Mutations and mutagenesis MPH 19 1-15

Mutations and Mutagenesis

1. DNA Mutations and Mutagenesis MPH 1-19-15

2. Learning Objectives By the end of this lecture……….we all should be able to appreciate: The definition of mutation Chromosome and gene mutations Types of Mutagens

3. Mutation A heritable alteration or change in the genetic material.

4. Why mutations occur? Spontaneously Exposure to mutagens

5. Types of Mutation

6. Types of Mutations

7. Substitution

8. Substitution A substitution is the replacement of a single nucleotide by another . M ost common type of mutation. If substitution involves replacement by the same type of nucleotide Two types: Transition: (More frequent) A pyrimidine for a pyrimidine (C for T or vice versa) A purine for a purine (A for G or vice versa); Transversion : A pyrimidine by a purine A purine for a pyramidine

9. Substitution/Point Mutation

10. Deletion Loss of one or more nucleotides. Small deletions may lead to frame shift Larger deletions may result in partial or complete gene deletions and may arise through unequal crossover.

11. Insertion

12. Insertion An insertion involves the addition of one or more nucleotides into a gene. Small insertions may lead to frame shift. Tri-nucleotide repeat sequences Unstable trinucleotide repeats may be within coding or non-coding regions of genes and hence vary in their pathogenic mechanisms

13. Frameshift Mutation

14. Chromosomal Rearrangements

15. Trinucleotide Repeats

16. Trinucleotide repeats

17. Polymorphisms Sequence variants with no obvious effect upon phenotype may be termed polymorphisms.

18. Structural Effects of mutations Non-synonymous mutations Missence Nonsence Frameshift Synonymous mutations

19. Non-synonymous mutations If a mutation leads to an alteration in the encoded polypeptide, it is known as a non-synonymous mutation.

20. Missense Mutations A single base-pair substitution can result in coding for a different amino acid and the synthesis of an altered protein, a so-called missense mutation.

21. Nonsense Mutations A substitution that leads to the generation of one of the stop codons will result in premature termination of translation of a peptide chain, or what is termed a nonsense mutation.

22. Frameshift mutations If a mutation involves the insertion or deletion of nucleotides that are not a multiple of three, it will disrupt the reading frame and constitute a frameshift mutation.

23. MUTATIONS IN NON-CODING DNA In general, mutations in non-coding DNA are less likely to have a phenotypic effect. Exceptions include mutations in promoter sequences or other regulatory regions that affect the level of gene expression. Mutations in miRNA or siRNA binding sites within UTRs are also likely to result in disease

24. What causes mutations? Spontaneous Mutations Mistakes in replication Induced Mutations Caused by a mutagen Mutagens Chemical Physical

25. Radiation can cause mutations

26. Effects of UV Radiation Thymine dimers Base pairing on opposite strand does not occur Polymerase skips during replication Fortunately these are repaired

27. Effect of UV on DNA structure

28. Ionizing radiation Any radiation capable of displacing electrons from atoms or molecules, thereby producing ions. Causes breaks in the phosphodiester backbone, DNA cannot be replicated unless repaired Some examples are alpha, beta, gamma, and X-rays Causes formation of free radicals, and toxic oxygen .