2. 1. Silent Mutations  Change in nucleotide has no effect on amino acid in protein  Occurs:  Introns  Wobble effect

3. Intron Mutations  Variable effects

4. Intron Mutations  m1: Mutations in the promoter region may affect gene transcription may lead to non- functional (null) alleles.promoter  m2: Mutations in exons, if they result in the substitution of an amino acid in the active site or other critical region of the protein, also lead to alleles with modified (reduced) functionality.exons  m3: In contrast, exon mutations that result in changes outside the active sites or at 3rd codon positions may have little or no effect on gene function. These mutations are called silent (if the amino acid is unchanged) or neutral (if the change has no effect).  m4: Mutations at critical positions near intron / exon junctions may affect mRNA splicing and lead to the deletion or retention of entire exons, and result in null alleles.mRNA splicing  m5: Mutations that occur in non-coding introns, or  m6: 5' or 3' flanking portions of the gene, may have little or no effect on gene function. able effects

5. 2. Missense Mutations  Change in DNA base sequence alters a codon  A different amino acid is added to protein  Examples:  Sickle Cell Anemia  Hemophilia

6. Sickle Cell Anemia  GAA  GUA  GLU  VAL

7. Haemophilia  Sex-linked (X-chromosome) disorder that impairs blood clotting  Dominant in males, recessive in females  Used to stop bleeding when a vessel breaks  1 in 5,000-10,000  G  A  GLU  LYS *Affecting the protein necessary for blood clotting

8. 3. Nonsense Mutations  Change in DNA base sequence causes a stop codon to replace a normal codon  Lethal to cell as protein function is lost  DEPENDING ON where the stop codon is  If occurs at beginning of protein sequence  lethal  If occurs at end of protein sequence  may lose function  Example: Thalassemia and DMD

9. Thalassemia  Mutation that reduces the rate at which one protein in hemoglobin (Hb) is synthesized  Creating incomplete or abnormal Hb  lower function  AAG  UAG at the 57 codon of the gene  LYS  STOP

10. DMD = Duchenne Musclar Dystrophy  X-linked trait that causes rapid deterioration of muscles  Loss of motion, then eventual death  Affects in 1 in 3500 males  Females only affected if both parents have allele  C A G or C A A  U A G or U A A  GLN  STOP

11. DMD = Duchenne Musclar Dystrophy  Dystrophin protein no longer functions properly  Responsible for connecting muscle fibers to the basal layer of skin  Absence of dystrophin permits excess Ca2+ to enter the cell  Eventually cell is destroyed from oxidative processes

12. 4. Frameshift Mutations  Change in DNA base sequence causes the reading frame of codon to change due to:  Insertion of base(s)  Deletion of base(s)  *INDEL mutations  Single or double INDEL will cause an amino acid change  Triplet INDEL will have milder consequences  Multiple triplet INDEL can have major effects  Ex. Fragile X, Cystic Fibrosis

13. Fragile X Associated with:  Martin-Bell Syndrome, the most common form of inherited predisposition to mental retardation  Protein FMR1 is not made  Required for normal neural development  Characterized by high amounts of CGG triplet repeats

14. Fragile X

15. Cystic Fibrosis  Recessive disease that causes progressive body wide disability  First recognized in the early 1930s  Scarring of the pancreas  Early death ~35 years old  Symptoms (few of the many):  Difficulty breathing (from lung infections)  Poor growth  Diarrhea  Infertility  1 in 25 people of European descent

16. Cystic Fibrosis  Caused by a mutation in the gene for the protein CFTR  Regulates sweat, digestion processes, and mucus  3 base pairs are deleted  Normal DNA sequence  T A G A A A  A U G U U U  ILE + PHE  Mutated DNA sequence  T A A  A U U  ILE *ILE is still present but we lose PHE

17. 5. Translocation  Transfer of a DNA fragment from one site to another  May get altered function depending on where it was cut Ex. Leukemia

18. Leukemia  An uncontrolled proliferation of one kind of white blood cell (leukocyte)  All descended from a cell that lost ability to maintain cell cycle  Translocation between chromosome 9 and 22  Chromosome 9 is longer than normal  Chromosome 22 is shorter than normal

19. 6. Inversion  Chromosomal segment that has reversed its orientation  No gain or loss of genetic information  But gene may be disrupted  Protein function loss