Mutation

for bachelor level student.

1. Mutation Binaya Tamang UCMS-TH

2. Introduction Any sudden change occurring in hereditary material is called as mutation For e.g., Changes in the nucleotide sequence of DNA Can happen at any time : miosis of cell division, during DNA replication, or anytime if DNA is damaged by mutagens Change in phenotype may be seen : DNA  mRNA  protein( enzyme, structural protein, antibody, receptor etc.)

3. Mutagens Simply: mutation + generating  mutagens TWO types Chemical Base analogs: 5-bromouracil Alkylating agents: Ethyl methyl sulfonate, nitrogen mustards Acridine dyes Intercalating agents (Ethidium Bromide) Reactive oxygen species Physical/ Radiation Ionizing ( X-ray, ⍺-ray, β-ray, 𝛾-ray) Non Ionizing –UV rays Thymine dimers

4. Classified based upon Site ( gene or chromosome)  imp Tissue origin ( somatic or germinal) Cause ( spontaneous or induced) Out come ( Silent, missense , Nonsense, frameshift)  imp

5. On the basis of site Two type: a) Gene /point. and b ) chromosomal mutation Gene mutation Due to Substitution Deletion Insertion Lets describe each type Substitution: Transition: same class base is replaced by same type (e.g. purine by purine or pyrimidine by pyrimidine) Transversions : one class of base is replaced by another class ( e.g. purine by pyrimidine or vice versa)

6. Insertions & deletions: Insertion : Addition of one or more nucleotide base pair in a gene. (Huntington's chorea, Duchenne muscular dystrophy) Deletion: Removal of one of more nucleotide pair more nucleotide pair. ( alpha thalassemia , hemophilia , cystic fibrosis)

7. If change is seen in only a single nucleotide  point mutation. Point mutation: Includes the deletion, insertion, or substitution of ONE nucleotide in a gene Best e.g. is Sickle Cell disease  one nucleotide substitution Occurs in the hemoglobin gene.

8. All these changes in gene can show effect  another base of classification Based on effect due to substitution of single base/point mutation. Missense mutation Silent mutation Nonsense mutation due to insertion or deletion of one or more nucleotides ( point + > 1 base ) Frame shift mutation Lets explain each type a) Missense mutation : a base is substituted  alters a codon in the mRNA  a different amino acid ( missense) E.g. HbS or sickle- cell hemoglobin

9. Silent and Non-sense mutation b) Silent mutation : a base is changed but due to degeneracy of the codon, same amino acid coded  mutation is silent and no effect on phenotype. c) Nonsense mutation : changes a sense codon into a nonsense codon or stop codon (UAG,UAA,UGA) . Nonsense mutation early in the mRNA  premature termination of translation. protein is shorter than usual  most likely nonfunctional

10. Frame shift mutation Occurs when bases of not multiple of 3 are added or deleted . It changes the reading frame of codon. Like of sentence THE CAT ATE RAT If one “ C ” is added in front of CAT, the reading frame will be like THE C CA TAT ERA T… ( reading frame is shifted which changes the sentence) R esult s : T otally different amino acids seq uence OR T runcated pr otein due to termination codon. E.g crohn’s dis, Tay -S achs dis

11. 2. Chromosomal/ large scale mutation : Morphological: changes in chromosome structure Deletion Duplication Inversion Translocation Numerical : changes in chromosome number (n) Euploidy Polyploidy Aneuploidy

12. Deletion: a seg. of a chr is deleted Duplication : a seg. of a chr is duplicated Inversion: a seg get cut & attached inversely (180 o ) Translocation: a seg of chr get attached to different chr. Morphological: changes in chr. structure

13. Numerical : changes in chr. number Euploidy: no. of Chr changes by a set (n) n  haploid 2n diploid 3n triploid Many time  polyploid Aneuploidy: no of chr changes by (∓)1 or (∓) 2 in individual chromosome. Human: 2n (diploid). Lets take 12 th chr. Out of 2 , If one chromosome is lost  monosomy: 2n-1 Out of 2 , If both chromosomes are lost  nullisomy : 2n-2 Similarly, if one is added  Trisomy: 2n+1 If two are added  tetrasomy: 2n+2. E.g, Down’s syndrome( trisomy 21), patau syndrome (trisomy 13), Edward syndrome (trisomy 18)

14. Other classification Based on tissue of origin Somatic: vegetative  doesn't transmit to next generation. E.g. Skin cancer Germinal  gametic or reproductive cell  transmitted to next generation. Cause of mutation Spontaneous : spontaneously or naturally with out any intervention of any chemical mutagens. Eg. Methylation followed by deamination of cytosine.Very slow process Induced: due to treatment with either a chemical or physical agent called mutagens. E.g X- rays causing mutation in cereals

15. Mutation and Polymorphism Mutation: Rare Genetic change ( Less than 1%) Alter the function of the protein or the Enzyme. May occur on average 1 on every 10 6 base pairs. Polymorphism: is common variation (greater than 1%) no change in function or small effect occur on average one every 200-1000 base Pairs. Polymorphism is change with no effect in the phenotype.

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