Chapter 12 Mutation A change in the nucleotide sequence of a gene 1 If present in 1 polymorphism May occur at the molecular or chromosomal level The effect of mutations vary Loss of function most are recessive no protein too much protein wrong protein Gain of function dominant alters function in positive way Mutant refers to an unusual phenotype the result of a mutation Types of Mutations 1 Cells 2 Cause a Somatic b Germinal gametes a Spontaneous Induces b 3 Outcome what happens to the DNA itself when it mutates Somatic Mutations Affects subsequent somatic cell descendants Occur in any cell of the body except the germline gametes Not transmitted to offspring Happens during your lifetime cancers Germline Mutations Mutations that occur in the germline cells Possibility of transmission to offspring Full of Hemoglobin alpha and beta chains normal protein forms Glu glumatic acid Mutation sickle cell anemia changes base to A creates valine instead Hemoglobin sticks together Sickle Cell Anemia Mutation encodes valine in place of glutamic acid Phenotype associated with homozygotes autosomal recessive Altered surface of hemoglobin allows molecules to link in low oxygen conditions Creates sickle shape of RBC Sickling causes anemia joint pain and organ damage when RBC become lodged in small blood vessels Hemoglobin is linked and stick together Makes RBCs rigid and block vessels Heterozygotes have advantage against malaria Homozygous Dominant normal Heterozygous sickle cell trait carrier may present problems but is rare Homozygous Recessive full blown disease Thalessemia Caused by another beta hemoglobin mutation Too few beta hemoglobin molecules Excess of alpha hemoglobin leads to iron release which destroys RBC damages heart liver and endocrine glands Thalassemia minor Heterozygous mild usually asymptomatic Thalassemia major homozygous recessive for mutation and more severe Collagen 60 of protein in bone tissue 50 90 of proteins in connective tissues most abundant protein comes from about 35 genes Mutations in Collagen Mistakes made in the folding One gene one disorder One gene multiple disorders One Gene different disorders in different tissues Spontaneous Mutation Errors in DNA replication Not caused by exposure to known mutagen chemical outside substance DNA bases have slight chemical instability Exist in alternating forms called tautomers bases As replication fork unzipping genes encounters unstable tautomers mispairing can occur Grab unstable version and add it to a base its not supposed to pair with g is unstable and fits well enough causes problems later 2 different base pairs this location Hairpin loop this gets skipped because it has folded in on itself DNA polymerase cannot get to it Induced Mutations Caused by mutagens many are also carcinogens and cause cancer outside interference Examples remove a base add or remove base add ethidium bromide to detect changed break chromosomes delete a few nucleotides creates thymidine dimers thymines bond together and cause kinks in Alkylating agents Acridine dyes X rays UV radiation DNA which can lead to skin cancer Ionizing radiation charges atoms gamma penetrates everything in its path Point Mutations A change of a single nucleotide Simplest type of mutation Transition in point mutation purine replaces purine A to G or G to A pyrimidine replaces pyrimidine C to T or T to C Transversion in point mutation purine replaces pyrimidine or pyrimidine replaces purine A G to T C or T C to A G Missense Mutation Point Mutation A type of point mutation that changes the codon Causes a substitution of an amino acid Missense mutations may affect protein function severely mildly or not at all Example Hemoglobin mutation Glutamic acid to valine causes sickle cell anemia Nonsense Mutation point mutation A point mutation changing a codon for an amino acid into a stop codon Creates truncated proteins that are often nonfunctional Some have dominant effects due to interference with normal functions A factor XI deficiency is a nonsense mutation changing glutamic acid to a stop Short protein cannot function in clotting leads to Hemophilia type C Example Splice Site Mutations slice site where intron exons meet and become separated Alters a site where introns are normally removed Intron translated recognition site removed intron stays in or exon skipped recognition site added exon gets deleted Examples CF mutation Cl channel doesn t work properly causes build up of mucous in lungs BRCA1 breast cancer missense mutation Familial dysautonomia FD Example of slice site added Second exon is cut out exon chain doesn t fit together Insertions or Deletions The genetic code is read in triplet nucleotides Addition or subtraction of nucleotides not in multiples of three leads to a change in the reading frame CTA CAA TAG G CTA CAT AGG Causes a frameshift and alters amino acids after mutation Addition or subtraction of nucleotides in multiples of three leads to addition or subtraction of entire amino acids Expanding Repeats Insertion of triplet repeats leads to extra amino acids TAT CAT TAT CAT CAT Some genes are particularly prone to expansion of repeats Number of repeats correlates with earlier onset and more severe phenotype more repeats means a shorter fuse and earlier onset of disease Anticipation is the expansion of the triplet repeat with an increase in severity of phenotype with subsequent generations each generation has a more sever version than the one before Example Huntington Disease 10 35 repeats normal 40 121 repeats disease Factors that lesson the effect of mutation Mutations are necessary for genetic variation 1 Synonymous codons change that still produces the same amino acid 3rd position wobble only change is in the third spot makes similar codon silent mutation 2 Second position similar amino acid produced chemically lessens change to protein 3 Conditional mutation specific environment causes these Example G6PD deficiency can cause anemia Triggers include illness certain infections painkillers fever reducing drugs and antibiotics Excision Repair Damaged DNA is removed by excision cut out and replaced of the bases Bases are replaced by a DNA polymerase Nucleotide excision repair Replaces up to 30 bases Used in repair of UVB and some carcinogens Base excision repair Replaces 1 5 bases Repairs oxidative damage oxygen free radicals Repairing Strand Breaks Both strands enzymes get information from sister chromatid or homologous chromosome and repairs it One strand