Mutation
Timothy G. Standish, Ph. D.
©1999 Timothy G. Standish
The Modern Synthesis
Charles Darwin recognized that variation existed
in populations and suggested natural selection as
a mechanism for choosing some variants over
others resulting in survival of the fittest and
gradual changes in populations of organisms.
 Without a mechanism for generation of new
variation, populations would be selected into a
corner where only one variation would survive
and new species could never arise.
 The Modern Synthesis combines the mechanism
of mutation in DNA to generate variation with
natural selection to produce new species.

©1999 Timothy G. Standish
Mutation
Mutation = Change
 Biologists use the term “mutation” when talking
about any change in the genetic material. Not all
result in a change in phenotype.
 There are two major types of mutations:
 Macromutations - Also called macrolesions and
chromosomal aberations. Involve changes in
large amounts of DNA.
 Micromutations - Commonly called point
mutations and microlesions.

©1999 Timothy G. Standish
Macromutations

1
2
3
4
Four major types of Macromutations are
recognized:
Deletions - Loss of chromosome sections
Duplications - Duplication of chromosome
sections
Inversions - Flipping of parts of
chromosomes
Translocations - Movement of one part of a
chromosome to another part
©1999 Timothy G. Standish
Macromutation - Deletion
Chromosome
Centromere
Genes
A
B
C
D
E
F
A
B
C
D
G
H
G
H
E
F
©1999 Timothy G. Standish
Macromutation - Duplication
Chromosome
Centromere
Genes
A
B
C
D
E
F
G
H
A
B
C
D
E
F
EE
FF
G
H
Duplication
©1999 Timothy G. Standish
Macromutation - Inversion
Chromosome
Centromere
Genes
A
B
C
D
E
F
A
B
C
D
F
E
Inversion
G
H
G
H
©1999 Timothy G. Standish
Macromutation - Translocation
Chromosome
Centromere
A
B
C
A
B
E
Genes
D
F
E
C
F
G
H
D
G
H
©1999 Timothy G. Standish
Micro or Point Mutations
Two major types of Macromutations are
recognized:
1 Frame Shift - Loss or addition of one or two
nucleotides
2 Substitutions - Replacement of one nucleotide
by another one. There are a number of
different types:

– Transition - Substitution of one purine for another
purine, or one pyrimidine for another pyrimidine.
– Transversion - Replacement of a purine with a
pyrimidine or vice versa.
©1999 Timothy G. Standish
Frame Shift Mutations
3’AGTTCAG-TAC-TGA-ACA-CCA-TCA-ACT-GATCATC5’
5’AGUC-AUG-ACU-UGU-GGU-AGU-UGA-CUAGAAA3’
Met
Thr
Cys
Gly
Ser
3’AGTTCAG-TAC-TGA-AAC-CAT-CAA-CTG-ATCATC5’
5’AGUC-AUG-ACU-UUG-GUA-GUU-GAC-UAG-AAA3’
Met
Thr
Leu
Val
Val
Val
Frame shift mutations tend to have a dramatic effect on proteins as
all codons down stream from the mutation are changed and thus
code for different amino acids. As a result of the frame shift, the
length of the polypeptide may also be changed as a stop codon will
probably come at a different spot than the original stop codon.
©1999 Timothy G. Standish
Substitution Mutations
3’AGTTCAG-TAC-TGA-ACA-CCA-TCA-ACT-GATCATC5’
5’AGUC-AUG-ACU-UGU-GGU-AGU-UGA-CUAGAAA3’
Transition
Met
Thr
Cys
Gly
Ser
3’AGTTCAG-TAC-TGA-ATA-CCA-TCA-ACT-GATCATC5’
5’AGUC-AUG-ACU-UAU-GGU-AGU-UGA-CUAGAAA3’
Met
Thr
Tyr
Gly
Ser
Pyrimidine to
Pyrimidine
3’AGTTCAG-TAC-TGA-ACA-CCA-TCA-ACT-GATCATC5’
5’AGUC-AUG-ACU-UGU-GGU-AGU-UGA-CUAGAAA3’
Transversion
Met
Thr
Cys
Gly
Ser
3’AGTTCAG-TAC-TGA-AAA-CCA-TCA-ACT-GATCATC5’
5’AGUC-AUG-ACU-UUU-GGU-AGU-UGA-CUAGAAA3’
Met
Thr
Phe
Gly
Ser
Purine to
Pyrimidine
©1999 Timothy G. Standish
Transitions Vs Transversions





Cells have many different mechanisms for preventing
mutations
These mechanisms make mutations very uncommon
Even when point mutations occur in the DNA, there
may be no change in the protein coded for
Because of the way these mechanisms work,
transversions are less likely than transitions
Tranversions tend to cause greater change in proteins
than transitions
©1999 Timothy G. Standish
The Genetic Code
Neutral Non-polar
Polar
Basic
Acidic
F
I U
R
S C
T
†Have amine
groups
*Listed as
non-polar by
some texts
B A
A
S G
E
SECOND
U
UUU
UUC
UUA
UUG
CUU
CUC
CUA
CUG
Phe
Leu
Leu
C
UCU
UCC
UCA
UCG
CCU
CCC
CCA
CCG
AUU
AUC Ile
AUA
AUGMet/start
ACU
ACC
ACA
ACG
GUU
GUC
GUA
GUG
GCU
GCC
GCA
GCG
Val
BASE
A
Ser
UAU
UAC
UAA
UAG
Tyr
Pro
CAU
CAC
CAA
CAG
His
Thr
AAU
AAC
AAA
AAG
Asn†
Ala
GAU
GAC
GAA
GAG
Asp
Stop
Gln†
Lys
Glu
G
UGU
UGC
UGA
UGG
CGU
CGC
CGA
CGG
AGU
AGC
AGA
AGG
GGU
GGC
GGA
GGG
Cys
Stop
Trp
U
C
A
G
Arg
U
C
A
G
Ser
Arg
Gly*
U
C
A
G
U
C
A
G
T
H
I
R
D
B
A
S
E
©1999 Timothy G. Standish
The Sickle Cell Anemia Mutation
Normal b-globin DNA
C
Mutant b-globin DNA
T
T
C
G A
A
G U A
mRNA
mRNA
Normal b-globin
Mutant b-globin
Glu
H2 N
C
C
A T
Val
O
OH
H
CH2
H2C
C OH
O Acid
H2 N
C
C
O
OH
H
CH
CH3
H3C
Neutral
Non-polar
Sickle Cell Anemia:
A Pleiotropic Trait
Mutation of base 2 in b globin codon 6 from A to T
causing a change in meaning from Glutamate to Valine
Mutant b globin is produced
Breakdown of
Red blood cells
Anemia
Clogging of small
Blood vessels
Tower skull
Weakness
Heart failure
Impaired
mental function
Accumulation of sickled
Cells in the spleen
Red blood cells sickle
Brain
damage
Paralysis
Pain and
Fever
Damage to
other organs
Rheumatism
Kidney
failure
Spleen
damage
Infections
Especially
Pneumonia
©1999 Timothy G. Standish
The Likely and the Unlikely
Arguments about evolution frequently revolve
around probability. Meaningful complexity is
unlikely to result from random events.
Organisms are meaningfully complex. Some
claim that natural selection overcomes much of
this problem as, while change (mutation) may
be random, selection is not.
 Science is about predicting what is likely and
what is unlikely. Everyone is in agreement that
the events leading to production of living
organisms are unlikely.

©1999 Timothy G. Standish
In a Long Time
and Big Universe


It has been argued that given massive lengths of time
and a universe to work in, the unlikely becomes likely:
Given infinite time, or infinite opportunities, anything
is possible. The large numbers proverbially furnished
by astronomy, and the large time spans characteristic of
geology, combine to turn topsy-turvy our everyday
estimates of what is expected and what is miraculous.
Richard Dawkins (1989) The Blind Watchmaker: Why the
evidence of evolution reveals a universe without design. W.
W. Norton and Co. New York. p139.
©1999 Timothy G. Standish
Little or Big Changes?

Not all mutations improve fitness, they may:
– Improve the fitness of an organism (very unlikely)
– Be neutral, having no effect on fitness
– Be detrimental, decreasing an organisms fitness (most likely)



The bigger the change the more likely it is to be
significantly detrimental
Darwin argued that evolution is the accumulation of many
small changes that improve fitness, big changes are
unlikely to result in improved fitness.
“Many large groups of facts are intelligible only on the
principle that species have been evolved by very small
steps.”
– The Origin of Species Chapter VII under “Reasons for disbelieving in great
and abrupt modifications”
©1999 Timothy G. Standish
Understanding Complexity
Allows Better Estimates of
Probability
From Darwin’s time until the molecular revolution
in biology, his explanation for the origin of
organisms seemed reasonable as their complexity
was not understood fully.
 “First simple monera are formed by spontaneous
generation, and from these arise unicellular
protists . . .”
The Riddle of the Universe at the close of the
Nineteenth Century by Ernst Haeckel, 1900.

©1999 Timothy G. Standish
Behe’s Insight


Michael Behe contends that when we look at the protein
machines that run cells, there is a point at which no parts
can be removed and still have a functioning machine.
He called these machines “irreducibly complex.”
We encounter irreducibly complex devices in everyday
life. Behe used a simple mouse trap is an example of an
irreducibly complex device:
Staple
Trigger
Hammer
Board
Cheese
Bait holder
Spring
©1999 Timothy G. Standish
Irreducibly Complex Protein
Machines



Cells are full of irreducibly complex devices - Little
protein machines that will only work if all the parts
(proteins) are present and arranged together correctly.
Natural selection does not provide a plausible mechanism
to get from nothing to the collection of parts necessary to
run a number of irreducibly complex protein machines
needed to have a living cell
Evolution of these protein machines must occur in single
steps, not gradually, as to be selected a protein must be
functional in some way. Each protein machine is fairly
complex, thus evolution in a single step seems unlikely.
©1999 Timothy G. Standish


How Can Irreducibly Complex
Protein Machines be Made?
The evolution model suggests two mechanisms:
Mechanism 1
– Random events produce proteins with some minimal function
– These proteins mutate and less functional variants are removed
by natural selection
– Some of these proteins cooperate with one another to do tasks
– From this, emergent properties of the system come about, these
only occur when all the components are present

Note that this mechanism only works if each protein
involved has individual properties conferring added fitness
©1999 Timothy G. Standish
What If Proteins Have No
Independent Function?




Evolutionary Mechanism 2:
If the function of each protein in an irreducibly complex
protein machine is completely dependant on the other
proteins, then the only way to select them would be if the
machine was already functional.
Getting a functional machine would require that all the
components come together by chance
This seems unlikely
©1999 Timothy G. Standish
©1999 Timothy G. Standish