1. Medical Genetics 03 基因突变 Gene Mutation

2. Medical Genetics Gene Mutation Change in genes caused by change in structure of the DNA.

3. Medical Genetics 1.Base(s) in DNA is (are) changed to other(s), or a base(s) is (are) added or removed. 2.Rearrangements of the chromosomes occur and are also considered.

4. Medical Genetics Mutations are heritable changes in genetic material.

5. Medical Genetics 1. Mutagens or Mutagenic Agents These are substances, conditions and forms that significantly increase the frequency of mutations.

6. Medical Genetics Mutations can occur at a spontaneous rate, or a far greater rate when there is exposure to mutagenic agents.

7. Medical Genetics Exposure to too high a level of mutagens can threaten the survival of a species; e.g., frog species in the states of Washington and Oregon are facing extinction. This appears to be caused by reduced atmospheric ozone, and the resulting increased level of ultraviolet radiation.

8. Medical Genetics A forms of energy Examples of a forms of energy are ultraviolet light, x-rays, cosmic energy, gamma radiation, alpha particles, beta particles and neutrons.

9. Medical Genetics Ultraviolet (UV) light UV light has shorter wavelengths than visible light. Though these waves are invisible to the human eye, some insects, like bumblebees, can see them!

10. Medical Genetics Scientists have divided the ultraviolet part of the spectrum into three regions: the near ultraviolet, the far ultraviolet, and the extreme ultraviolet.

11. Medical Genetics The three regions are distinguished by how energetic the ultraviolet radiation is, and by the "wavelength" of the ultraviolet light, which is related to energy.

12. Medical Genetics The near ultraviolet, abbreviated NUV, is the light closest to optical or visible light. The extreme ultraviolet, abbreviated EUV, is the ultraviolet light closest to X-rays, and is the most energetic of the three types. The far ultraviolet, abbreviated FUV, lies between the near and extreme ultraviolet regions. It is the least explored of the three regions.

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14. Ultraviolet Radiation causes pyrimidine dimers. These can block DNA replication. Also, dimers interfere with base pairing between the two DNA polymeres. U.V. light also generates free- radicals, which create other kinds of genetic damage.

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17. Gamma and X-Rays These can act directly on DNA; however, most damage is caused indirectly when molecules around the DNA such as water, are ionized, creating free-radicals, substances with unpaired electrons.

18. Medical Genetics Most often, the result is single or double stranded breaks in the DNA molecules. These breaks are hard to repair because they often leave a phosphate tacked onto the 3' OH, where the break occurs.

19. Medical Genetics Chemical Agents Examples of substances that are mutagens are nitrous acid, hydroxylamine, ethyl methanesulfonate, 5-bromouracil, celery, benzo (a) pyrene, acridine dyes, fungally contaminated peanuts or peanut butter, and many, many more.

20. Medical Genetics Hydroxylating agents (hydroxylamine ， HA)

21. Medical Genetics Nitrous acid is a deaminating agent. Deaminating agents cause the loss of the amino group. We covered spontaneous deamination of cytosine above. Deaminating agents would increase the frequency of cytosine deamination, greatly.

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23. Ethyl methanesulfonate (EMS) Alkylating agents are chemicals that donate alkly groups to other molecules.

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25. Base analogs Base analogs are similar to the actual correct base and so get incorporated into the DNA as would its natural counterpart. The problem is that, if they are more prone to tautomeric shifts than the natural base, the frequency for mutation goes up, substantially. The compound 5- bromouracil is an example of an analog to thymine. It undergoes a tautomeric shift to base pair with guanine instead of adenine, causing a transition.

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27. Intercalation agents are compounds that can slide between the nitrogenous bases in a DNA molecule. This tends to cause a greater likelihood for slippage during replication, resulting in an increase in frameshift mutations.

28. Medical Genetics Viruses Viruses that can integrate into the genome are also mutagenic agents

29. Medical Genetics 2. Mechanism of Mutation Static mutation Dynamic mutation

30. Medical Genetics Static mutation Microalterations Macroalterations

31. Medical Genetics Microalterations involve single base pairs. Transitions: Purine changes to an alternate purine; pyrimidine changes to an alternate pyrimidine. Transversions: A position with a pyrimidine changes to have a purine; or, purine to pyrimidine

32. Medical Genetics Transitions occur more commonly than transversions even though more theoretical combinations of transversions are possible. For example, the only possible transition for the base A is to change to the base G. Two transversions are possible for the base A: C and T.

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34. The reason transitions are more common is due to the nature of the underlying causes of mutations and to the size of the bases.

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36. A purine can be altered so that it base pairs like the other. It is impossible for a purine to be altered to resemble a pyrimidine, or vice versa.

37. Medical Genetics Also, remember that purines always hydrogen bond to pyrimidines. This leaves the same distances between each pair in the middle of the DNA polymer. This reduces the likelihood that these types of mistakes are made by DNA polymerase during replication.

38. Medical Genetics Macroalterations are large changes, such as duplications, deletions, inversions or rearrangements of a large number of bases.

39. Medical Genetics Dynamic mutation The term ‘ dynamic mutation ’ was introduced to distinguish the unique properties of expanding, unstable DNA repeat sequences from other forms of mutation. The past decade has seen dynamic mutations uncovered as the molecular basis for a growing number of human genetic diseases and for all of the characterized ‘ rare ’ chromosomal fragile sites.

40. Medical Genetics While the dynamic mutation mechanism explains some unusual genetic characteristics, unexpected findings have raised new questions and challenged some assumptions about the pathways that lead from mutation to disease.

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42. 3. Result of mutation missense mutation When a single base pair causes the substitution of one amino acid for another, it is called a missense mutation.

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46. nonsense mutation When a single base pair change, deletion or insertion result in the generation of a premature translation termination because of the generation of a new stop codon, this is called a nonsense mutation.

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49. Frameshift mutations Frameshift mutations are the result of a single base, or more, insertion or deletion. The result can be the generation of an entirely different protein from the point within the coding region where it occurs.

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53. Because they may involve many bases or just one, frameshifts are sometimes macroalterations and sometimes microalterations.

54. Medical Genetics 4. functional effects of the change. 4. functional effects of the change. Morphological Mutants have altered shape.

55. Medical Genetics Lethal Mutants die as a result of having the mutation, can be dominant or recessive, but most often are recessive. This makes sense because there are so many enzymes an organism must have to live; if both copies are defective, the organism would fail to survive.

56. Medical Genetics Conditional Mutants are normal under one condition (permissive), but abnormal under another (restrictive). These are extremely useful for studying processes such as development and DNA replication.

57. Medical Genetics Biochemical Mutants cause defects in biochemical pathways for a substance, which is then deficient.

58. Medical Genetics Loss-of-Function mutations cause a loss of function that is found normally in wild-type.

59. Medical Genetics Gain-of-function mutations create a new function not normally found in the wild-type. Hairy-faced people would be an example.

60. Medical Genetics A seven-month old baby with a genetic mutation that boosts muscle growth is seen in an undated black and white image released by the New England Journal of Medicine on Wednesday June 23, 2004. The discovery, reported in Thursday's New England Journal of Medicine, represents the first documented human case of such a mutation. The boy's mutant DNA segment was found to block production of a protein called myostatin that limits muscle growth.

61. Medical Genetics 5.Genetic Effects of mutation Another classification of mutations has to due with multicellular organisms where cells might belong to the germ-line, if they contribute genetic information to future generations; or, if part of the body that will never contribute genetic information to future generations, the somatic cell line.

62. Medical Genetics Somatic mutation is one that will never contribute to the germ-line of the effected individual. Germinal mutation is one that occurs in a cell that is a progenitor to a germ cell(s). For example, if a human embryo sustains a mutation in a cell that later becomes a germ cell: a sperm or egg, it is a germinal mutation. –Otherwise, it is a somatic cell mutation.

63. Medical Genetics 6. Repair of Mutation There are many different repairs systems used by organisms.

64. Medical Genetics Photolyase Repair of pyrimidine dimers is the simplest system to understand, and is quite interesting. An enzyme, photolyase, sits on top of the dimer, then using a wavelength of light longer than U.V. as a source of energy, it breaks the cross-links to restore the DNA to its original form.

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66. Excision Repair can be considered the second choice for repair of pyrimidine dimers. It is more complicated and involves removing a whole stretch of a strand of DNA, which leaves a section of single-stranded DNA followed before and after by double-stranded.

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68. Postreplication repair involves recombination between single-strands of daughter double-stranded DNA near the replication fork

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70. Error-Prone repair will be are last example of the sample of the many repair systems. It is also called error prone repair. It eliminates gaps as a last ditch effort to preserve a chance at life. It basically adds whatever bases, but at least usually the right number of bases. It is probably responsible for most of the observed transversions.

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