Genetics Lecture Notes - DNA Mutation (PDF)

Genetics DNA Mutation LECTURE (10) DR. El-Sawy 0  Genetics DNA Mutation Def  Permanent change...

Genetics DNA Mutation LECTURE (10) DR. El-Sawy 0  Genetics DNA Mutation Def  Permanent change of base sequence of nucleotides.  Acc. to size: a. Gross at chromosome level. b. Small at DNA level.  Acc. to cell type: Germinal mutations Somatic mutations Occur in germ cells. Occur in somatic cells. Can be transmitted to Cannot be transmitted to future generations offspring Types 1. Defect in mRNA. General 2. Defect in polypeptide chain. Effects 3. Defect physiological function of proteins. DR. El-Sawy 1  Genetics DNA Mutation 1. Uncorrected replication errors 2. Transcription errors 3. Spontaneous mutations : Spontaneous depurination CAUSES Oxidative deamination of cytosine to uracil 4. Induced mutations: caused by mutagens Physical Chemical Biological DR. El-Sawy 2  Genetics DNA Mutation  Some DNA damage results in modified nucleotide or small group of nucleotides that cannot be read by RNA polymerase.  When RNA polymerase complex reache these spots they will bypass damage by adding in nucleotides in an effort to continue going, even if it means putting in the wrong thing.  This process is known as transcriptional mutagenesis → it may play significant role in development of cancer. Oxidative deamination of cytosine Spontaneous depurination to uracil  Purine base → less stable than  If not repaired before replication: pyrimidine under normal condition. Adenine will pair with the  N glycosidic bond (linking purine to template strand containing uracil sugar phosphate of DNA) → (adenine replace guanine) → usually broken. producing serious mutation.  If not corrected before replication: C=G base pairing in parent DNA Any base may be added to replaced by T-A pairing in complement the missing base offspring. during replication. DR. El-Sawy 3  Genetics DNA Mutation Definitions: Induced Mutations  Mutation occur when cells exposed to external mutagens. Mutagens  Physical, chemical or biological agent can cause mutation. Causes of induced mutation : 1. Ionizing radiation: gamma & X-rays. 2. Non ionizing ration Physical a) UV radiation b) Electromagnetic (Mobile phone, satellite, computer). ‫فهد بيشرب سجاير‬ a. Free radicals and oxidizing agents. b. Aflatoxin (leading to liver cancer) Chemical c. Hetrocyclic amines (found in over-cooked food) d. Drugs (some of Chemotherapy and antibiotic) e. Cigarette smoke.  Viruses cause cancer: a. Hepatitis C virus (HCV) → Heptocellular carcinoma (HCC) b. Human papiloma virus (HPV) → cancer cervix Biological c. Human Herpes virus (HHV) → sarcoma  Bacteria cause cancer: d. H. pylori → cancer stomach. DR. El-Sawy 4  Genetics DNA Mutation Classification of Mutations Small scale Mutation Large scale Mutation  1-20 base mutation.  Ranged from Exon to whole gene.  Point substitution Mutations  Large deletion  Frame shift Mutation  Inversion  Splicing Mutation  Duplication  Regulatory Mutation  Translocation Definition:  Single base change = one base is replaced by other altering the codon on the mRNA. Types: Transition Transversions  Exchange purine for  Exchange purine for purine (A ↔ G) or pyrimidine (A ↔ C/T) or Point  Exchange pyrimidine for  Exchange pyrimidine for Mutations (base pyrimidine (C ↔ T). purine (C ↔ A/G). substitution) DR. El-Sawy 5  Genetics DNA Mutation Effects OF POINT MUTATION :  Change of one codon to another for the Silent same amino acid. mutations  So no effect on protein production.  Change of one codon to another for a different amino acid. Acceptable: resulting protein not Missense different from normal one mutations Partially acceptable: with partial but abnormal function Non acceptable: non functioning protein Point  Change a normal codon to termination Nonsense Mutations codon mutations  Change a termination codon to one that Sense mutations codes for amino acids. DR. El-Sawy 6  Genetics DNA Mutation  Due to additions or deletions of one or more nucleotides lead to alter the reading frame (reading sequence)  The resulting amino acid sequence may become completely different from the wild type. Frame shift mutations  It's due to alteration of exon-intron junction sequences Splicing  Interfere with mRNA splicing Mutation  May lead to production of abnormal proteins.  Mutation in regulatory element which lead to abnormal Regulatory level of gene expression Mutation  Ranges from abnormal high expression level to no expression level. DR. El-Sawy 7  Genetics DNA Mutation  When number of bases removed from DNA.  Resulting in protein with fewer amino acids than normal. Deletion  Occurs when a portion of a chromosome is repeated. Duplication  Orientation of DNA segment reverses. Inversions  Large DNA segment moves to new location.  It is very common in some cancers  diagnosis of disease.  Example: exchange ( ) chromosomes 9 and 22 in 90% of patients with chronic myelogenous leukemia (CML). Translocations DR. El-Sawy 8  Genetics DNA Mutation Definition:  The study of the molecular basis of benign (anemia) & malignant (leukemia) hematological disorders. Example:  Benign disorders as hemoglobinopathies :  Group of disease related to abnormal hemoglobin synthesis. Def  The best example for point mutation. 1. Sickle cell Disease (SCD) Examples 2. Beta thalassemia. 3. Alpha thalassemia. DR. El-Sawy 9  Genetics DNA Mutation β-Thalassemia Alpha Thalassemia Sickle Cell Disease (SCD) (Cooley’s, Mediterranean Anemia) (α thalassemia) Inheritance Autosomal recessive (AR). Type of  Missense point mutation.  More than 200 different gene mutations.  Large (exon or gene) deletion mutation. mutation  Mutation in codon 6 of beta globin gene (GAG→ GTG) → This change 6th amino acid in beta- chains of HB from  Mutation in α1-globin gene on Causes  Mutations on chromosome 11. glutamic acid to valine. chromosome 16.  This leads to polymerization of Hb & distortion of RBCs into a sickle shape.  Reduced synthesis of hemoglobin beta chain  Decreased alpha-globin production → that results in : excess of β chains in adults. a. ↓↓ amount of hemoglobin A (HbA)  The excess β chains form unstable  Chronic hemolytic anemia. Characterized b. ↑↑ amount of HB A2 and HB F. tetramers (called Hemoglobin H or  Presence of abnormal insoluble by c. microcytic hypochromic anemia HbH of 4 beta chains) which have hemoglobin S (Hb S).  It include all types of mutation. abnormal oxygen dissociation curves.  One patient may have one or more of these mutations. DR. El-Sawy 10