Chapter 12

Molecular Mechanisms of Mutation and DNA Repair

Outline
• What is a mutation?
• How are mutations classified?
• When and how do they occur?
• How are potential mutations prevented?
• Transposable elements
What is a mutation?
• A mutation is any heritable change in the genetic material
• The simplest type is a single base substitution (resulting in a single
nucleotide variant, or SNV)
• Several classes of mutations

Which is more frequent?

Types of mutations
• A mutation is any heritable change in the genetic material
Types of mutations
• A mutation is any heritable change in the genetic material
Types of mutations
• A mutation is any heritable change in the genetic material
Types of mutations
• A mutation is any heritable change in the genetic material

Are heritable changes in DNA methylation or histone

modifications considered mutations?
Types of mutations
• Depending on DNA context, mutation may be synonymous (silent) or
non-synonymous
• Severity of the resulting phenotype depends on this context
Somatic vs germline mutation

An Introduction to Genetic Analysis. 7th edition.

Are all of our cells REALLY identical?
• Somatic mosaicism

Campbell, Ian M. et al.

Trends in Genetics , Volume 31 , Issue 7 , 382 - 392
Effects of mutations on gene function
• Mutations can also be classified according to their effects on gene
function:
 loss-of-function mutation (a knockout or null)
 hypomorphic mutation
 Hypermorphic mutation
 gain-of-function mutation
Single amino acid replacement: sickle cell
anemia
• sickle-cell anemia is caused by a mutant gene for b-globin
• GAG, which codes for glutamic acid -> codon GUG, which
codes for valine

Fda.gov
Are there particular regions prone to
mutation?
• Fragile-X
• Replication slippage in CGG repeats

http://medgen.genetics.utah.edu/photographs/pages/fragile_x.htm
Dynamic mutation in the CGG repeat

Other genetic diseases associated with dynamic mutation

include:
The neurological disorders myotonic dystrophy (with an
unstable repeat of CTG)
Kennedy disease (AGC)
Friedreich ataxia (AAG)
Spinocerebellar ataxia type 1 (AGC)
Huntington disease (AGC)
How do we know where a mutation will
occur?
• Mutations may occur randomly but some DNA regions may be more
prone to mutation than others (hotspots)
• Example (5mC -> T), Fragile-X
How do we know when a mutation will occur?
• Hint: we don’t for sure
• Mutations are statistically random
• Demonstrated by replica plating
(Joshua and Esther Lederberg)
Increasing the when with mutagens
DNA repair mechanisms
• Specific enzymes recognize specific
mismatches or damaged bases

Mismatch repair
DNA repair mechanisms
• Nucleotides are prone to deamination and oxidation even during
ideal (non-stressed) physiological conditions
• Water can hydrolize purine nucleotides (depurination)
• AP sites are cut by AP endonuclease
DNA repair mechanisms
• Nucleotide Excision Repair (NER)
• Only repair pathway for UV-induced damage
(pyrimidine dimers) in mammals

What happens if not repaired?

 DNA repair mechanisms
• Photolyases
• Enzyme that repairs major UV-R
induced damage:
1. Cyclobutane pyrimidine dimers
2. 6-4 photoproducts

http://slideplayer.com/slide/2493135/
DNA repair mechanisms
• Postreplication repair
• DNA damage bypass
• Error rate?
Homologous and Non-homologous end
joining
Transposable elements
• Commonly referred to as TE’s
• Discovered in Proks and Euks
• ~50% of human genome consists of TE’s
• Different classes based on mechanism
• LINEs and SINE elements most common in human genome
Cut-and-paste Tes (DNA transposons)
Long terminal repeat (LTR) retrotransposons

Figure 12.09: Sequence organization of a copia transposable element in

Drosophila melanogaster.