1. CS262 Discussion Section 4

2. Agenda for today Brief coverage of mutations. Discussion of material related to HMMs (on the blackboard)

3. Mutation A mutation is a permanent change in the DNA sequence. It can have profound consequences It can severely compromise an organism’s fitness if the change occurs in a vital position in the DNA sequence. A single nucleotide change causes the disease sickle- cell anemia. Note: We will not discuss the molecular mechanisms responsible for the creation of mutations.

5. http://www.defiers.com/sc.jpg

6. Somatic vs Germ line cell lineages

7. Somatic vs Germ line mutations A mutation that occurs in the germ line, is passed on to the next generation. A mutation in a somatic cell is not transmitted to the organism’s offspring. But it may have unfortunate consequences for the individual in whom it occurs (such as cancer) In tracking the genetic changes that accumulate during evolution, we concentrate on events that occur in the germ line.

8. Classification of mutations according to the length of the DNA sequence affected Point mutation A single nucleotide is affected Segmental mutation Several adjacent nucleotides are affected.

9. Classification of mutations according to the effect on the DNA molecule 1. Substitution: The replacement of one nucleotide by another TCTCGCATGGTAGGT AGAGCGTACCATCCA 5’- -5’ -3’ 3’- TCTCGCATGGTAGAT AGAGCGTACCATCTA 5’- -5’ -3’ 3’-

10. Classification of mutations according to the effect on the DNA molecule Substitution mutations in protein-coding regions are classified according to their effect on the protein synthesized. Synonymous: No change in the amino-acid specified. Most of them are silent. (no changes detected at the amino acid level) A synonymous mutation may not always be silent. Non-synonymous: Change in the amino-acid.

12. Non-synonymous (amino-acid altering) mutations could be either Missense mutation: changes the affected codon into a codon that specifies a different amino acid from the one previously encoded. Nonsense mutation: changes a sense codon into a termination codon, thus prematurely ending the translation process and ultimately resulting in the production of a truncated protein.

13. Classification of mutations according to the effect on the DNA molecule 2. Deletion: A block of one or more nucleotide pairs is lost from a DNA molecule. TCTCGCATGGTAGGT AGAGCGTACCATCCA 5’- -5’ -3’ 3’- TCTCTGGTAGGT AGAGACCATCCA 5’- -5’ -3’ 3’-

14. Classification of mutations according to the effect on the DNA molecule 3. Insertion: The addition of one or more nucleotide pairs. TCTCGCATGGTAGGT AGAGCGTACCATCCA 5’- -5’ -3’ 3’- TCTCAAGCATGGTAGGT AGAGTTGCAACCATCCA 5’- -5’ -3’ 3’-

15. Indels Deletions and insertions are collectively referred to as indels, because when two sequences are compared, it is impossible to tell whether a deletion has occurred in one, or an insertion has occurred in the other. In a coding region, an indel that is not a multiple of 3 nucleotides causes a frameshift mutation.

16. Frameshift mutation Shift in the reading frame: The coding sequence downstream of the gap will be read in the wrong phase. Indels may not only introduce numerous amino acid changes… … but may also obliterate the termination codon… …or bring into phase a new stop codon, resulting in a protein of abnormal length.

17. Classification of mutations according to the effect on the DNA molecule Inversion: 180 degree rotation of a segment of the DNA molecule. TCTCGCATGGTAGGT AGAGCGTACCATCCA 5’- -5’ -3’ 3’- TCTTACCATGCGGGT AGAATGGTACGCCCA 5’- -5’ -3’ 3’- Site of inversion

18. Classification of mutations according to the effect on the DNA molecule 5. Recombination: The exchange of a sequence with another. 5’-AACT-3’ 5’-CACG-3’ 3’-TTGA-5’ 3’-GTGC-5’ 5’-AACG-3’ 3’-TTGC-5’ 5’-CACT-3’ 3’-GTGA-5’

19. Spatial distribution of mutations Mutations do not occur randomly throughout the genome. Some regions are more prone to mutate than others (hotspots of mutation). One such hotspot is the dinucleotide 5’-CG-3’ (also called C P G) in which cytosine is frequently methylated in many animal genomes, changing it to 5’-TG’-3’