Transcript 06_20_cancer_age.jpg

06_20_cancer_age.jpg
Gene Mutation: Origins and
Repair Processes
GAATTC  GTATTC
Aa
Skin cancers from
Xeroderma pigmentosum, a
recessive hereditary disease
caused by a deficiency in a
DNA repair enzyme
Mutations
Gene
Transcription
Translation
Normal
DNA
Mutational event
Normal protein
gene product
Phenotype
Altered
Phenotype
Mutated gene
Gene:
• nucleotide sequence on a
chromosome that encodes
a specific protein
Abnormal protein
gene product
• partially functional
• nonfunctional
• no gene product
DNA Mutations: An Overview
Mutations
Heritable changes in base sequences that modify
the information content of DNA
Forward mutation: a mutation that changes the wildtype
allele of a gene to a different allele. The resultant allele
can be either dominant or recessive to the original
wildtype
a Forward Recessive
A+
a+
A
Forward Dominant
Reverse mutation or reversion : a mutation that
causes a mutant allele to revert back to wildtype.
a
A+
A
a+
Remember: wild alleles
designated with a “+”
La mayoría de las mutaciones
ocurre durante la replicación del
DNA o durante su reparación
Mistakes during DNA replication can also
alter genetic information
Replication errors are extremely rare, generally
occurring once per 109 base pairs
The rate of replication errors is kept low due to
correction or ‘proofreading’ activity, which
reduces the error rate to one in 106 bases copied
by DNA polymerase (in vitro)
Both DNA polymerase I and II have “proofreading”
ability. It is a 3’ to 5’ nuclease activity
Classes of DNA mutations
Substitution: base at certain position is substituted
by one of other 3 bases
Transition* purine (A/G) for purine or pyrimidine (C/T) for pyrimidine
Transversion purine (A/G) to pyrimidine (C/T) or visa versa
Deletion Mutation:
block of ONE or more
nucleotide pairs is lost
from a DNA molecule
Insertional Mutation:
• block of ONE or more
nucleotide pairs is added
to a DNA molecule
Inversion Mutations:
• 180° rotation of segment of DNA molecule
Translocations:
• Parts of nonhomologous chromosomes change place
Overview
•
•
Hereditable change in DNA resulting from change in
nucleotide sequence
Mutation changes one allelic form to another and is
the ultimate source of genetic variation.
– Mutational variation underlies the study of genetics.
•
Mutations are produced by mutagens or occur
spontaneously.
– Each base pair has a certain probability of undergoing change
•
•
•
Point mutations include single base-pair
substitutions, additions or deletions.
Specialized forms of mutation include expansion of
trinucleotide repeats and insertion of transposable
elements.
Many types of mutation can be repaired.
Mutation
• Hereditable change in DNA resulting from change in
nucleotide sequence
• Multiple causes
– DNA replication/repair errors
– Mutagens; spontaneous DNA damage
– Insertion of transposons
• Several categories of mutation
– Point mutations
• Swap one base for another; insert a base; delete a base
– Alter the number of copies of a short repeat
– Large insertions into a gene
Point Mutations
• Single or few base pair changes
• Provide “background rate” of mutation
– critically important to evolution
• More likely to lead to loss of function than gain of
function
• Origin of point mutation
– Induced, by geneticist for example
• action of mutagen; environmental agent that alters nucleotide
sequence
• process of inducing mutations by mutagens called mutagenesis
– Spontaneous
• arise in absence of known mutagen
• may be caused by errors in DNA replication
Types of point mutation
• Base substitution
– transition
• A  G (purine  purine) (A·T  G·C)
• C  T (pyrimidine  pyrimidine) (C·G  T·A)
– transversion
• purine  pyrimidine (e.g., A  C) (A·T  C·G)
• Addition or deletion of nucleotide pairs (base-pair
addition or deletion)
– also called indel mutations
Molecular Consequences
Terminación Prematura por
mutaciones “sin sentido” (non sense)
Mutaciónes supresoras
intragénicas
Figure 27.27: How an intergenic suppression mutation can overcome a nonsense mutation.
Efecto de mutaciones supresoras
intergénicas
Mutación supresora Ambar
Mutación supresora Opalo