Genetics Chapter on Mutations

Mutation

• Mutations alter the nucleotide sequences of genes.
• Examples include substitution of one base pair for another or deletion or addition of one or more base pairs.

Base Substitutions

• A transition replaces a pyrimidine with another pyrimidine or a purine with another purine.
• A transversion replaces a pyrimidine with a purine or a purine with a pyrimidine.
• There are 12 different possible base substitutions in DNA.

Tautomeric Shifts

• Movement of hydrogen atoms within a base can occur.
• This shifts the base to different tautomeric forms (rare form).
• The shift in position causes changes in base form.
• Rare forms cause incorrect base pairing during DNA replication.

Tautomeric Shifts Affect Base Pairing

• Hydrogen-bonded A:C and G:T base pairs form when cytosine and guanine are in their rare imino and enol tautomeric forms.
• These pairings lead to permanent changes in the DNA sequence, causing mutations during replication.

Mutation Caused by Tautomeric Shifts

• Rare enol tautomeric form of guanine (G*) pair to Thymine (T) during DNA replication
• Results in a mutation of the DNA sequence.
• This change is carried over to the daughter cells.

Simple Tandem Repeats

• These are sequences of nucleotides that repeat consecutively (e.g. CCG, GAGCC).
• Trinucleotide repeats have increased copy numbers, causing inherited diseases.
• Examples include CCG repeats (6 to 50 copies) on the X chromosome causing Fragile X Syndrome.
• Other repeats (CAG and CTG) lead to Huntington's disease and spinocerebellar ataxia.
• Disease severity increases as the trinucleotide repeat copy number increases.

Mutations by Transposons

• Transposable elements (jumping genes) move within the genome.
• Their movement can cause gene disruptions and mutations.
• Results in the addition or deletion of genes, altering the original DNA sequence.
• This might result in an active gene product or truncated/inactive one.

Factors Influencing Rate of Spontaneous Mutations

• Accuracy of DNA replication machinery.
• Efficiency of DNA repair mechanisms for damaged DNA.
• Degree of exposure to environmental mutagens.

Induced Mutations

• Mutations occur due to exposure to physical or chemical mutagens.

Physical Mutagen

• Hermann J. Muller and Edgar Alternburg measured the frequency of X-linked recessive lethal mutations in Drosophila.
• Muller demonstrated that exposing Drosophila sperm to X-rays increased mutation frequency.
• Irradiation dosage correlates with mutation frequency.

Electromagnetic Spectrum

• Electromagnetic radiation with higher energy levels have more potential to cause mutation.

Mutagenesis by Ultraviolet Irradiation

• Hydrolysis of cytosine to a hydrate may lead to mispairing during replication.
• Cross-linking adjacent thymine forms thymidine dimers, blocking DNA replication.

Ionizing Radiation Causes Changes in Chromosome Structure

• Ionizing radiation breaks chromosomes and causes deletions, duplications, inversions, and translocations.

Types of Chemical Mutagens

• Chemicals mutagenic to both replicating and non-replicating DNA include alkylating agents and nitrous acid.
• Chemicals mutagenic only to replicating DNA include base analogs and acridine dyes.

Alkylating Agents

• Chemical mutagens that donate alkyl groups to DNA molecules.
• Induce transitions, transversions, frameshifts, and chromosome aberrations.
• Change base-pairing properties of both replicating and non-replicating DNA.
• Can also activate DNA repair mechanisms.

Chemical Mutagens - Alkylating Agents (Examples)

• Di-(2-chloroethyl) sulfide (Mustard gas)
• Ethyl methane sulfonate (EMS)
• Ethyl ethane sulfonate (EES)

Ethyl Methane Sulfonate (EMS)

• Add ethyl group to Guanine, becoming 7-ethylguanine
• 7-ethylguanine base pairs with Thymine instead of Cytosine.
• Resulting in a transition from G:C to A:T.
• When DNA replicates, GC pairs converts to AT pairs during DNA replication.

Chemical Mutagens - Deamination Agent (Nitrous Acid)

• Acts on either replicating and non-replicating DNA.
• Converts amino groups to keto groups.
• Converts adenine to hypoxanthine, causing AT to GC transition.
• Converts cytosine to uracil, resulting in GC to AT transition.
• Oxidative deamination of bases causes changes in their chemical structure.

Base Analogs

• Structures similar to normal DNA bases.
• Incorporated into DNA during replication.
• Examples include 5-Bromouracil and 2-Aminopurine.

A Base Analog: 5-Bromouracil

• 5-Bromouracil mimics thymine.
• Can pair with either adenine or guanine.
• In its keto form, 5-Bromouracil pairs with adenine.
• In its enol form, 5-bromouracil pairs with guanine.
• This change in pairing during replication leads to mutations.

Mutagenic Effects of 5-Bromouracil (5-BU)

• 5-BU can mimic T or C bases in DNA.
• Depending on its form (enol or keto), 5-BU base pairs with inappropriate bases during replication.
• Lead to A:T to G:C changes.

Chemical Mutagens - Acridines Dyes

• Induce frameshift mutations.
• Intercalate between stacked base pairs.
• Acridine dyes become inserted between base pairs.
• During replication, they can cause insertions or deletions of one or more base pairs.
• The frameshift mutations cause changes in the reading frame of the genetic code resulting in changes in the amino acid sequence of the protein.

Explore the fascinating world of mutations and their impact on genetic sequences. This quiz covers base substitutions, tautomeric shifts, and their roles in causing permanent changes in DNA during replication. Test your understanding of these critical concepts in genetics.