene GGTCTCCTCACGCCA ↓ CCAGAGGAGUGCGGU Codons ↓ Pro-Glu-Glu-Cys-Gly Amino acids Addition mutation GGTGCTCCTCACGCCA ↓ CCACGAGGAGUGCGGU ↓ Pro-Arg-Gly-Val-Arg A frame shift mutation © 2010 Paul Billiet ODWSODWS

14. Mutations: Deletions Normal gene GGTCTCCTCACGCCA ↓ CCAGAGGAGUGCGGU Codons ↓ Pro-Glu-Glu-Cys-Gly Amino acids Deletion mutation GGTC/CCTCACGCCA ↓ CCAGGGAGUGCGGU ↓ Pro-Gly-Ser-Ala-Val A frame shift mutation © 2010 Paul Billiet ODWSODWS

15. The genetic code is degenerate A mutation might not have a negative effect on the phenotype Changes in the third base of a codon often have no effect. This is called wobble © 2010 Paul Billiet ODWSODWS

16. Frameshift Mutation- More than one base is affected One or more bases (A, T, C, or G) are added or deleted Causes: Cystic Fibrosis Caused by: –Insertion: adding a base –Deletion: removing a base

17. Example: Cystic Fibrosis (CF) What is it? –Autosomal, recessive disorder Symptoms –Thick mucus in the lungs and digestive track –Constant lung infections and impaired digestion

18. Cystic Fibrosis (CF) Who gets it? –Anyone –Most common in Caucasians Prevalence –1 in ~3,000 Americans has CF –1 in 23 white Americans carries the mutant allele!

19. Cause of Cystic Fibrosis (CF) The “CFTR” gene is mutated –3 base pairs are deleted Mutant protein is missing an amino acid and cannot fold correctly vs

20. Chromosomal Mutations Any change in the structure or number of chromosomes Large scale: Affect many genes

21. 5 Types 1.Deletion 2.Duplication 3.Inversion 4.Translocation 5.NonDisjunction

22. Chromosomal Deletion One or more genes are removed Causes: Wolf-Hirschhorn syndrome (severe mental retardation) cri du chat syndrome (mewing sounds, mental retardation)

24. Deletions Examples of disorders caused by deletions: –Prader-Willi Syndrome Deletion of the long arm on chromosome 15 Characterized by compulsive eating

25. Chromosomal Duplication A segment of genes is copied twice and added to the chromosome Causes: Charcot–Marie–Tooth disease (high arched foot, claw feet, confined to a wheelchair)

27. Chromosomal Inversion a segment of genes flip end-to-end on the chromosome Causes: Four-Ring Syndrome (cleft palate, club feet, testes don’t descend)

28. Chromosomal Translocation Material is swapped with another chromosome Causes: Burkitt’s Lymphoma (cancer of the lymph nodes, in children)

29. Nondisjunction Chromosomes FAIL TO SEPARATE during meiosis

30. Nondisjunction Produces gametes (and therefore a baby) with one missing chromosome or one extra chromosome

31. Chromosomal Mutations Most chromosomal mutations are harmful or lethal If the fetus survives: Tend to cause wide-spread abnormalities Example: Down Syndrome

32. Trisomy 21 - Down Syndrome

33. Down Syndrome Cause: Nondisjunction of chromosome 2 1 “TRISOMY 21”

34. Disease-Associated Mutations Alter Protein Function Functional protein Nonfunctional or missing protein

35. Are all mutations harmful? Sequence changes or variants can be –Silent (no change in product): Polymorphism We have thousands of these –Manifesting (changing RNA or protein product): Mutation We all carry 7-10 gene mutations Can lead to VARIATION

36. Polymorphism A change in DNA sequence that is not disease causing Occurs usually in greater than 1% of population Usually does not change an amino acid sequence or produces a significant change (ie: valine for isoleucine) Can produce codominance or changes in coloration or appearance

38. Variations: Co-dominant expression Definition: alleles that are both expressed when they occur in the heterozygous state. Example: ABO blood group antigens

39. ABO blood typing: co-dominant alleles A/-B/- BB B/- ABAB A/--/- ABAB BB A/-

40. Variations: New Mutations Occur at a rate of 10 -4 to 10 -7 per locus per cell division “Hot spots” occur: CG pairs (8.5 x higher rate) More easily seen in a very large gene Paternal age effects ( remember why?)

41. Autosomal dominant: new mutation often as heterozygous dd Dd

42. Achondroplasia Autosomal dominant 1/26000: most common genetic dwarfism 80% new mutations Features –upper arms and thighs are short –lumbar lordosis (lower spine curves out) –large head –intact intellect –Mutation in FGFR3: activating mutation

43. Effects of homozygosity dd Dd dd Dd DD

44. Homozygosity for some dominant traits is lethal Homozygosity for achondroplasia causes very severe phenotype http://www.echt.chm.msu.edu/courseware/blockII/Pathology/382131.jpeg

45. Autosomal Dominant and variable expression Pleiotropy: one gene, many effects on different systems Random chance Modifier genes

46. Marfan Syndrome: variable expression Skeletal findings- disproportionate long bone growth Tall Stature Eyes- dislocated lenses Heart-dilation of aortic arch http://medgen.genetics.utah.edu /

48. Familial Retinoblastoma: a recessive state in the cell inherited as AD trait http://www.retinoblastoma.com/Images/CT%20Scan.jpg http://www.people.virginia.edu/~rjh9u/retblst.html

49. KEY POINT #2 Mutation of a gene = Mutant protein Dysfunctional proteins cause the symptoms of the disorder

50. Testing for mutations Ultrasound Amniocentesis Blood draw Direct to Consumer testing (DTC)

52. Genetic Screening - Amniocentesis

54. Unusual Human Mutations Progeria

55. Epidermodysplasia Verruciformis

56. Ectrodactyly

57. Proteus syndrome

58. Trimethylaminuria