YIJC [H2 BIOLOGY] CI2.6 DNA Mutations

2024 JC1 BIOLOGY LECTURE NOTES CORE IDEA 2: GENETICS AND INHERITANCE TOPIC 2.6: GENE MUTATION Learning Outcomes: (l) Explain what is meant by the terms gene mutation and chromosomal aberration. For gene mutation, knowledge of how substitution, addition and deletion could change the amino acid sequence (including frameshift) is required. (m) Explain how gene mutations can result in diseases (including sickle cell anaemia) Use the knowledge gained in this section in new situations or to solve related problems. References: Reece, J. B. et al. (2018). Campbell Biology (11th Ed). Chapter 17: From Gene to Protein, pp407 – 410. Reece, J. B. et al. (2018). Campbell Biology (11 th Ed). Chapter 15: Linkage and Chromosomes, pp356 – 359. Note: This textbook is available in our library. You may wish to borrow it to supplement your reading when necessary. CONTENTS 1. Introduction 2. Point Mutations 2.1 Base-pair substitution a) Consequence 1: Missense Mutation b) Consequence 2: Nonsense Mutation c) Consequence 3: Silent Mutation 2.2 Base-pair insertion/deletion a) Frameshift Mutation 3. Sickle Cell Anaemia H2

2 1. Introduction Genetic information is stored in linear sequences of base-pairs in DNA. Transcription and translation convert this genetic information into polypeptides, which become functional proteins. Mutations are changes in the nucleotide sequen ce o f DNA or structure/number of the chromosome. This results in an alteration to an organism’s phenotype. Mutation can be spontaneous (e.g. errors during DNA replication resulting in base pair mismatches) or induced by a mutation-causing agent (e.g. Ethidium Bromide) DNA mutations can have numerous biological implications  Disease causing (e.g. mutations to proto-oncogenes contribute to onset of cancer)  Creation of new gene variants, which contributes to diversity of genes and allows natural selection and evolution to take place There are two main types of mutation: gene mutation and chromosomal aberration. 1. 2. 3. Transcription Translation 4. Determine phenotype (Observable traits, e.g. hair colour) Recall the Central Dogma of Molecular Biology What is the significance of a change in DNA structure and sequence? DNA mutations Chromosomal Aberrations Numerical Aberrations Structural Aberrations Change in number of chromosomes Change in structure of chromosomes Gene mutations Involves chemical changes in linear DNA sequence Change in DNA nucleotide sequence More will be elaborated on in Topic 2.7 Focus of this topic (Topic 2.6)

3 What is the relationship between gene mutation and protein synthesis process? Mutation in DNA resulting in change in …………………………… Change in …………………………….. Change in …………………………….. Affect ……………… of polypeptide into specific …………………………….. Change in ……………………….. Change in ………………………..

4 2. Point Mutations Gene mutation is a change in the sequence of nucleotide bases of DNA in a particular gene. A point mutation usually refers to a single nucleotide base change in a gene. There are 3 different ways that DNA sequence can be changed. 1. Substitution 2. Insertion 3. Deletion 2.1 Base-pair Substitution Substitution mutation replaces one base with another. Fig 2.1.1: Substitution mutation, where Cytosine in DNA is substituted with a Thymine Learning Outcome 2(l) modified: Explain what is meant by the term’s gene mutation. For gene mutation, knowledge of how substitution, addition and deletion could change the amino acid sequence (including frameshift) is required.

5 Base-pair substitution mutation can result in 3 possible consequences: a) Consequence 1: Missense mutation Missense mutation is when the substitution causes a change in DNA sequence and subsequent change in mRNA codon , eventually resulting in a single amino acid change in the primary structure of the protein. Fig 2.1.2: No DNA mutation present. Fig 2.1.3: Missense mutation as a result of base-pair substitution (T replaces C in DNA template strand), leading to a change in mRNA sequence (A replaces G) and a change in amino acid sequence (from Gly to Ser). IMPORTANT: What happens when the amino acid changed is chemically similar or chemically dissimilar to the original amino acid ? Chemically Similar Chemically Dissimilar Change in amino acid in 1˚ protein structure  new amino acid has same R grp property  No change in folding of polypeptide  No change in specific 3D configuration of protein  No change in function of protein  No change phenotype Change in amino acid in 1˚ protein structure  new amino acid has different R grp property  Change folding of polypeptide  Change specific 3D configuration of protein  Change function of protein  Change in phenotype

6 b) Consequence 2: Nonsense mutation Nonsense mutation is when the substitution results in a premature stop codon (UAG/UAA/UGA) in the resultant mRNA. During translation, the synthesis of the polypeptide is terminated prematurely resulting in a truncated polypeptide chain (a shorter polypeptide chain than usual). Most nonsense mutation frequently results in non - functional protein especially if the mutation occurs at the beginning of the protein. This results in a phenotypic change in the individual. Fig 2.1.4: Nonsense mutation as a result of base -pair substitution (A replaces T in DNA template strand), leading to a change in mRNA sequence (U replaces A). This results in a stop codon (UAG) and polypeptide is truncated. c) Consequence 3: Silent mutation Silent mutations is when the substitution results in change in the DNA sequence and mRNA codon but no change in amino acid sequence. Hence no phenotypic change is observed in the individual. This is due to degeneracy of genetic code. Silent mutations usually occur when the mutation affects the third base of the codon resulting in a degenerate code coding for the same amino acid. Fig 2.1.5: Silent mutation as a result of base-pair substitution (A replaces G in DNA template strand), leading to a change in mRNA sequence (U replaces C) but no change in amino acid sequence. Refer to Fig 3.1.2, both GGC and GGU code for Gly. This is due to degeneracy of genetic code.

7 2.2 Base-pair Insertion and Deletion Base-pair insertion or deletion is the addition or removal of one nucleotide in the DNA sequence. Fig 2.2.1: Insertion and deletion mutation If the base -pair addition or base -pair deletion does not occur in multiples of 3 nucleotides, a frameshift mutation can occur. Frameshift mutations cause a change in the reading frame of the codons, which leads to severe consequences.

8 Frameshift mutation have severe consequences:  nonsense mutation (Fig 2.2.2) or  extensive missense mutation, extensive change of sequence of amino acids downstream of the mutation (Fig 2.2.3). This is usually more severe than substitution mutation as a larger part of the polypeptide will be changed due to the change in reading frame resulting in the change of multiple amino acids downstream of the mutation site. Fig 2.2.2: Frameshift mutation as a result of base-pair insertion (extra A inserted in between 3rd and 4th base in DNA template strand), leading to a nonsense mutation. Fig 2.2.3: Frameshift mutation as a result of base -pair deletion (A at 9 th position removed in DNA template strand), leading to an extensive missense mutation.

9 In Summary, Normal DNA sequence (non-mutated)

10 Checkpoint 1: a) Identify the consequence of mutation shown in each point mutation. Point Mutation Consequence of mutation ……………… ………………