Mutagens, types of mutations

MICROBIOLOGY

1. MUTAGENS & TYPES OF MUTATIONS PRESENTED BY: MOUSAMI JARIA ST. GEORGE COLLEGE OF MANAGEMENT AND SCIENCE MSC MICROBIOLOGY SEMESTER - 2

2. INTRODUCTION Mutagens are the known agents either physical, chemical or biological cause mutations by altering the genotype or gene expression which results in genetic abnormality. Not all mutations are caused by mutagens only induced mutations were caused by mutagens. Spontaneous mutations are naturally occuring mutations. Mutagens causing cancer, are likely to be known as carcinogens .

3. DISCOVERY The first mutagens to be identified were carcinogens . The mutagenic property of mutagens was first demonstrated in1927 by Muller , he discovered that X-rays can cause genetic mutations in fruit flies. Edger Altenburg also demonstrated the mutational effect of UV radiation in 1928. Charlotte Auerbach and J.M Robson found that mustard gas can cause mutations in fruit flies.

4. EFFECTS At chromosomal level mutagens alter the structure or number of chromosomes, as deletion, duplication, insertion, translocation, monosomy and nondisjunction are some of the chromosomal abnormalities caused by mutagens. Teratogens are class of the mutagens which causes congenital malformations. Eg : X-rays, valporate , toxoplasma . Carcinognes are the class of mutagens which induces tumour formation and thus cause cancer.

5. Carcinogenic agents include X-rays/ UV rays, aflatoxins , retrovirus etc. Clastogens are the class of mutagens responsible for chromosomal –breakage, deletion, duplication and rearrangements. UV rays, bleomycins , HIV virus are common type of clastogens . Mutagens also alters the codon , deletes bases, alters bases, breaks hydrogen bonds, phosphodiester bonds or changes gene expression .

6. TYPES OF MUTAGENS Three different types of common mutations are observed in nature physical, chemical & biological agents. Many mutagens are not mutagenic by themselves , but can form mutagenic metabolites through cellular process. Such mutagens are called promutagens . Physical agents: Heat and radiation Chemical agents : Base anlogues

7. Intercalating agents Alkylating agents Deaminating agents Metal ions Biological agents : Viruses Bacteria Transposons .

8. PHYSICAL MUTAGENS RADIATION: The first mutagenic agent reported in1920. Radiations directly damage the DNA or nucleotide structure which might be either lethal or sub lethal Radiation causes cross linking of DNA or protein, chromosomal break, stand break or loss of chromosomes. At the molecular level it causes deletion of bases or DNA strand bases.

9. X-RAY RADIATION : X-rays are one of the most common types of ionizing radiation used in many of the medical practices. At molecular level the lethal dose of X-ray (350-500rems) breaks phosphodiester bonds between DNA and thus results in strands breakage. It causes multiple strand breakage. If strand breakage occurs in both the strands , it becomes lethal for cell.

10. b. UV- rays : It is non ionizing type of radiation having less energy in it. The major causes of UV radiation are base deletion ,strand breakage, cross linking and generation of nucleotide dimers . UV induced mutations are dimer formation, thymine-thymine dimer & thymine-cytosine dimers are commonly formed as the lesions block replication as well as transcription. Formation of pyrimidine dimerization cause distortion in structure of DNA and prevents formation of replication fork.

11. CHEMICAL MUTAGENS BASE ANALOGS : They are similar to the bases of DNA- purine and pyrimidines or structurally resemble the DNA bases. Bromouracil and aminopurine are two common base analogs incorporated in DNA instead of normal bases. Bromouracil pairs with adenine as like the thymine and causes mutation . Aminopurines cause AT to GC or GC to AT transition during replication.

12. ALKYLATING AGENTS : Ethylnitrosourea , mustard gas and vinyl chloride are common alkylating agents, add alkyl group to the DNA and damages it. The agents cause base pairing errors by increasing ionization and produces gaps in DNA strand. Alkylated purine bases are removed by the phenomenon called depurination . Common alkylating agents are : Methylhydrazine , Temozolomide , Busulfan , Thio -TEPA, Dimethyl sulphate , Ethyl ethane sulphate .

13. INTERCALATING AGENTS : Ethidium bromide, proflavine , acridine orange are few intercalating agents. The molecules intercalate between the bases od DNA & disrupt its structure. If incorporated during replication, it can cause frameshift mutation. It may also block transcription. METAL IONS: Nickel, chromium, cobalt, cadmium are common metal ions that cause mutations.

14. The metal ions work by producing ROS(reactive oxygen species), hindering DNA repair pathway, cause DNA hypermethylation or may directly damage DNA. OTHER CHEMICAL MUTAGENS : ROS, benzene, synthetic rubber and rubber products, sodium azide , aromatic amines, deaminating agents etc are other mutagens which create different mutations.

15. BIOLOGICAL MUTAGENS Viruses, bacteria and transposon are biological mutagens. VIRUS: Virus insert their DNA into our genome and disrupt the normal function of DNA or a gene. Once it inserts DNA, the DNA is replicated transcribed and translated viral protein instead of our own protein. Eg : HIV.

16. BACTERIA: Some bacteria can cause inflammation . It provokes DNA damage and DNA breakage . TRANSPOSONS: They are non coding DNA sequences, jumps from one place to another in a genome and influence function of genes .

17. TYPES OF MUTATIONS The sequence of a gene can be altered in a number of ways. The types of mutation includes: Point Mutation Transition Transversion Missense Nonsense Silent Frameshift Mutations.

18. POINT MUTATIONS A point mutation or single base substitution is a type of mutation that causes the replacement of a single base nucleotide with another nucleotide of genetic material. There are three types : Missense , nonsense and silent. It is a random SNP( single nucleotide polymorphism) mutation in DNA that occurs at one point.

19. CATEGORIZING POINT MUTATIONS TRANSITION/ TRANSVERSION Categorizaton : In 1959 Ernst Freese coined the terms ‘’transitions’’ or ‘’ transversions ’’ to categorize different types of point mutations. Transition: replacement of a purine base with another purine or replacement of pyrimidine with another pyrimidine . Transversion : Replacement of purine with a pyrimidine or vice versa.

20. FUNCTIONAL CATEGORIZATION : MISSENSE MUTATIONS: This type of mutation is a change in one DNA base pair that results in the substitution of one amino acid for another in the protein made by a gene NONSENSE MUTATION: Code for a stop , which can shorten the protein. A nonsense mutation converts an amino acid codon into termination codon Causes the protein to be shortened .

21. SILENT MUTATION : Codes for same amino acid. No effect on functioning of protein Silent mutations are changes in the sequence of codon that do no alter the encoded amino acid.

22. DISEASES CAUSED BY POINT MUTATIONS Sickle cell anemia : Caused by point mutation in the beta- globin chain of haemoglobin , causing the hydrophillic amino acid glutamic acid to be replaced with the hydrophobic amino acid valine at sixth position. Cystic Fibrosis : A defect in cystic fibrosis transmembrane conductance regulator (CFTR) gene causes cystic fibrosis. This causes thick, sticky mucus, salty sweat. Color blindness

23. FRAMESHIFT MUTATIONS This type of mutation occurs when the addition or loss of DNA base changes a gene’s reading frame. Reading frame consists of group of three bases that each code for one amino acid A frameshift mutation shifts the grouping of these bases and changes the code for amino acids Resulting protein is usually nonfunctional Insertions, deletions and duplications can all be frameshift mutations.

24. INSERTION : Mutations in which extra base pairs are inserted into a new place in the DNA. DELETION: Mutations in which sections of DNA is lost, deleted . DUPLICATION: A duplication consists a piece of DNA that is abnormally copied one or more times . May alter the function of resulting protein.

25. DISEASES ASSOCIATED Hypertrophic Cardiomyopathy : Most common cause of sudden death in young people, athelets . Caused by mutations in genes encoding proteins of the cardiac sarcomere Mutations in Troponin C gene (TNNC1). Tay -Sachs Disease : Fatal disease affecting central nervous system. Found in infants and children.

26. Tay sachs disease

27. Smith Magenis Syndrome : Complex syndrome involving intellectual disabilities, sleep disturbance , behavioural problems and a variety of craniofacial, skeletal, visceral anomalies Cystic Fibrosis. Crohn’s Disease : Affects intestine in humans. Fat wraps around the intestine.