2. Rate of mutations in the Human Genome A study published in Current Biology in 2009, shows that in total, we all carry 100-200 new mutations in our DNA. This is equivalent to one mutation in each 15 to 30 million nucleotides. Fortunately, most of these are harmless and have no apparent effect on our health or appearance.

3. Mutations mutations – errors in the DNA can have a bad resultant effect can have no effect can have a positive resultant effect Mutations are usually not an issue because we have two copies of each gene.

4. Mutations Changes in DNA result in: 1. silent mutations 2. missense mutations 3. nonsense mutations

5. Silent Mutations silent mutation – has no effect on the function of the cell; sequence of amino acids is not affected often found in the non-coding regions (introns) If introns in mRNA are spliced out, then the mutation never surfaces Some amino acids can be coded for by multiple codons. (referred to as redundancy in the genetic code) It is possible that one change in the base pair will still produce the same amino acid

6. Missense Mutation missense mutation – nucleotide sequence is changed such that a different amino acid is coded for protein function may or may not be affected Sickle cell anemia is a result of a missense mutation.

7. Sickle Cell Anemia In the DNA, the mutant template strand has an A where the wild-type template has a T. The mutant mRNA has a U instead of an A in one codon. The mutant (sickle-cell) hemoglobin has a valine (Val) instead of a glutamic acid (Glu). Mutant hemoglobin DNAWild-type hemoglobin DNA mRNA Normal hemoglobinSickle-cell hemoglobin Glu Val C TT C AT G AA G UA 35 35 5353

8. Sickle Cell Anemia

9. Type I diabetes mellitus – a misense mutation Mutations affecting ER processing of insulin, appear to result in loss of β-cells (cells of the pancreas that produce insulin). The severity of the defect, as well as other factors that define the β-cell’s capacity to cope with ER stress, determine the rate of β-cell death and thus the age of onset and severity of clinical disease

10. Nonsense Mutations nonsense mutation – nucleotide sequence is changed such that an amino acid is replaced with an early stop codon short proteins are made; usually digested by proteases nonsense mutations usually are lethal, even if a child is born with a nonsense mutation they usually do not live very long

11. Mutation DNA: 5' - ATG ACT CAC CGA GCG CGA AGC TGA - 3‘ 3' - TAC TGA GTG GCT CGC GCT TCG ACT - 5' mRNA: 5' - AUG ACU CAC CGA GCG CGA AGC UGA - 3' Protein: Met Thr His Arg Ala Arg Ser StopMetThrHisArgAlaArgSer DNA: 5' - ATG ACT CAC TGA GCG CGA AGC TGA - 3‘ 3' - TAC TGA GTG ACT CGC GCT TCG ACT - 5‘ mRNA: 5' - AUG ACU CAC UGA GCG CGU AGC UGA - 3‘ Protein: Met Thr His StopMetThrHis Template Strand

12. Other Types of DNA Changes 1. Point Mutation (Base-Pair Substitution) 2. Frameshift Mutation 3. Chromosomal Mutation

13. Type of DNA Change: Point Mutations point mutation – nucleotide changes where one base pair (bp) is replaced by another bp. Point mutation are specific to one base pair Point mutations are also known as substitution mutations and include silent, insertion and deletion mutations.

14. Silent mutation

15. Type of DNA Change: Frameshift Mutation frameshift mutations – changes in the DNA sequence which modify the translation reading frame 1. Deletions – removal of one or more NTs 2. Insertions – addition of one or more NTs

16. This disease is caused by mutations which occur in a huge gene (>6000 nucleotides) on chromosome 7 that encodes a protein of 1480 amino acids called the cystic fibrosis transmembrane conductance regulator (CFTR). The CFTR protein transports chloride ions out of cells and when mutated causes problems that involves both the lungs and the gastrointestinal tract. This disease results from a number of different mutations in the CFTR gene. These include the deletion of a codon resulting in the deletion of the amino acid phenylalanine, a missense mutation resulting in an aspartic acid being substituted for a glutamic acid, a nonsense mutation resulting in a stop codon instead of one that codes for glycine and hence a truncated protein. Cystic Fibrosis

18. Type of DNA Change: Chromosomal Mutations Sections of chromosomes can break off and reattach abnormally. 1. Translocation mutations 2. Inversion mutations

19. Chromosomal Mutation translocation mutations – large portions of DNA are exchanged

20. Translocation

21. Philadelphia Chromsome Philadelphia Chromsome - is a translocation that fuses parts of chromosomes 9 and 22, which produces a new gene product that functions as an oncogene called Abl, which is implicated in chronic myelogenous leukemia.

22. Chromosomal Mutations inversion mutations – sections of a chromosome are reversed

24. Causes of Mutations 1. spontaneous errors due to enzymes 2. induced errors due to mutagenic agents UV radiation X-rays chemical (Agent Orange) 3. transposable elements

25. Spontaneous Errors A replication error may arise in regions of DNA containing tandemly repeated sequences. This slippage displaces the newly synthesized strand back along the template strand (dark blue), with its 3 ′ end still paired with the template. As a result, the DNA- synthesizing enzymes copy a region of the template strand a second time, leading to an increase in length of nine nucleotides (yellow) in this example

26. Visualization of Mutations

27. Transposable Elements some DNA sequences naturally move themselves around the genome – transposons http://www.youtube.com/watch?v=QHQ4p0vJW2A http://www.youtube.com/watch?v=CuoQNLNYZbU

28. Classwork/Homework Pg. 263 #1-8