DNA Damage and Mutations
Mutations
• Heritable changes in genetic material that aren’t due to genetic recombination
• Ultimate source of differences among species
• Most genetic variation due to genetic recombination and sex - Reciprocal exchange
of genetic material between pairs of homologous chromosomes. Independent
assortment of paternal and maternal chromosomes during meiosis
• The cause of inherited diseases
• Cause of cancer
• Individuals carry on average 1-2 recessive lethal mutations
• Mutations are random events that can occur at any position in the genome
• Certain DNA sequences are mutational hotspots
• Can be classified into 2 broad groups
1. Point mutations – minor changes in the DNA sequence involving only one or a few
nucleotides (relative)
2. Rearrangements – extensive chromosomal alterations involving hundreds of base
pairs or even whole chromosomes
• Cancer can start as point mutation and become rearrangement
Wild-type
• The normal sequence prior to mutation
• Due to genetic variation, is not easily defined
• Often, wild-type is arbitrarily chosen and used as a reference
• In the case of disease genes the wild-type will refer to the “non-diseased” version of
the gene
Classification of mutations
• Based on origin, cell type, expression, effect of function, molecular change, effect on
translation
Classification by origin
Spontaneous
• Occurs in absence of known mutagen
• Due to errors in DNA replication or effect of compounds present in the cell e.g.
reactive oxygen species (ROS). Damage DNA and responsible for aging.
• ROS – produced due to aerobic metabolism. Can’t be avoided. Cells produce proteins
that absorb ROS so they don’t get to DNA, but in some cases they can
Induced
• Occurs in presence of known mutagen
• Mutagen – chemical or physical agent that increases rate of mutagenesis
• Natural or synthetic chemicals that can damage DNA
• Physical mutagens – include ionising radiation and ultraviolet (UV) radiation
, Classification by Cell Type
Somatic
• Occurs in nonreproductive cells
• Somatic mutations not passed onto next generation
• Can lead to disease e.g. cancer and are responsible for aging
Germ-line
• Occurs in reproductive cells
• Germ-line mutations will be passed onto the next generation
• Germ-line mutations are ultimately responsible for genetic variation
Classification by effect on function
• Loss of function/knockout/null mutation – eliminates normal function
• Hypomorphic/leaky – reduces normal function. Most mutations are leaky.
• Hypermorphic – increases normal function e.g. mutation in promoter sequence.
• Gain of function (ectopic expression) – expressed at incorrect time or in
inappropriate cell types
Effect on Function
• Mutations may be positioned in junk DNA, control sequences or protein coding
regions. mRNA will carry mutation so different amino acids inserted and protein is
wrong
• Mutations in promoter sequence which affect whether or not a gene is transcribed –
level and timing. Can reduce activity of promoter. Still wild-type protein made.
• Can respond to different environmental signals. Mutation can stop different signals.
• Promoter can be turned on under certain conditions
Classification by Molecular Change
Base substitution
• one base pair replaced with different base pair.
• Transition – pyrimidine to pyrimidine or purine to purine
• Transversion – pyrimidine to purine or purine to pyrimidine
• Insertion – one or more extra nucleotides present
• Deletion – one or more missing nucleotides
• Indels are relatively rare. Base substitutions more common
Classification by Effect on Translation
• Missense mutation (non-synonymous) – change in amino acid encoded
• Nonsense (terminator) – creates translation termination codon. TGA (opal), TAA
(ochre), TAG (amber). Truncated protein that doesn’t work properly
• Neutral – change in amino acid encoded to one with a similar function
• Silent (synonymous) – no change in amino acid encoded (wobble)
• Frameshift – shifts triplet reading of codons out of correct phase. Formed from
insertions and deletions.
• Cystic fibrosis most commonly a three base insertion
Mutations
• Heritable changes in genetic material that aren’t due to genetic recombination
• Ultimate source of differences among species
• Most genetic variation due to genetic recombination and sex - Reciprocal exchange
of genetic material between pairs of homologous chromosomes. Independent
assortment of paternal and maternal chromosomes during meiosis
• The cause of inherited diseases
• Cause of cancer
• Individuals carry on average 1-2 recessive lethal mutations
• Mutations are random events that can occur at any position in the genome
• Certain DNA sequences are mutational hotspots
• Can be classified into 2 broad groups
1. Point mutations – minor changes in the DNA sequence involving only one or a few
nucleotides (relative)
2. Rearrangements – extensive chromosomal alterations involving hundreds of base
pairs or even whole chromosomes
• Cancer can start as point mutation and become rearrangement
Wild-type
• The normal sequence prior to mutation
• Due to genetic variation, is not easily defined
• Often, wild-type is arbitrarily chosen and used as a reference
• In the case of disease genes the wild-type will refer to the “non-diseased” version of
the gene
Classification of mutations
• Based on origin, cell type, expression, effect of function, molecular change, effect on
translation
Classification by origin
Spontaneous
• Occurs in absence of known mutagen
• Due to errors in DNA replication or effect of compounds present in the cell e.g.
reactive oxygen species (ROS). Damage DNA and responsible for aging.
• ROS – produced due to aerobic metabolism. Can’t be avoided. Cells produce proteins
that absorb ROS so they don’t get to DNA, but in some cases they can
Induced
• Occurs in presence of known mutagen
• Mutagen – chemical or physical agent that increases rate of mutagenesis
• Natural or synthetic chemicals that can damage DNA
• Physical mutagens – include ionising radiation and ultraviolet (UV) radiation
, Classification by Cell Type
Somatic
• Occurs in nonreproductive cells
• Somatic mutations not passed onto next generation
• Can lead to disease e.g. cancer and are responsible for aging
Germ-line
• Occurs in reproductive cells
• Germ-line mutations will be passed onto the next generation
• Germ-line mutations are ultimately responsible for genetic variation
Classification by effect on function
• Loss of function/knockout/null mutation – eliminates normal function
• Hypomorphic/leaky – reduces normal function. Most mutations are leaky.
• Hypermorphic – increases normal function e.g. mutation in promoter sequence.
• Gain of function (ectopic expression) – expressed at incorrect time or in
inappropriate cell types
Effect on Function
• Mutations may be positioned in junk DNA, control sequences or protein coding
regions. mRNA will carry mutation so different amino acids inserted and protein is
wrong
• Mutations in promoter sequence which affect whether or not a gene is transcribed –
level and timing. Can reduce activity of promoter. Still wild-type protein made.
• Can respond to different environmental signals. Mutation can stop different signals.
• Promoter can be turned on under certain conditions
Classification by Molecular Change
Base substitution
• one base pair replaced with different base pair.
• Transition – pyrimidine to pyrimidine or purine to purine
• Transversion – pyrimidine to purine or purine to pyrimidine
• Insertion – one or more extra nucleotides present
• Deletion – one or more missing nucleotides
• Indels are relatively rare. Base substitutions more common
Classification by Effect on Translation
• Missense mutation (non-synonymous) – change in amino acid encoded
• Nonsense (terminator) – creates translation termination codon. TGA (opal), TAA
(ochre), TAG (amber). Truncated protein that doesn’t work properly
• Neutral – change in amino acid encoded to one with a similar function
• Silent (synonymous) – no change in amino acid encoded (wobble)
• Frameshift – shifts triplet reading of codons out of correct phase. Formed from
insertions and deletions.
• Cystic fibrosis most commonly a three base insertion
