Download Mutation

The Biology and Genetic
Base of Cancer.
2
(Mutation)
From cellular to molecular biology
Chromosome
Gene
DNA Molecule
Chemical bases
Mutation the effect from chromosome to Protein
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.
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Ex. Adaptive mutation
Definition of mutation
A change in DNA
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2.
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4.
Arrangement.
Context.
Dosage.
Sequence.
Causes of mutations
Size of mutation
Point
mutation.
Submicroscopic mutation.
Microscopically visible
mutation.
Loss of a whole chromosome.
Types of mutations
Somatic or germinal?
Del(5)(p15)
Germinal mutation
Type of Mutations
 Familiar.
 Sporadic.
Born with mutation 2nd event
Normal
1st event
2nd event
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
Acquired
mutations
Hereditary
mutations
Methods detect
mutations
Three common methods
For acquired mutation
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
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
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Mutation may be viewed as the
engine that drives evolution
Is mutation rate determined (selected) by evolution?
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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:
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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)
Types of mutations
 Point
mutations: Change of the normal
base to another
 Possible
 Silent
consequences:
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
Deletion
Duplication
Inversion
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
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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
Types of mutation
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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
Major mutation types
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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
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
Location, location, location