Ch. 19: Gene Mutation and DNA repair

mutation

• refers to a heritable change in the genetic material

effects of mutations on gene structure and function

• changes in chromosome structure

• changes in chromosome number

• changes in DNA of a single genes

point mutation

• a change in a single base pair

• can be a transition or a transversion

transition

• mutation that is a purine for a purine or a pyrimidine for a pyrimidine

  • A —→ G

  • G —→ A

  • T —→ C

  • C —→ T

transversion

• more common mutation

• mutation is a purine for a pyrimidine for a purine or a purine for a pyrimidine

• very pronounced error

• distorts shape and size of helix

deletion

• removal of a short sequence of DNA

insertion

• addition of a short sequence of DNA

missense mutation

• base substitution in which an amino acid change does occur

• Ex.: sickle cell disease

• will have a neutral or inhibitory effect on protein function

silent mutation

• base substitution which does not alter the amino acid produced

• no likely effect on protein function

nonsense mutation

• base substitution which alters amino acid into a stop amino acid terminating transcription

• will likely have negative effects on protein function

frameshift mutation

• addition or deletion of DNA

• alters many amino acids and likely has a negative effect on protein function

promoter mutation

• may increase or decrease the rate of transcription

enhancer/operator mutation

• may disrupt the ability of the gene to be properly regulated

5’-UTR/3’-UTR mutation

• may alter the ability to mRNA to be translated

• may alter mRNA stability

splice site recognition mutation

• may alter the ability of pre-mRNA to be properly spliced

• will retain introns and end up translating them

forward mutation

• changes the wild-type genotype into some new variation

reverse mutation

• changes a mutant allele back to wild-type

  • also called a reversion

suppressor mutation

• reverse the phenotypic effects of another mutation

deleterious mutations

• mutation characterized by their differential ability to survive

• decrease the chances of survival

  • the most extreme are lethal mutations

beneficial mutation

• mutation characterized by their differential ability to survive

• enhance the survival or reproductive success of an organism

conditional mutation

• They affect the phenotype only under a defined set of condition

• An example is a temperature-sensitive mutation

breakpoint

• A chromosomal rearrangement may affect a gene because the chromosomal site of breaking and rejoining occurs within the gene

position effect

• a gene may be left intact, but its expression may be altered because of its new location

germ line mutation

• occurs in gametes

• mutation is passed to half of the gametes in the next generation

  • mutation is found in whole body

somatic mutation

• result in patches of affected area

  • the size of the patch will depend on the timing of the mutation

    • the earlier the mutation, the larger the patch

  • An individual with somatic regions that are genotypically different from the rest of the body is called a genetic mosaic

  • mutations are not present in gametes

trinucleotide repeat expansion (TNRE)

• unusual mutation that causes several human genetic diseases

• In individuals without disease symptoms, these sequences are transmitted from parent to offspring without mutation

• in persons with this mutation the length of the repeat has increased above a certain critical size resulting disease symptoms

Huntington Disease

• disease caused by trinucleotide repeat expansion

• 9-35 repeats have been identified in normal controls

• >40 repeats: have been found to be pathological

• CAG repeat in the gene (encodes for Gln) = polyglutamine repeat

• gene is expressed predominantly in the brain

• When too many repeats, protein misfolds and forms aggregates

  • These eventually kill the neurons

• can cause repeat expansion due to strand slippage

Mechanism of Trinucleotide Repeat Expansion

• the contain at least one C and one G

  • this allows formation of hairpin

• during DNA replication a hairpin can lead to an increase or decrease in the length of the DNA

  • polymerase can slip off DNA

  • hairpin forms and pulls strand back

  • DNA polymerase hops back on

    • begins synthesis from a new location

• these changes can occur during gamete formation

• offspring will have very different numbers of repeats

• can also increase repeats in somatic cells

  • this can increase severity of the disease with age

anticipation

• feature of TNRE disorders in which they progressively worsen in future generations

• onset, severity, and outcome gets worse and worse in future generations

causes of mutations

• spontaneous mutations

  • result from abnormalities in cellular/biological processes

• induced mutations

  • caused by environmental agents

  • agents that are known to alter DNA structure are termed mutagens

spontaneous mutations

• mutations are random events

• Unrelated to any adaptive advantage it may confer on the organism in its environment

• A potentially favorable mutation does not arise because the organism has a need for it

• they preexist in the population and are selected for under certain conditions

depurination

• The removal of a purine (guanine or adenine) from the DNA forms an apurinic site

• the covalent bone between deoxyribose and a purine base is somewhat unstable

  • it occasionally undergoes a spontaneous reactions with water that releases the base from the sugar

• apurinic sites can be repaired

  • but if the repair system fails a mutation may result during subsequent rounds of DNA replication

    • polymerase will add a random base

deamination of cytosine

• removal of an amino group from the cytosine base

  • the other bases are not readily deaminated

• DNA repair enzymes can recognize uracil as an inappropriate baser and remove it

  • but is the repair system fails, a C-G to A-T mutation will result during subsequent rounds of RNA replication

Deamination of 5-methylcytosine

• 5-methylcytosine can be deaminated into thymine, a normal constituent of DNA

• Repair enzymes cannot determine which of the two bases on the two DNA strands is the incorrect base

• For this reason, methylated cytosine bases tend to create hot spots for mutation

induced mutations

• mutagens that alter the structure of DNA and cause mutations

• The public is concerned about mutagens for two main reasons

  • Mutagens are often involved in the development of human cancers

  • Mutagens can cause gene mutations that may have harmful effects in future generations

• an enormous array of agents can act as mutagens

• mutagenic agents are usually classified as chemical or physical mutagens

types of chemical mutagens

• base modifiers

• intercalating agents

• base analogues

base modifiers

• Some covalently modify base structure

• Others disrupt pairing by alkylating bases

intercalating agents

• directly interfere with replication process

base analogues

• Incorporate into DNA and disrupt structure

• Some tautomerize at a high rate