Download Mutation

Mutation
Dan Graur
1
From an evolutionary viewpoint, a
mutation is a DNA sequence in the
germline that differs from its
counterparts in somatic cells, and
which is passed on from parents to
progeny, thereby endowing an
individual in the next generation with a
novel genetic constitution. Mutations
are the ultimate source of variation
and novelty in evolution.
2
Mutations: Classification Schemes
3
The Mutational “Balancing Act”
Too many mutations
Too few mutations
No Life
No Evolution
4
Mutations can occur in either
somatic or germline cells.
Somatic mutations are not
inherited in animals.
They are, therefore,
evolutionarily irrelevant.
5
Vascular plants do not
have a sequestered
germline and,
therefore, the
distinction between
somatic and germline
mutations is not
absolute.
6
Replication-dependent mutations
Replication-independent mutations
7
DNA sequences are usually
copied exactly during DNA
replication.
Rarely, however, errors occur,
giving rise to novel sequences.
These errors are called
replication-dependent mutations.
8
Mutations may be divided into induced
and spontaneous mutations according to
whether or not the mutation was caused
by an external mutagen, such as caffeine,
nitrous acid, ethidium bromide, or
ionizing and ultraviolet radiation.
9
10
Examples of mutagens:
Chernobyl
Hiroshima
Mutations affect the genotype.
Mutations may or may not affect
the phenotype.
A strict unambiguous
correspondence between genotype
and phenotype does not exist.
12
Mutations that affect the phenotype may
be:
amorphic (loss of function),
hypomorphic (partial loss of function),
hypermorphic (increase in function),
neomorphic (gain of function)…
13
An amorphic mutation in tyrosinase and
its consequences.
MLLAVLYCLLWSFQTSAGHFPRACVSSKNLMEKECCPPWSGDRSPCGQLSGRGSCQNILL
SNAPLGPQFPFTGVDDRESWPSVFYNRTCQCSGNFMGFNCGNCKFGFWGPNCTERRLLVR
RNIFDLSAPEKDKFFAYLTLAKHTISSDYVIPIGTYGQMKNGSTPMFNDINIYDLFVWMH
YYVSMDALLGGSEIWRDIDFAHEAPAFLPWHRLFLLRWEQEIQKLTGDENFTIPYWDWRD
AEKCDICTDEYMGGQHPTNPNLLSPASFFSSWQIVCSRLEEYNSHQSLCNGTPEGPLRRN
PGNHDKSRTPRLPSSADVEFCLSLTQYESGSMDKAANFSFRNTLEGFASPLTGIADASQS
SMHNALHIYMNGTMSQVQGSANDPIFLLHHAFVDSIFEQWLRRHRPLQEVYPEANAPIGH
NRESYMVPFIPLYRNGDFFISSKDLGYDYSYLQDSDPDSFQDYIKSYLEQASRIWSWLLG
AAMVGAVLTALLAGLVSLLCRHKRKQLPEEKQPLLMEKEDYHSLYQSHL
Pro81Leu
NAIROBI, Kenya — The belief that albino body parts have magical
powers has driven thousands of Africa's albinos into hiding, fearful of
losing their lives to dealers who can sell their limbs for as much as
14
$75,000.
A neomorphic mutation in a nongenic region between the a-globin
genes and their upstream regulatory elements causes a-thalassemia
Acquisition of a new
transcription factor binding site
The sequence 5'-TAATAA-3’ changed into 5'-TGATAA-3’, creating a
15
new binding site.
Point
Substitution
Deletion
Mutations
Insertion
Substantive
Segmental
Inversion
Contextual
Recombination
16
transition
substitutions
transversion
recombination
deletion
insertion
inversion
17
18
synonymous
nonsynonymous
nonsense
19
20
21
Codons that can mutate to
a termination codon by a
single nucleotide
substitution, e.g., UGC
(Tyr), are called
pretermination codons.
22
Mutations in stop
codons causing the
translation to
continue are called
“sense” mutations.
23
Each sense codon can mutate to nine
other codons by means of a single
nucleotide substitution.
Example: CCU (Pro) can experience
six nonsynonymous substitutions, to
UCU (Ser), ACU (Thr), GCU (Ala),
CUU (Leu), CAU (His), or CGU (Arg),
and three synonymous substitutions,
to CCC, CCA, or CCG.
24
Since the standard genetic
code consists of 61 sense
codons, there are:
61  9 = 549
possible nucleotide
substitutions.
25
Relat ive fr equencies o f differe nt ty pes of m utational
substitut ions in a random prote in-coding se quence

Substitution
Number
Perce nt

Total in all codons
Synonymous
549
134
100
25
Nonsynony mous
Misse nse
415
392
75
71
Nonsense
Total in first co don
Synonymo us
Nonsynony mous
Misse nse
Nonsense
23
183
8
175
166
9
4
100
4
96
91
5
Total in seco nd codon
Synonymo us
183
0
100
0
Nonsynony mous
Misse nse
183
176
100
96
Nonsense
Total in third codo n
Synonymo us
Nonsynony mous
7
183
126
57
4
100
69
31
Misse nse
50
27
Nonsense
7
4

26
Recombination
27
28
reciprocal
29
nonreciprocal
30
Reciprocal recombination is a powerful
generator of variability. For example,
recombinations between 5’—AACT—3’ and
5’—CTTG—3’ may result in 6 novel
sequences:
5’—ATTG—3’
5’—CACT—3’
5’—AATG—3’
5’—CTCT—3’
5’—AACG—3’
5’—CTTT—3’
31
The more variants there are, the more
variants will come into being through
recombination, and the rate of
generating new genetic variation will
become quite high.
“Variation begets variation.”
Golding and Strobeck (1983)
32
Insertion & Deletion
33
Insertion
Insertion
Unequal Crossing Over
34
Intrastrand
Deletion
35
36
When two sequences are
compared, it is impossible to tell
whether a deletion has occurred
in one or an insertion has
occurred in the other.
INsertions and DELetions are
collectively referred to as
INDELs.
37
The number of nucleotides
in an indel range from one
or a few nucleotides to
contiguous stretches of
thousands of nucleotides.
38
Indel lengths exhibit a bimodal
frequency distribution, with short
indels (up to 20–30 nucleotides) being
caused by errors of DNA replication,
such as slipped-strand mispairing, and
with long indels occurring mainly
because of unequal crossing-over, sitespecific recombination, DNA
transposition, or horizontal gene
transfer.
39
Inversion
(a) chromosome breakage and rejoining
(b) intrachromosomal crossing-over between two
homologous segments that are oriented in opposite
directions
40
Spatial
Distribution
of
Mutations
41
Mutations do not occur randomly
throughout the genome. Some regions are
hotspots of mutation.
One such hotspot is the dinucleotide
5'CG3' (CpG), in which the cytosine
is frequently methylated in many animal
genomes, and may mutate to 5'TG3'.
42
Mutations do not occur randomly
throughout the genome. Some regions are
hotspots of mutation.
The dinucleotide 5'TT3' is a hotspot
of mutation in many prokaryotes, but not
in eukaryotes.
43
Palindromes
44
Molecular palindrome
45
46
47
Fluctuation test. Salvadore Luria and Max
Delbrück. 1943.
48
Replica plating. Ester and
Joshua Lederberg. 1952.
49
A mutation is expected to occur
with the same frequency under
conditions in which it confers an
advantage on the organism
carrying it, as under conditions in
which it confers no advantage or is
deleterious.
“It may seem a deplorable imperfection
of nature that mutability is not
restricted to changes that enhance the
adeptness of their carriers.”
Theodosius Dobzhansky (1970)
50