283973_lecture 12. Mutation.pdf

Benjamin A. Pierce

GENETICS ESSENTIALS Concepts and Connections SECOND EDITION

CHAPTER 13

Gene Mutations, Transposable Elements, and DNA Repair © 2013 W. H. Freeman and Company

OUTLINE • Mutations Are Inherited Alterations in the DNA Sequence • Mutations Are Potentially Caused by a Number of Different Natural and Unnatural Factors • Transposable Elements Are Mobile DNA Sequences Capable of Inducing Mutations

• A Number of Pathways Repair Changes in DNA.

•tinman gene •Nkx2.5

MUTATIONS ARE INHERITED ALTERATIONS IN THE DNA SEQUENCE • The Importance of Mutations • Categories of Mutations • Types of Gene Mutations • Phenotypic Effects of Mutations • Suppressor Mutations

THE IMPORTANCE OF MUTATIONS • Source of all genetic variation, which further provides the raw material for evolution • Source of many diseases and disorders • Useful for probing fundamental biological processes.

CATEGORIES OF MUTATIONS • Somatic Mutations • Germ-line Mutations • Gene vs. Chromosomal Mutations.

TYPES OF GENE MUTATIONS (BASED ON THEIR MOLECULAR NATURE) • Base substitutions • Transition • Transversion

• Insertions and deletions • Frameshift mutations • In-frame insertions and deletions

• Expanding nucleotide repeats Increase in the number of a copies of a set of nucleotides

PHENOTYPIC EFFECTS OF MUTATIONS • Forward mutation: wild type  mutant type • Reverse mutation: mutant type  wild type

• Missense mutation: amino aciddifferent amino acid • Nonsense mutation: sense codon nonsense codon • Silent mutation: codonsynonymous codon • Neutral mutation: no change in function

PHENOTYPIC EFFECTS OF MUTATIONS • Loss-of-function mutations • Usually recessive

• Gain-of-function mutations • Usually dominant

• Conditional mutations • Require specific conditions

• Lethal mutations

SUPPRESSOR MUTATIONS • Suppressor mutation: a mutation that hides or suppresses the effect of another mutation •Intragenic •Intergenic

SUPPRESSOR MUTATIONS • Intragenic

SUPPRESSOR MUTATIONS • Intergenic

MUTATION RATES • Factors affecting mutation rates • Variation in mutation rates

• Adaptive mutations

FACTORS AFFECTING MUTATION RATES • Frequency with which a change takes place in DNA • The probability that when a change takes place, that change will be repaired. • The probability that a mutation will be detected.

ADAPTIVE MUTATION • Genetic variation critical for evolutionary change that brings about adaptation to new environments

• Stressful conditions, where adaptation might be necessary to survive, induces increased mutation in bacteria

MUTATIONS ARE POTENTIALLY CAUSED BY A NUMBER OF DIFFERENT NATURAL AND UNNATURAL FACTORS

Spontaneous and Induced • Spontaneous Replication Errors • Spontaneous Chemical Changes • Chemically Induced Mutations • Radiation

SPONTANEOUS REPLICATION ERRORS • Tautomeric shifts • Mispairing due to other structures

• Incorporation errors and replication errors • Causes of deletion and insertions • Strand slippage • Unequal crossing over

SPONTANEOUS REPLICATION ERRORS • Tautomeric shifts • Mispairing due to other structures • Wobble pairing

SPONTANEOUS REPLICATION ERRORS • Incorporation errors and replication errors

SPONTANEOUS REPLICATION ERRORS • Causes of deletion and insertions • Strand slippage

SPONTANEOUS REPLICATION ERRORS • Causes of deletion and insertions • Unequal crossing over

SPONTANEOUS CHEMICAL CHANGES • Depurination: loss of purine • Deamination: loss of an amino group

Depurination: loss of purine

SPONTANEOUS CHEMICAL CHANGES • Deamination: loss of an amino group

CHEMICALLY INDUCED MUTATIONS • Mutagen • Base analogs

CHEMICALLY INDUCED MUTATIONS • Alkylating agents: donate alkyl group • Ethylmethylsulfonate EMS • Mustard gas

• Deamination: nitrous acid • Hydroxylamine: add hydroxyl group

CHEMICALLY INDUCED MUTATIONS

• Oxidative reaction: superoxide radicals • Hydrogen peroxide

• Intercalating agents: proflavin, acridine orange, and ethidium bromide

CHEMICALLY INDUCED MUTATIONS • Intercalating agents: proflavin, acridine orange, ethidium bromide, and dioxin

RADIATION • Pyrimidine dimer: two thymine bases block replication.

• SOS system in bacteria: SOS system allows bacteria cells to bypass the replication block with a mutation-prone pathway.

MUTATIONS ARE THE FOCUS OF INTENSE STUDY BY GENETICISTS •Detecting Mutations with the Ames Test •Radiation Exposure in Humans

TRANSPOSABLE ELEMENTS CAUSE MUTATIONS •Transposable elements: sequences that can move about the genome •Transposition: movement of the transposons

•Features: •Flanking direct repeats •Terminal inverted repeats

TRANSPOSABLE ELEMENTS ARE MOBILE DNA SEQUENCES CAPABLE OF INDUCING MUTATIONS • General characteristics of transposable elements: • Flanking direct repeats • Terminal inverted repeats

TRANSPOSABLE ELEMENTS CAUSE MUTATIONS •Transposons cause mutations by: • Inserting into another gene • Promoting DNA rearrangements •Examples: • Approximately half of spontaneous mutations in Drosophila • Human genetic diseases • The color of grapes

TRANSPOSITION The mutagenic effects of transposition:

TRANSPOSITION Movement of transposon from one location to another • DNA transposons

• Retrotransposons • Replicative transposons • New copy is introduced on the new site, old copy remains on the original site

• Nonreplicative Transposons • Excises from old site and inserts in a new one (no copy increase)

A NUMBER OF PATHWAYS REPAIR CHANGES IN DNA • Mismatch Repair • Direct Repair • Base-excision Repair

• Nucleotide-excision Repair

A NUMBER OF PATHWAYS REPAIR CHANGES IN DNA Mismatch Repair

A NUMBER OF PATHWAYS REPAIR CHANGES IN DNA • Direct Repair

A NUMBER OF PATHWAYS REPAIR CHANGES IN DNA

• Base-excision Repair DNA glycosylases Uracil glycosylase

• Nucleotide-excision Repair Removes bulky DNA lesions (pyrimidine dimers)

A NUMBER OF PATHWAYS REPAIR CHANGES IN DNA

Genetics diseases and faulty DNA repair •Xeroderma pigmentosum •Hereditary non-polyposis colon cancer (HNPCC)