DNA Mutation Dr Eva Masiero 13 th January

DNA Mutation Dr Eva Masiero 13 th January 2020

Learning outcome: 1. Define the principle of DNA mutation and its severity, 2. Analysis of the different types of: Ø gene mutations (point mutation and frameshift) Ø chromosome abnormalities

The Central Dogma • Genes specify the proteins that are made by cells, • the process by which a double-stranded DNA molecule is copied to produce two identical DNA molecules: DNA replication, • DNA strand is copied into a class of messenger RNA: transcription, • The RNA instructs protein synthesis: translation.

The genetic code

What are mutations? Changes in the DNA sequence that affect genetic information

What are mutations? Ø A mutation may results from: • mistake during replication • mistake during DNA repair • a mutagen Ø A mutation may occur in: • somatic cells (are not passed to offspring) • gametes (eggs & sperm)

Are mutations good or bad? BOTH q Some mutations lead to genetic disorder q Some mutation may cause a beneficial trait

DNA mutation types 1. Gene mutations result from changes in a single gene 2. Chromosome abnormality involve changes in whole chromosomes

1. Gene mutations • Change in the nucleotide sequence of the DNA within a gene • May only involve a single nucleotide pair • May be due to copying errors, chemicals, viruses, etc.

1. Gene mutations: good or bad When the mutation happens in: noncoding region may not affect protein folding or the active site. may harmful effect changing the folding or the active domain of the resulting protein

Types of gene mutation Point mutation • Silent mutation • Missense mutation • Nonsense mutation Frame shift mutation • Insertion • Deletion

1. Gene mutations: point mutation A point mutation is a mutation that changes a single nucleotide in the DNA sequence.

1. Gene mutations: point mutation • synonymous mutation: the mutated codon has the same meaning as the original codon • nonsynonymous mutation: the mutated codon does not translate for the same amino acid. https: //www. ncbi. nlm. nih. gov/books/NBK 21955/

1. Gene mutations: point mutation Base substitution could be: Transition: occurs due to an interchange of purines (A ↔ G) or pyrimidines (C ↔ T) in DNA. Transversion: happens when a purine base is substituted with a pyrimidine base, or a pyrimidine base is substituted with a purine base https: //www. differencebetween. com/difference-between-transition-and-vs-transversion/

What is the difference between Transition and Transversion? https: //www. differencebetween. com/difference-between-transition-and-vs-transversion/

1. Gene mutations: point mutation It is divided in 3 categories: § Silent § Missense § Nonsense

1. Gene mutation: Silent mutation Normal DNA m. RNA protein TGC ACA CTT ACG UGU GAA Thr –Cys – Glu Mutant TGC ACG CTT ACG UGC GAA Thr – Cys - Glu The base substitutions results in no change of the amino acid

1. Gene mutation: Missense mutation Normal DNA m. RNA protein TGC ACA CTT ACG UGU GAA Thr –Cys – Glu Mutant TGC ACC CTT ACG UGG GAA Thr – Trp - Glu The mutation has altered the codon resulting in a different amino acid.

1. Gene mutation: Missense mutation

1. Gene mutation: Nonsense mutation Normal DNA m. RNA protein TGC ACA CTT ACG UGU GAA Thr –Cys – Glu Mutant TGC ACT CTT ACG UGA GAA Thr - STOP The mutation has altered the codon resulting in a stop codon amino acid.

1. Point mutation: effects on the protein function • Silent mutation: no effect on protein function • Missense mutation: may or may not have an effect on the protein function • Nonsense mutation: results in absence or truncated protein

1. Gene mutation: Sickle cell anemia • Sickle Cell disease is an example of disease causes by a point mutation • Occurs in the hemoglobin gene • Abnormal hemoglobin causes distorted red blood cells

1. Gene mutation: Frameshift Mutation • Changes the “reading frame” like changing a sentence • Inserting or deleting one or more nucleotides • Proteins are built incorrectly

1. Gene mutation: Frameshift Mutation- insertion Insertion mutation is the addition of one or more nucleotide base pairs into a DNA sequence. 1. Normal 2. Insertion AGC CGA TCC UCG GCU AGG Ser Ala Arg AGC CCG ATC C UCG GGC UAG G Ser Gly Stop

1. Gene mutation: Frameshift Mutation- deletion Deletion mutation is the lost of a nucleotide or a sequence of DNA during DNA replication. 1. Normal AGC CGA TCC UCG GCU AGG Ser Ala Arg 3. Deletion AGC GAT CC UCG CUA GG Ser Leu

1. Frame shift mutation: effects on the protein function Deletion Insertion no function protein

1. Gene mutation: Frameshift Mutation • Cystic fibrosis (CF) is an example of disease causes by a frameshift mutation • Occurs in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. • Abnormal cftr protein causes defective ion transport in/out of the cells resulting in production of a thick mucus.

2. Chromosome abnormality • May involve: – Changing the structure of a chromosome – Changing the number of the chromosome (Aneuploidy, Euploidy/polyploidy)

2. Chromosome abnormality • Four types exist: – Deletion – Inversion – Translocation – Duplication These changes affect protein production by changing the genes on the chromosome. https: //www. thoughtco. com/types-of-chromosome-mutations-1224525

2. Chromosome abnormality : Deletion. • Caused by breakage • A piece of a chromosome is lost If the deletion occurs within a gene that is vital for the survival of an individual, it could cause serious problems and even death for a zygote https: //ghr. nlm. nih. gov/primer/mutationsanddisorders/structuralchanges

2. Chromosome abnormality : Inversion • Chromosome segment breaks off • Segment flips around backwards • Segment reattaches inversions are not as serious and often keep the chromosome working properly. https: //ghr. nlm. nih. gov/primer/mutationsanddisorders/structuralchanges

2. Chromosome abnormality : Translocation • Involves two non-homologous chromosomes • Part of one chromosome is transferred to another chromosome this mutation cause serious problems by having the genes encoded on the wrong chromosome. https: //ghr. nlm. nih. gov/primer/mutationsanddisorders/structuralchanges

2. Chromosome abnormality : Duplication • Occurs when a gene sequence is repeated

Gene mutation vs Chromosome abnormality Gene Mutation Chromosome abnormality Definition A change in the nucleotide sequence in a particular gene An alteration of the nucleotide sequence of a segment of a chromosome which includes many genes Magnitude of the alteration Small-scale Serious alteration Number of genes changes One gene Include many genes Nature of the mutation These is only a slight structural alteration This is either a numerical or a structural changes in the entire DNA strand Ability to correct or repair Can sometimes be corrected It is difficult to be corrected Result Low influence Can be lead to lethal diseases

Learning outcome: 1. Define the principle of DNA mutation and its severity, 2. Analysis of the different types of: Ø gene mutations (point mutation and frameshift) Ø chromosome abnormalities

Drop-in session Friday 17 th January at 3 -4 pm in HB 1. 18

Exercise Given the following normal DNA/protein sequence drawn an example of the each type of DNA mutation: Normal DNA: TAT CCT AAG GAT Protein: Tyr His Pro Lys Val - Silent mutation Missense mutation Nonsense mutation Insertion Deletion

Exercise Given the following mutated DNA sequences – match the type of mutation with sequence Normal DNA CAC AAG TAT CAC Normal protein His Lys Tyr His Insertion Mutated DNA CAC AAA TAT CAC mutated protein His Lys Tyr His Nonsense Mutated DNA CAC AAT TAT CAC mutated protein His Asn Tyr His Deletion Mutated DNA CAC AAG CGC ACC TAT CAC mutated protein His Lys Arg Thr Tyr His Mutated DNA CAC AAG TAG CAC mutated protein His Lys STOP Mutated DNA CAC AAA TCA C mutated protein His Lys Ser Silent Missense

Exercise Draw the different types of chromosome abnormalities

1. Define the principle of DNA mutation 2. Discuss the different types of gene mutations 3. Discuss the different types of chromosomal abnormalities

Reading materials https: //www. nature. com/scitable/topicpage/genetic-mutation-441 https: //ghr. nlm. nih. gov/primer/mutationsanddisorders/genemutation https: //ghr. nlm. nih. gov/primer/mutationsanddisorders/structuralchanges https: //www. ncbi. nlm. nih. gov/books/NBK 21955/