Mutation: Origin of genetic variation

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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
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new alleles arise from changes in DNA sequence
point mutations deletions insertions transposition
inversion or translocation breakpoints
frameshift mutations
point mutations may either be synonymous
substitutions -- no change in amino acid
identity replacement substitutions --
changed amino acid
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60-70 of mutations are transitions (vs. exp.
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Transition Resistant
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Basic
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Polar
Acidic
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mutation rates vary considerably among species
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mutation rates vary considerably among genes
within a species
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most mutations are deleterious -- C. elegans
(Vassilieva et al. 2000)
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most mutations are deleterious WHY??
If all mechanisms were nearly perfect any
change would be detrimental.
Maybe
50 chance of improvement
Best place
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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.
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most mutations are only slightly deleterious
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Origins of new genes
duplications
novel functions
pseudogenes
Repeated arrays
Expression patterns Exon shuffling Internal
repeats
Function lost Mutations accumulate
e.g. Tandem repeats of rRNA genes
Absence of variation in repeats Suggests
functional requirements
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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
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ancestral trypsinogen gene
antifreeze glycoprotein gene
(from Graur Li 2000)
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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)
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new alleles are produced by mutation most
mutations are slightly deleterious duplication
is the most important mechanism for producing
new genes
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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 ?
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plumage variation in the snow goose, Chen
caerulescens
white phase
blue phase
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morphological variation in Panaxia dominula
P. d. dominula cdcd
P. d. medionigra cdcb
P. d. bimacula cbcb
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protein electrophoresis
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PO7 275kb
Microsatellite loci for Pogonomyrmex
occidentalis
PO8 250kb
PO3 160kb
PO1 175kb
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Quantifying population genetic variation
genotype frequency
particular genotype total number of
individuals
particular allele total number of alleles
allele frequency
by the law of proportions, both genotype and
allele frequencies always sum to one
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genotype A1A1 A1A2 A2A2 number 670
200 130
genotype 670 200 130 frequency 1000
1000 1000
geno freq. 0.67 0.20 0.13
1 2
frequency of A1 0.67 (0.20) 0.77
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frequency of A2 0.13 (0.20) 0.23
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genotype A1A1 A1A2 A2A2 number 670
200 130
Genotype 0.67 0.20 0.13 frequency
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
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genotype A1A1 A1A2 A2A2
Genotype G1 G2 G3 frequency
Allele frequency A1 p
A2 q
Expected genotype frequencies
p2 2pq q2
Remember pq 1 Therefore (pq) 2 12
, or p2 2pq q2 1
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When the observed genotype frequencies equal the
expected genotype frequencies the population is
said to be in Hardy-Weinberg Equilibrium
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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
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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 2(0.7)(0.3)
(0.3)2 0.49
0.42 0.09 49 42
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DO NOT say (0.7)2 2(0.7)(0.3) (0.3)2 1,
therefore HWE.
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• Compare observed and expected genotype
  distributions
• with a goodness of fit chi-square test with
• n-1 degrees of freedom (n number of
  categories)
• c2 dof

One additional degree of freedom is lost when
estimating allele frequencies dof (n - 2)
for the data on the previous page c2 2 27.4
Look up in Table critical values 0.05 .025 0.01
0.005 df 1 3.84 5.02 6.64 7.88
2 6.0 7.38 9.21 10.6 3 7.82 9.35 11.35 12.84
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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
A2A2 A1/ A2/
males females
allele frequencies are sex-specific pm, qm and
pf, qf
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Under random mating qm (qm qf)
males get an X-chromosome from each
parent qf qm females get their only
X-chromosome from their father
1 2
qm- qf ½ qm ½ qf - qm - ½(qm- qf )
gt
gt
1 3
1 3
2 3
2 3
p pm pf q qm qf
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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