1. silent mutations change in nucleotide has no effect on amino acid in protein occurs: introns ...

1. Silent Mutations

Change in nucleotide has no effect on amino acid in protein

Occurs: Introns Wobble effect

Intron Mutations

Variable effects

Intron Mutations m1: Mutations in the promoter region may affect gene transcription may

lead to non-functional (null) alleles.

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.

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.

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

2. Missense Mutations

Change in DNA base sequence alters a codon A different amino acid is added to

protein Examples:

Sickle Cell Anemia Hemophilia

Sickle Cell Anemia

GAA GUA GLU VAL

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

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

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

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

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

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

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

Fragile X

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

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

5. Translocation Transfer of a DNA fragment from one site to

another May get altered function depending on

where it was cut Ex. Leukemia

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

6. Inversion Chromosomal segment that has reversed its

orientation No gain or loss of genetic information But gene may be

disrupted Protein function

loss