Académique Documents
Professionnel Documents
Culture Documents
recombination
Jim Provan
A B A B
A B A b
a b a B
a b a b
Recombination (continued)
Homologous recombination
occurs between regions
Anti-Lepore
with similar sequences
d b d b
Unequal crossing-over is a
major mechanism in the
evolution of multigene d b
families:
Occurs when there is a mis-
d b
alignment between genes
during meiosis
Example is the Lepore
mutation in haemoglobin d b
Lepore
Gene conversion
Occurs when DNA sequence
of one gene is replaced
(“converted”) by sequence
from another g1 g1 g2 g2
More similar sequences g1 g2
have greater chance of
conversion g2
g1
Primate g-globin genes: g1 g1 g1 g2
TG “hot spot” TG “hot spot”
Conversion occurs at TG-
repeat “hot spots”
g1 genes can convert part of
the g2 gene
Factors affecting rates of mutation
Different sites are not equally susceptible to mutation:
sites that gain more mutations than expected are
called hotspots
Spontaneous deamination of 5-methylcytosine to thymine at
methylated 5’-CpG-3’ islands
Microsatellite length polymorphism
Enzymes for DNA replication etc. may have different
fidelity e.g. mitochondrial vs. nuclear genomes
High mutability in human and mammalian males:
Male/female ratio of substitution rate is ~6
Close to the ratio of the number of male/female germ-cell
divisions per generation
Natural selection and the fate of
mutations
The fate of a new mutation depends largely on
whether it is neutral, deleterious or advantageous
When competing genotypes differ markedly in fitness,
natural selection will operate:
Deleterious mutations will eventually be eliminated (purifying
or negative selection)
Mutations which confer a selective advantage will be
subjected to positive selection
Even a minor difference in fitness (s = 1%) may lead to
elimination of allele with lower fitness
In selectively neutral mutations, the fate of the new
genotype is determined by random genetic drift
Random genetic drift
The probability that a new mutation will become fixed
in a population also depends on the size of the
population
According to Kimura (1962), for a neutral allele the
fixation probability (P) equals its frequency in the
population:
Fixation occurs by random genetic drift
All alleles have equal probability of fixation
An advantageous mutation with selective advantage s
has a fixation probability of P=2s
Advantageous mutations are not always fixed
Even slightly deleterious mutations have a chance of fixation
The neutralist vs. selectionist debate
Selectionism considers selection as the only force that
drives the evolutionary process and that genetic drift
is of minor importance
The neutral theory of Kimura suggests that the
majority of evolutionary change is due to the random
fixation of neutral or nearly-neutral mutations
The neutralist / selectionist debate centres around the
frequency distribution and fitness of mutant alleles:
It is agreed that the majority of mutations are deleterious and
removed by purifying selection
Selectionists claim that very few mutations are neutral, whilst
neutralists maintain that most non-deleterious mutations are
neutral and very few are advantageous
Patterns of amino acid replacement
Since each codon can undergo nine types of
substitution (three positions x three substitutions),
point mutations in the 61 sense codons can lead to
549 types of substitution:
392 result in the replacement of one amino acid with
another (non-synonymous substitution)
134 result in “silent” (synonymous) mutations
Of non-synonymous substitutions, there are various
reasons why all do not occur with equal probability:
The genetic code - some interchanges require a single
substitution whilst others require two or three
Conservative changes are likely to be nearly neutral
Patterns of amino acid replacement
(continued)
Data collected by Dayhoff has shown striking
differences between the relative mutabilities of
different amino acids:
Asparagine, serine and alanine are the most mutable
Tryptophan, cysteine, tyrosine and phenylalanine are the
least mutable:
– Cysteine has several unique functions, most notably the ability
to form disulphide bonds
– Tryptophan, tyrosine and phenylalanine have bulky aromatic
side chains which are important in protein folding
20% of interchanges - far more than expected by
chance alone - involve changes of more than one
nucleotide - suggests the role of selection
Mutation data matrix
Favoured interchanges
C
S
12
0 2
between chemically
T
P
-2
-3
1
1
3
0 6
similar amino acids
A
G
-2
-3
1
1
1
0
1
-1
2
1 5 Patterns imposed by
N
D
-4
-5
1
0
0
0
-1
-1
0
0
0
1
2
2 4 natural selection against
E
Q
-5
-5
0
-1
0
-1
-1
0
0
0
0
-1
1
1
3
2
4
2 4 drastic changes
H -3 -1 -1 0 -1 -2 2 1 1 3 6
R
K
-4
-5
0
0
-1
0
0
-1
-2
-1
-3
-2
0
1
-1
0
-1
0
1
1
2
0
6
3 5
Key properties include:
M
I
-5
-2
-2
-1
-1
0
-2
-2
-1
-1
-3
-3
-2
-2
-3
-2
-2
-2
-1
-2
-2
-2
0
-2
0
-2
6
2 5
Size
L
V
-6
-2
-3
-1
-2
0
-3
-1
-2
0
-4
-1
-3
-2
-4
-2
-3
-2
-2
-2
-2
-2
-3
-2
-3
-2
4
2
2
4
6
2 4
Shape
F
Y
-4
0
-3
-3
-3
-3
-5
-5
-4
-3
-5
-5
-4
-2
-6
-4
-5
-4
-5
-4
-2
0
-4
-4
-5
-4
0
-2
1
-1
2
-1
-1 9
-2 7 10 Polarity
W -8 -2 -5 -6 -6 -7 -4 -7 -7 -6 -3 2 -3 -4 -5 -2 -6 0 0 17
Charge
C S T P A G N D E Q H R K M I L V F Y W
Ability to form bonds
The molecular clock
Idea developed from observation that number of
amino acid or nucleotide substitutions separating
orthologous proteins is roughly proportional to the
time that has passed since divergence from a
common ancestor
Another important observation is that different types
of genes change at vastly different rates which are
inversely proportional to structural and functional
constraints:
Histones can accept and fix a smaller number of mutations
Disruptive mutations are rejected by natural selection
The molecular clock (continued)
“Ticks” of the clock do not occur regularly - mutations
happen at random time intervals:
Poisson distribution originally used but actual variation is
significantly greater
Suggests that variation in evolutionary rates is greater than
that observed by chance alone:
– Mutation rates vary greatly among different evolutionary lineages
– Changes in functional constraint and selection: accelerated rates
of evolution in insulin in some rodents due to adaptive changes
– Substitutions at different sites may not be independent
– Environment may alter mutation rate directly or may change
functional constraints