DNA Mutations and Mutagenesis

MPH1-19-15

Learning Objectives

• By the end of this lecture……….we all should be able to appreciate:

– The definition of mutation

– Chromosome and gene mutations

– Types of Mutagens

Mutation

A heritable alteration or change in the genetic material.

Why mutations occur?

• Spontaneously

• Exposure to mutagens

Types of Mutation

Types of Mutations

Substitution

Substitution• A substitution is the replacement of a single nucleotide by

another. • Most common type of mutation. • If substitution involves replacement by the same type of

nucleotide• Two types:

– Transition: (More frequent) • A pyrimidine for a pyrimidine (C for T or vice versa)• A purine for a purine (A for G or vice versa);

– Transversion: • A pyrimidine by a purine • A purine for a pyramidine

Substitution/Point Mutation

Deletion

• Loss of one or more nucleotides.

– Small deletions may lead to frame shift

– Larger deletions may result in partial or complete gene deletions and may arise through unequal crossover.

Insertion

Insertion

• An insertion involves the addition of one or more nucleotides into

• a gene. • Small insertions may lead to frame shift.

• Tri-nucleotide repeat sequences

Unstable trinucleotide repeats may be within coding or non-coding regions of genes and hence vary in their pathogenic mechanisms

Frameshift Mutation

Chromosomal Rearrangements

Trinucleotide Repeats

Trinucleotide repeats

Polymorphisms

Sequence variants with no obvious effect upon phenotype may be termed polymorphisms.

Structural Effects of mutations

• Non-synonymous mutations

– Missence

– Nonsence

– Frameshift

• Synonymous mutations

Non-synonymous mutations

If a mutation leads to an alteration in the encoded polypeptide, it is known as a non-

synonymous mutation.

Missense Mutations

A single base-pair substitution can result in coding for a different amino acid and the

synthesis of an altered protein, a so-called missense mutation.

Nonsense Mutations

A substitution that leads to the generation of one of the stop codons will result in

premature termination of translation of a peptide chain, or what is termed a

nonsense mutation.

Frameshift mutations

If a mutation involves the insertion or deletion of nucleotides that are not a multiple of

three, it will disrupt the reading frame and constitute a frameshift mutation.

MUTATIONS IN NON-CODING DNA

• In general, mutations in non-coding DNA are less likely to have a phenotypic effect.

• Exceptions include mutations in promoter sequences or other regulatory regions that affect the level of gene expression.

• Mutations in miRNA or siRNA binding sites within UTRs are also likely to result in disease

What causes mutations?

Spontaneous Mutations Mistakes in replication

Induced Mutations Caused by a mutagen

Mutagens •Chemical •Physical

Radiation can cause mutations

Effects of UV RadiationThymine dimers

Base pairing on opposite strand does not occur

Polymerase skips during replication

Fortunately these are repaired

Effect of UV on DNA structure

Ionizing radiation•Any radiation capable of displacing electrons from atoms or molecules, thereby producing ions. •Causes breaks in the phosphodiesterbackbone, DNA cannot be replicated unless repaired•Some examples are alpha, beta, gamma, and X-rays•Causes formation of free radicals, and toxic oxygen

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