13: Mutations

mutation

alteration in DNA or chromosome structure

• the source of new alleles and fuel for natural selection

fitness

refers to an organism's ability to survive and reproduce in its environment, ultimately passing on its genes to the next generation

three types of fitness effects

1. deleterious - harmful mutations to the fitness of an individual (most common)

2. neutral - mutations that do not have any effect on fitness

3. beneficial - advantageous mutations that increase the fitness of the individual

distribution of fitness effects

the relative frequencies of fitness effect mutations

• differ between organisms/species

spontaneous mutations

mutations that occur naturally due to

• errors in DNA replication

• errors in DNA repair

• or because of changes in the cellular environment

induced mutations

caused by mutagen agents

• external factors like UV radiation, X-rays, chemicals, viruses

• can be used to create variability in populations

mutations can occur in

• coding regions of a gene (i.e., exons)

• non-coding regions of a gene (introns, promoters, regulatory sequences, enhancers, splicing signals)

• somatic cells (non heritable)

• germ cells (heritable)

loss-of-function mutations

mutations that reduce or eliminate the function of a gene product

• ex. indels - change the reading frame (= frameshift)

  • change amino acid sequence, premature stop

gain-of-function mutations

mutations that lead to a gene product with enhanced, negative, or new functions

• can be beneficial or harmful

substitution mutations

these mutations are otherwise known as point mutations and are either

• synonymous or silent

• non-synonymous or nonsense or missense

synonymous mutation

silent

• when a substitution/point mutation codes the same amino acid as original codon sequence

• due to redundancy of the genetic code

• 3rd position

synonymous mutations can still have fitness effects because

1. codon usage bias (differs in the freq of occurence of synonymous codons in coding DNA)

2. variations in abundance/availability between tRNAs

   • changes the rate and efficiency of translation

3. increased GC content in the genome influences which codons are used more freq like extremophiles

4. change affinity of the promoter to the RNA polymerase

non-synonymous mutations

• substitution/point mutations that code for a different amino acid, therefore changing the amino acid sequence

• 1st or 2nd position

• either:

  • nonsense

  • missense (conservative or nonconservative)

nonsense mutation

non-synonymous substitution mutation that changes codon sequence to code for stop codon by affecting the 1st position

• usually causes premature termination of amino acid sequence and faulty proteins

conservative missense mutation

nonsynonymous mutation that affects 2nd position of codon sequence

• resulting amino acid has similar chemical/physical properties to original codon for amino acid

non-conservative missense mutation

nonsynonymous mutation that affects 2nd position of codon sequence

• resulting in amino acid with very different chemical properties like from polar to non-polar

wobble hypothesis

during translation the 3rd position in an anticodon in tRNA can align in several ways to allow it to recognize more than one base in the codon of mRNA

• allows for flexibility

• a mutation in the 3rd position often does not require different tNRA as the same amino acid is incorporated even if a mutation occurs = synonymous mutation

__ different tRNA species are necessary to accommodate the 61 amino acid specifying codons

31

• single amino-acyl-tRNA can pair with more than one codon in mRNA

wobble hypothesis consequences

1. reduces the number of tRNAs needed

2. increases translation efficiency

3. minimizes impact of mutations

4. allows adaptation to different codon usage by favouring certain tRNAs based on codon bias

base pairs between tRNA and mRNA

base at first position 5’ end of tRNA anticodon = base at 3rd position 3’ end of mRNA codon

G = C or U

U = A or G
I = A, U or C

mutations in Sars-Cov2 spike (S) protein

some regions of the genome have elevated mutation rates (i.e., mutation hot spots) increasing its replication rate in the S protein

• increase the fitness of the virus

• 25% of variants have a phenotypic effect

mutation rates during replication

• vary between organisms and tend to increase with genome size (except viruses)

mismatch mutations

mutations that lead to incorrect geometries between non-complementary base pairs

• destabilizes DNA structure

tautomeric shifts

change of the covalent structure of the nucleotide (isomers), allowing hydrogen bonding with non-complementary bases

• = tautomers (shift in state)

• lead to permanent base-pair changes and mutations

• shift itself is not the mutation, it is a transient change between common form to alternative form

• the shift in one strand leads to a transition mutation in the complementary strand

transition mutation

type of point mutation (substitution)

• interchange of purine with a purine or pyrimidine with a pyrimidine

• resulting bond is preserved (after rounds of replication)

transversion mutation

type of point mutation (substitution)

• purine is substituted with a pyrimidine or vice versa

mutagens

agents like UV rays, X-rays, chemicals, ionization, and viruses that cause induced mutations like single or double strand breaks

• cause an increase in the rate of mutations

oxidative radicals

type of mutagen that can modify a guanine which then pair with an adenine

= causes G to T transversion

C≡G to A=T

intercalating agents

type of mutagen that insert themselves between adjacent bases in DNA which results in:

• single-nucleotide indels during replication

  • distortion in DNA structure

  • frameshifts

deaminations

type of mutation that removes an amino group from a molecule

• ex. C to U

• C≡G to U=A to T=A

• G to A transition

mutagens that cause transitions

EMS

Nitrous Acid

Hydroxylamine

Deaminations

mutagens that cause transversions

oxidative radicals