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Mutation: Origin of genetic variation
sources of new alleles
rate and nature of mutations
sources of new genes
highly repeated functional sequences
new alleles arise from changes in DNA sequence
point mutations
deletions
frameshift mutations
insertions
transposition
inversion or translocation breakpoints
point mutations may either be
synonymous substitutions -- no change in amino
acid identity
replacement substitutions -- changed amino acid
60-70% of mutations are transitions (vs. exp. 33%)
Transition Resistant
Basic
Polar
Acidic
mutation rates vary considerably among species
mutation rates vary considerably among genes
within a species
most mutations are deleterious -- C. elegans
(Vassilieva et al. 2000)
most mutations are deleterious
WHY??
If all mechanisms were nearly ‘perfect’ any change
would be detrimental. Maybe
Best place
50% chance
of improvement
most mutations are deleterious
WHY??
If all mechanisms were nearly ‘perfect’ any change
would be detrimental. Maybe
Suppose two dimensions
Chance of improvement
Less than 50%
With many more dimensions
the chance of improvement
goes to zero.
most mutations are only slightly deleterious
Origins of new genes
duplications
pseudogenes
Repeated arrays
Function lost
Mutations accumulate
novel functions
e.g. Tandem repeats
of rRNA genes
Absence of variation in repeats
Suggests functional requirements
Expression patterns
Exon shuffling
Internal repeats
New genes via internal duplications:
antifreeze glycoprotein in Antarctic Toothfish
(Dissostichus mawsoni)
waters of the
Antarctic Ocean -1.9oC
most fish freeze at
-1.0oC to –0.7oC
ancestral
trypsinogen gene
antifreeze
glycoprotein gene
(from Graur & Li 2000)
New genes via exon shuffling:
tissue plasminogen activator evolves from four
unrelated genes
protease
kringle (plasminogen)
epidermal growth factor
fibronectin type-1
(from Graur & Li 2000)
new alleles are produced by mutation
most mutations are slightly deleterious
duplication is the most important mechanism
for producing new genes
Populations are affected by two sets of processes:
1. Genetic -- mutation, recombination, independent
assortment, transposition, meiotic drive
2. Ecological -- changes in population size, dispersal,
mating system, environmental variation
How do these processes affect population
genetic variation ?
plumage variation in the snow goose, Chen caerulescens
white phase
blue phase
morphological variation in Panaxia dominula
P. d. dominula
cdcd
P. d. medionigra
cdcb
P. d. bimacula
c bc b
protein electrophoresis
PO7 275kb
Microsatellite loci for
Pogonomyrmex
occidentalis
PO8 250kb
PO3 160kb
PO1 175kb
Quantifying population genetic variation:
# particular genotype
genotype frequency =
total number of individuals
allele frequency =
# particular allele
total number of alleles
by the law of proportions, both genotype and allele
frequencies always sum to one
genotype
A1A1
A1A2
A2A2
number
670
200
130
genotype
frequency
670
1000
200
1000
130
1000
geno freq.
0.67
0.20
0.13
frequency of A1 = 0.67 +
1
2
(0.20) = 0.77
frequency of A2 = 0.13 +
1
2
(0.20) = 0.23
genotype
A1A1
A1A2
A2A2
number
670
200
130
Genotype
frequency
0.67
0.20
0.13
Allele frequencies:
A1 = 0.77
A2 = 0.23
What are the expected genotype frequencies?
A1A1
A1A2
A2A2
.77x.77
2x(.77x.23)
.23x.23
.59
.35
.05
genotype
A1A1
Genotype
frequency
G1
Allele frequency
A1
A1A2
A2A2
G2
G3
p
A2
q
Expected genotype frequencies:
p2
Remember:
2pq
q2
p+q = 1
Therefore (p+q)
2
= 12 , or
p2 + 2pq + q2 =1
When the observed genotype frequencies
equal the expected genotype frequencies
the population is said to be in
Hardy-Weinberg Equilibrium
Hardy-Weinberg Equilibrium
In the presence of certain conditions, the genotype
frequencies of a population will be stable over time, and
will be directly predictable from the allele frequencies.
If the population is not at equilibrium, it will achieve it
after one generation of random mating.
Assumes: no mutation, no selection, infinite population
size, no gene flow, random mating
Null model for describing population genetic
variation
How do we know whether a population is in HWE:
genotype
MM
MN
NN
number
60
20
20
obs. gen. fr.
0.6
0.2
0.2
f (M) = 0.6 + 0.1 = 0.7 f (N) = 0.2 + 0.1 = 0.3
exp. gen. fr.
f (M)2
2f (M)f (N)
f (N)2
(0.7)2
0.49
49
2(0.7)(0.3) (0.3)2
0.42
0.09
42
9
DO NOT say: (0.7)2 + 2(0.7)(0.3) + (0.3)2 = 1, therefore HWE.
Compare observed and expected genotype distributions
with a goodness of fit chi-square test with
n-1 degrees of freedom (n = number of categories)
One additional degree of freedom is lost
when estimating allele frequencies dof = (n - 2)
c2
dof
=
S
(observed # - expected #)2
(expected #)
for the data on the previous page:
c2
Look up in Table:
critical values
df
1
2
3
2
= 27.4
0.05
3.84
6.0
7.82
.025
5.02
7.38
9.35
0.01
6.64
9.21
11.35
0.005
7.88
10.6
12.84
HWE and sex-linked genes
autosomes: half of the alleles in each sex
sex chromosomes: two-thirds of the alleles in the
homogametic (XX) sex
if males are homogametic,
A1A1
A1A2
males
A2A2
A1/
A2/
females
allele frequencies are sex-specific: pm, qm and pf, qf
Under random mating:
qm’ =
qf’ =
1
2
(qm + qf) males get an X-chromosome
from each parent
qm
females get their only X-chromosome
from their father
qm’- qf’ = ½ qm + ½ qf - qm = - ½(qm- qf )
>
p =
2
3
pm +
1
3
pf
q =
2
3
qm + 13 qf
1.2
Frequency of A2
1.0
0.8
0.6
0.4
0.2
0.0
0
2
4
6
8
Generation
10
12
FEMALE
MALE
genetic diversity characterizes most natural
populations
Hardy-Weinberg Equilibrium represents a null
model for the evolution of genotype frequencies
basis for mathematically examining the effects of:
mutation, selection, genetic drift, gene flow,
and non-random mating
dynamics of HWE differ for sex-linked genes