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GENE
MUTATION

GENETIC MATERIAL
• DNA
– Primary function permanent storage of information
– Does not normally change
– Mutations do occur

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MUTATIONS
• Mutation
– Heritable change in the genetic
material
– Permanent structural change of
DNA
• Alteration can be passed on to
daughter cells
• Mutations in reproductive cells
can be passed to offspring

MUTATIONS
• Mutations
– Provide allelic variation
• Ultimate source of genetic variation
• Foundation for evolutionary change
– Various phenotypic effects
• Neutral
• Harmful
• Beneficial

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MUTATIONS
• Mutations
– Most mutations are neutral
– More likely to be harmful than beneficial to the
individual
• More likely to disrupt function
than improve function

MUTATIONS
• Mutations
– Many inherited diseases result from mutated genes
– Diseases such as various cancers can be caused by
environmental agents known to
cause DNA mutations
• “Mutagens”

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MODEL ORGANISMS
• Much of our understanding of mutations is a
result of the study of model organisms
– e.g., Bacteria, yeast, Drosophila, etc.
• Amenable to analysis
• Short generation time, numerous offspring, etc.
– Often exposed to mutagenic environmental agents
• Effects of mutations are studied

CODIGO GENÉTICO

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5’-ATGGGATTATGGCTTGTATTCGGCCTATCGGTCCCGGGAGGGGAGCTGAATC-3’DNA
3’-TACCCTAATACCGAACATAAGCCGGATAGCCAGGGCCCTCCCCTCGACTTAG-5’

5’-AUG GGA UUA UGG CUU GUA UUC GGC CUA UCG GUC CCG GGA GGG GAG CUG AAU C-3’

Met-Gly-Leu-Trp-Leu-Val-Phe-Gly-Leu-Ser-Val-Pro-Gly-Gly-Glu-Leu-Asn

Cambio
5’-AUG GGA UUA UGG UUU GUA UUC GGC CUA UCG GUC CCG GGA GGG GAG CUG AAU C-3’
Met-Gly-Leu-Trp-Phe-Val-Phe-Gly-Leu-Ser-Val-Pro-Gly-Gly-Glu-Leu-Asn

Inseción
5’-AUG GGA UUA UGG CUU GUA AUU CGG CCU AUC GGU CCC GGG AGG GGA GCU GAA UC-3’
Met-Gly-Leu-Trp-Leu-Asp-Ile-Pro-Pro-Ile-Gly-Pro-Gly-Arg-Gly-ala-Glu

Deleción
5’-AUG GGA UUA UGG CUU GUA UUC GCC UAU CGG UCC CGG GAG GGG AGC UGA AUC-3
Met-Gly-Leu-Trp-Leu-Asp-Phe-Ala-Try-Arg-Ser-Arg-Glu-Gly-Ser-Stop
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TYPES OF MUTATIONS
• Types of mutations
– Chromosome mutations
• Changes in chromosome structure
– Genome mutations
• Changes in chromosome number
– Single-gene mutations
• Relatively small changes in DNA
structure
• Occur within a particular gene

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TYPES OF MUTATIONS
• Mutations involve the permanent alteration of a
DNA sequence
– Alteration of base sequence
– Removal or addition of one or more nucleotides

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MUTATIONS
• Point mutations
– Change in a single base pair within the DNA
– Two main types of point mutations
• Base substitutions
– Transition
– Transversion
• Small deletions or insertions

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MUTATIONS
• Two types of base substitutions
– Transition
• Pyrimidine changed to another pyrimidine
– e.g., C ! T
• Purine changed to another purine
– e.g., A ! G
– Transversion
• Purines and pyrimidines are
interchanged
– e.g., A ! C
• More rare than transitions

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EFFECTS OF MUTATIONS
• Mutations within the coding sequence of a gene
can have various effects on the encoded
polypeptide’s amino acid sequence
– Silent mutations
– Missense mutations
• Included neutral mutations
– Nonsense mutations
– Frameshift mutations

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EFFECTS OF MUTATIONS
• Silent mutations
– Amino acid sequence is not altered
• e.g., CCC ! CCG (pro ! pro)
– Genetic code is degenerate
– Alterations of the third base of a codon
often do not alter the encoded amino acid
– Phenotype is not affected

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EFFECTS OF MUTATIONS
• Missense mutations
– Amino acid sequence is altered
• e.g., GAA !GTA (glu ! val)
– Phenotype may be affected

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EFFECTS OF MUTATIONS
• Neutral mutations
– Type of missense mutation
– Amino acid sequence is altered
• e.g., CTT !ATT (leu ! ile)
• e.g., GAA !GAC (glu ! asp)
– No detectable effect on protein
function
• Missense mutations substituting
an amino acid with a similar
chemistry to the original is likely
to be neutral

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EFFECTS OF MUTATIONS
• Nonsense mutations
– Normal codon is changed into a stop
codon
• e.g., AAA ! AAG (lys ! stop)
– Translation is prematurely terminated
• Truncated polypeptide is formed
– Protein function is generally affected

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EFFECTS OF MUTATIONS

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EFFECTS OF MUTATIONS

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EFFECTS OF MUTATIONS
• Mutations occasionally produce a polypeptide
with an enhanced ability to function
– Relatively rare
– May result in an organism
with a greater likelihood
to survive and reproduce
– Natural selection may
increase the frequency of
this mutation in the
population

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MUTATION TYPES
• Genetic terms to describe mutations
– Wild-type
• Relatively common genotype
• Generally the most common allele
– Variant
• Mutant allele altering an organism’s phenotype
– Forward mutation
• Changes wild-type allele into something else
– Reverse mutation
• “Reversion”
• Restores wild-type allele
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MUTATION TYPES
• Genetic terms to describe mutations
– Deleterious mutation
• Decreases an organism’s chance of
survival
– Lethal mutation
• Results in the death of an organism
• Extreme example of a deleterious
mutation
– Conditional mutants
• Affect the phenotype only under a
defined set of conditions
• e.g., Temperature-sensitive (ts) mutants
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MUTATION TYPES
• Genetic terms to describe mutations
– Suppressor mutation
• Second mutation that restores the wild-type phenotype
• Intragenic suppressor
– Secondary mutation in the same gene as
the first mutation
– Differs from a reversion
» Second mutation is at a different site
than the first
• Intergenic suppressor
– Secondary mutation in a different gene
than the first mutation

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MUTATION TYPES
• Two general types of intergenic suppressors
– Those involving an ability to defy the genetic code
– Those involving a mutant structural gene

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MUTATION TYPES
• Intergenic suppressor mutations involving an
ability to defy the genetic code
– e.g., tRNA mutations
• Altered anticodon region
• e.g., Recognize a stop codon
– May suppress a nonsense mutation
in a gene
– May also suppress stop codons
in normal genes

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MUTATION TYPES
• Intergenic suppressors involving a mutant
structural gene
– Usually involve altered expression of one gene that
compensates for a loss-of-function mutation affecting
another gene
• Second gene may take over the functional role of the first
• May involve proteins participating in a common cellular
function
– Sometimes involve mutations in genetic regulatory
proteins
• e.g., Transcription factors activating other genes that can
compensate for the mutation in the first gene
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MUTATION TYPES
• Mutations occurring outside of coding sequences
can influence gene expression
– Mutations may alter the core promoter sequence
• Up promoter mutations
– Mutant promoter becomes more like the consensus sequence
– Rate of transcription may be increased
• Down promoter mutations
– Mutant promoter becomes less like the consensus sequence
– Affinity for regulatory factors is decreased
– Rate of transcription may be decreased

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MUTATION TYPES

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CAUSES OF MUTATIONS
• Two causes of mutations
– Spontaneous mutations
• Result from abnormalities in biological
processes
• Underlying cause lies within the cell
– Induced mutations
• Caused by environmental agents
• Cause originates outside of the cell

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CAUSES OF MUTATIONS
• Induced mutations are caused by mutagens
– Chemical substances or physical agents originating
outside of the cell
– Enter the cell and then alter the DNA structure

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CAUSES OF MUTATIONS
• Spontaneous mutations are random events
– Not purposeful
– Mutations occur as a matter of chance
• Some individuals possess beneficial mutations
– Better adapted to their environment
– Increased chance of surviving and reproducing
• Natural selection results in differential reproductive success
– The frequency of such alleles increases in the population

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CAUSES OF MUTATIONS
• Joshua and Ester Lederberg (1950s)
– Interested in the relationship between mutation and
the environmental conditions shat select for mutations
• Scientists were unsure of the relationship
• Two competing hypotheses
– Directed mutation hypothesis
» Some scientists still believed that selective conditions could
promote specific mutations
– Random mutation theory
» Mutations occur at random
» Environmental factors affecting survival select for those
possessing beneficial mutations

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CAUSES OF MUTATIONS
• Joshua and Ester Lederberg (1950s)
– Plated large number of bacteria onto a master plate
• Contained no selective agent
– Transferred colonies to
secondary plates containing
selective agent (T1 phage)
• “Replica plating”
• Only mutant cells would grow

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CAUSES OF MUTATIONS
• Mutation rate
– Likelihood that a gene will be altered
by a new mutation
– Expressed as the number of new
mutations in a given gene per
generation
• Generally 1/100,000 – 1/billion
10-5 – 10-9

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CAUSES OF MUTATIONS
• Mutation rate
– Mutation rate is not a constant number
• Can be increased by environmental
mutagens
– Induced mutations can increase beyond
frequency of spontaneous mutations
• Mutation rates vary extensively
between species
– Even vary between strains of the
same species

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CAUSES OF MUTATIONS
• Hermann Muller (1927)
– Showed that X rays can cause induced mutations
• Reasoned that a mutagenic agent might form defective
alleles
• Experimental approach focused on
formation and detection of X-linked
genes in Drosophila melanogaster

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CAUSES OF MUTATIONS
• The public is concerned about mutagens for two
important reasons
– Mutagenic agents are often
involved in the development
of human cancers
– Avoiding mutations that may
have harmful effects on future
offspring is desirable

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CAUSES OF MUTATIONS
• An enormous array of agents can act as mutagens
– Chemical agents and physical agents

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CAUSES OF MUTATIONS
• Certain non-mutagenic chemicals can be altered
to a mutagenically active form after ingestion
– Cellular enzymes such as oxidases can activate some
mutagens
• Certain foods contain chemicals acting as
antioxidants
– Antioxidants may be able to counteract the effects of
mutagens and lower cancer rates

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CAUSES OF MUTATIONS
• Mutagens alter DNA structure in various ways
– Nitrous acid (HNO3) replaces amino groups with keto
groups
• -NH2 ! =O
• Can change cytosine
to uracil
– Pairs with A, not G
• Can change adenine
to hypoxanthine
– Pairs with C, not T

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CAUSES OF MUTATIONS
• Mutagens alter DNA structure in various ways
– Alkylating agents covalently attach methyl or ethyl
groups to bases
• e.g., Nitrogen mustards, ethyl
methanesulfonate (EMS)
– Appropriate base pairing is
disrupted

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CAUSES OF MUTATIONS
• Mutagens alter DNA structure in various ways
– Some mutagens directly interfere with the DNA
replication process
– e.g., Acridine dyes such as proflavin
• Flat, planar structures interchelate into the double helix
– Sandwich between adjacent base pairs
• Helical structure is distorted
• Single-nucleotide additions and deletions can result

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CAUSES OF MUTATIONS
• Mutagens alter DNA structure in various ways
– DNA molecules are sensitive to physical agents such
as radiation
• e.g., Ionizing radiation such as X rays and gamma rays
– Short wavelength and high energy
– Can penetrate deeply into biological materials
– Creates “free radicals”
» Chemically reactive molecules
– Free radicals alter DNA structure in a variety of ways
» Deletions, single nicks, cross-linking, chromosomal breaks

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