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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 DNA Gene Mutational event Mutated gene TranscriptionTranslation Normal protein gene product Normal Phenotype Abnormal protein gene product partially functional partially functional nonfunctional nonfunctional no gene product no gene product Altered PhenotypeGene: nucleotide sequence on a chromosome that encodes a specific protein

DNA Mutations: An Overview

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 Mutations A+A+A+A+a a+a+a+a+ A Forward Recessive Forward Dominant Reverse mutation or reversion : a mutation that causes a mutant allele to revert back to wildtype. A+A+A+A+a a+a+a+a+ A Remember: 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 10 9 base pairs The rate of replication errors is kept low due to correction or ‘proofreading’ activity, which reduces the error rate to one in 10 6 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 by one of other 3 bases Transition* Transition* purine ( A/G ) for purine or pyrimidine ( C/T ) for pyrimidine Transversion G C 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 moleculeTranslocations: nonhomologous 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