1. Mutations

2. Learning Objectives By the end of this class you should understand: The pedigree of a spontaneous mutation The concept of mutation rates and how they can be measured Sources of mutations Types of mutations The consequences of lengthening repeated sequences of DNA Mechanisms of DNA repair The role of gender in DNA imprinting

3. Mutation Any change in the DNA of a cell is a mutation A certain number of mutations occur every time DNA is replicated or exposed to mutagens – If a somatic cell (adult or stem cell) mutates it may affect the individual – If the gametes mutate, the mutation is passed on to offspring

4. Mutation Rate The number of new mutations can be measured indirectly – Much easier to do on dominant mutations Pedigree can track where a mutation originated

5. Mutation Rate The more vital a gene is, the lower its mutation rate – Why? Most mutations are lethal! This can be used to estimate how closely related animals are to each other

6. Mutation Rates of Genes

7. Mutagens There are many mutagens – Similar list to teratogens Radiation – Includes ordinary radiation from space (background radiation) Chemicals – Typically bind to DNA

8. Radiation Sources

9. Radiation Damage High-energy light (UV, X- rays) and nuclear radiation can alter DNA Prominent example: UV light can cause two adjacent thymines to connect (thymine dimer) This interferes with DNA replication, causing many errors around the dimer

10. Mutagenic Chemicals One class of chemical mutagen is base analogs that mimic a DNA base 5-bromouracil is added to DNA as though it were thymine, but pairs with guanine If not repaired, mutates DNA after replication 5'-ACGTAGA-3' #1 3'-TGCABCT-5' #2 Replication: 5'-ACGTAGA-3' #1 3'-TGCATCT-5' 5'-ACGTGGA-3' 3'-TGCABCT-5' #2

11. 5-Bromouracil

12. Base Modification DNA bases are also sensitive to modification by chemicals such as nitrous acid

13. Other Chemical Mutagens Acridine Orange and Ethidium Bromide bind to DNA and twist its shape Damages DNA in a way that is not easy to repair – Ethidium bromide is a DNA fluorescent stain May cause more complex mutations than the previous point mutations

14. Mutation Types There are structural and functional classifications of mutations Structural: what has happened to the DNA sequence – Point mutation/Substitution – Insertion – Deletion – Inversion

15. Functional Classifications If a mutation has not effectively changed anything it is a silent mutation If a mutation changes the amino acid sequence it is a missense mutation If a mutation causes the amino acid sequence to lengthen it is a sense mutation If a mutation ruins the amino acid sequence it is a nonsense mutation

16. Frameshift Mutations Many insertions and deletions (of 1 or 2 bases) cause the reading frame to change THE FAT CAT ATE HIS HAT (normal) THE FAT BAT ATE HIS HAT (point) THF ATC ATA TEH ISH AT (frameshift) These may produce nonsense or sense mutations, rarely a missense and never a silent

17. Functional Mutation Classifications

18. Allelic Expansion Some genes have repeated sequences that may be accidentally expanded – This is called allelic expansion These sequences, usually three repeated DNA bases, may be vital to the gene function Expansion may reduce expression or completely deactivate the gene

19. Allelic Expansion A number of genetic disorders are caused by allelic expansion of the repeated sequence This expansion may also get worse with each generation

20. Anticipation If a genetic disorder appears sooner and/or stronger in each subsequence generation it may be suffering from anticipation Caused by ever- increasing allelic expansion of the defective gene

21. DNA Repair DNA is subject to normal errors in addition to radiation and chemicals Many repairs are caught and fixed automatically in DNA replication and when cells are inactive

22. DNA Repair Failure Xeroderma pigmentosum is a genetic failure of DNA repair molecules Normally repair thymine dimers and other UV damage Extremely sensitive to sunlight and blacklights Individuals are at great risk of skin cancer

23. Mutations and Proteins Hemoglobin is a prominent example of a single point mutation causing sickle cell anemia Cystic fibrosis is caused by many different possible mutations on the CFTR gene – Some more severe than others!

24. Mutation and Cancer Thursday's lesson!