The Biology and Genetic Base of Cancer. 2 (Mutation)

1
The Biology and Genetic Base of Cancer.
2(Mutation)
2
From cellular to molecular biology
3
Mutation the effect from chromosome to Protein
4
Mutation Bad .Good

• It is good, it is bad also!!
• Mutation in the long term it is essential to our
  existance.
• Without mutation there Could be no change and
• without change life cannot evolve.
• Ex. Adaptive mutation

5
Definition of mutation

• A change in DNA
• Arrangement.
• Context.
• Dosage.
• Sequence.

6
Causes of mutations
7
Size of mutation

• Point mutation.
• Submicroscopic mutation.
• Microscopically visible mutation.
• Loss of a whole chromosome.

8
Somatic or germinal?
Types of mutations
9
Cri-du-chat syndrome
Del(5)(p15)
Germinal mutation
10
Type of Mutations

• Familiar.
• Sporadic.

Born with mutation
2nd event
Normal
1st event
2nd event
11
(No Transcript)
12
Mutation

• Chromosomal level
• Aneuploidy, robertsonian translocation
• Change in DNA sequence arrangement
• Genomic regional level e.g. translocation,
  inversion,
• Retrotransposition.
• Change in sequence context
• Whole gene level e.g. whole gene deletion or
  duplication
• Change in gene dosage
• Nucleotide level e.g. change, deletion,
  duplication of one
• or a few bases Change of nucleotide sequence

13
Acquired mutations
14
Hereditary mutations
15
Methods detect mutations
Three common methods
16
For acquired mutation
17
Mutation

• Chromosomal level
• Aneuploidy, robertsonian translocation
• Change in DNA sequence arrangement
• Genomic regional level e.g. translocation,
  inversion,
• Retrotransposition.
• Change in sequence context
• Whole gene level e.g. whole gene deletion or
  duplication
• Change in gene dosage
• Nucleotide level e.g. change, deletion,
  duplication of one
• or a few bases
• Change of nucleotide sequence

18
Mutation reflects the event, not its consequences

• Does a mutation need to relate to an effect
  (gain, loss or alteration) on gene function?
• Is a new sequence change with no effect on the
  individual a mutation?
• Context may be important e.g. polymorphism that
  leads to disease susceptibility
• e.g. new recessive mutation
• e.g. point mutation with no effect on the
  protein sequence

19
Mutation may be viewed as the engine that drives
evolution

• Is mutation rate determined (selected) by
  evolution?
• mutation rate as a balance between benefit and
  liability
• too low leads to a species that is not adaptive.
• too high leads to a species in which there is
  disease and decreased fitness.
• Mutation rate reflects
• Replication error the major contributor.
• Copying, proofreading, repair tuned to the
  optimum error rate
• Damage and repair may be primarily somatic.
• Other biological processes with built-in error
  rates (e.g. recombination)

20
Types of mutations

• Point mutations Change of the normal base to
  another
• Possible consequences
• Silent mutation No consequence
• Missense mutation changes the codon to one
  encoding a different amino acid
• Nonsense mutation Changes codon from one
  encoding an amino acid to a stop codon
• Splice site alteration can abolish or create a
  splice site
• Regulatory region mutation Can result in net
  increased or decreased gene expression

21
Deletion
Duplication
Inversion
22
What is the mutation rate

• Overall rates consider the fidelity of DNA
  replication
• - in vitro fidelity, studies in model organisms
• - 10 -9 10 11 per bp per replication (10 -6
  10 8 per gene per division)
• - Deleterious mutation rate ( per zygote) is
  difficult to accurately determine
• - Disease-based estimate extrapolate from
  incidence of one disease
• - individual genes may not be representative
• - Population-based estimate molecular clock
  based on species divergence
• - estimate the neutral mutation rate in
  non-coding vs. coding
• - infer the lost, presumably deleterious,
  mutations lost
• - extrapolate over the whole genome
• - use time since split, generation time, gene
  number estimates
• - estimated 3 deleterious mutations/zygote

23

• 6. In the face of the deleterious mutation rate,
  how can a species persist?
• - The rate of accumulation of deleterious
  mutations must be balanced by loss
• - Highly deleterious mutations are purged
  individually (Haldane)
• - Mildly deleterious mutations persist initially
  and are then lost by selection, drift
• - Crow quasi truncation selection model
• - assume 3 new deleterious mutations per
  generation
• - assume mutations persist for 100 generations
• - question what level of loss (genetic death) is
  needed to balance the load?
• - average of 16 reproduction failure
• - as the load increases, a point is reached at
  which fitness decreases
• - a probabilistic model relating load to fitness
  (reproduction)
• - variables that could affect the result
• - number of mutations, persistence
• - environmental improvements lead to increased
  tolerance
• - medical intervention leads to increase tolerance

24
Types of mutation

• Point mutations single nucleotide changes
  synonymous (silent), nonsynonymous (missense,
  nonsense)
• - microdeletions/duplications one or a few
  nucleotides
• - may be mediated by short repeated sequences
• - larger deletions/duplications large portions
  of a gene or genes
• - single gene or contiguous gene disorders
• - often mediated by larger repeat elements e.g.
  LINE1, Alu
• - microsatellite repeat deletion/expansion CA
  or trinucleotide repeats

25
Major mutation types

• Single base substitutions that cause premature
  termination of protein synthesis, change of amino
  acid, suppress termination of protein
  translation, alter level of gene expression, or
  alter patterns of mRNA splicing
• Translocations, that bring disparate genes or
  chromosome segments together
• Deletions of a few nucleotides up to long
  stretches of DNA
• Insertions and duplications of nucleotides up to
  long stretches of DNA
• Many different mutations can occur within a given
  gene, although it appears that genes have
  different degrees of mutability
• Different mutations affecting a gene can result
  in distinct clinical syndromes

26
Types of mutations

• Translocations
• Fusion of one chromosomal segment or gene
  fragment with another
• May result in disruption of gene(s)
• May result in a hybrid gene with novel function
  or combination of the functions of both genes

27
Location, location, location