PROTEIN FORM AND FUNCTION

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PROTEIN FORM AND FUNCTION PROTEIN
EVOLUTION Mike Wallis
Sequence variation Gene/protein
families Extended proteins Domain shuffling
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CYTOCHROME c An example of accumulation of
point mutations during evolution Sequence
comparisons Constant features Variable
features - even distribution across
sequence Neutral theory - constant evolutionary
rate? (the idea of the molecular clock)
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BUT - ADAPTIVE EVOLUTION DOES HAPPEN So not all
changes can be neutral

• Even for cytochrome c, not everything fits for
  the neutral theory
• Distribution of substitutions in the 3D structure
• Replacement of yeast cyt c gene by horse cyt c
  gene
• Variable rate of evolution

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Cytochrome c (reduced)
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RATES OF EVOLUTION
Conventional view that the rate of evolution is
usually constant for any one protein, but varies
widely between proteins Differences between
proteins are due to different strengths of
purifying selection
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RATES OF PROTEIN EVOLUTION
Rate of
Evolution Fibrinopeptides 9.0 Luteinizing
hormone ?-chain 3.0 Lactalbumin 2.7 Ribonuclease
2.1 Serum albumin 1.9 Haemoglobin
?-chain 1.2 Lysozyme 1.0 Myoglobin 0.9 Trypsi
n 0.6 Insulin 0.4 Cytochrome
c 0.2 Glutamate dehydrogenase
0.09 Histone 0.01 _____________________________
____________ Substitutions/ amino acid site/
109 years
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ARE RATES OF MOLECULAR EVOLUTION CONSTANT?
The neutral theory holds that the rate of
evolution is normally constant for any one
protein, but varies from one protein to another,
as the table shown earlier implies. But there
are many exceptions, including
insulin haemoglobin cytochrome c
growth hormone (and many other polypeptide
hormones) lysozyme histones
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PHYLOGENETIC TREE FOR MAMMALIAN GHS

GP
Chevrotain
Marmoset
Loris
Dolphin
Horse
Elephant
Man
Alpaca
Ox
Sheep
Goat
Dog
Rat
Mouse
Rabbit
Rhesus
Hamster
Possum
Deer
Pig
0
0
0
2
0
0
2
1
1
2
4
12
3
3
0
7
0
2
1
0
25
0
4
2
3
12
Million years before present
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76
50
11
2
7
0
0
75
Rate of evolution

slow phase 0.32
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ruminants (rapid phase) 3.9 Primates (rapid
phase) 22.2
_______________________ substitutions/aa
site/109yr
100
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EVOLUTION OF LYSOZYME IN HIGHER PRIMATES
From Messier Stewart (1997)
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POINT MUTATIONS THAT HAVE A BIG EFFECT

• Haemoglobin S - heterosis
• Chain termination mutants - chain elongation
• e.g. Haemoglobin Constant Spring -
  elongated C- terminus (lethal as homozygote)
• luteinizing hormone (LH) and human
  chorionic gonadotropin (hCG)

• Mutations at splice sites

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PROTEIN EVOLUTION AT THE SEQUENCE LEVEL
Sequence variation Gene/protein
families Extended proteins Domain shuffling
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HAEMOGLOBIN
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EVOLUTIONARY TREE RELATING HUMAN GLOBIN CHAINS
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HAEMOGLOBIN GENE CLUSTERS
Chromosome 16
Chromosome 11
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MECHANISM OF GENE DUPLICATION
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CONSEQUENCES OF RECOMBINATION BETWEEN DISPERSED
REPETITIVE DNA ELEMENTS
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THE HUMAN GROWTH HORMONE GENE CLUSTER
hGH-N
hPL-L
hPL-A
hGH-V
hPL-B
0
20
40
60
10
30
50
kbp
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?
Prevertebrate
ILs, GFs etc (cytokines)
Early vertebrate
GH
PRL
Mammals
PLs
PLs
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• Immediate consequences of gene duplication (fate
  of duplicated genes)
• One gene may drift until mutations
  /substitutions convert it to a pseudogene
• Retention. Second gene may be retained because
  more expression product required
• 3. Subfunctionalization. Both genes deteriorate
  slightly, or there is some separation of
  functionality, so that they have the same
  capacity between them as the original gene.
• 4. One gene may drift until mutations/substituti
  ons convert it to something usefully different.

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• Long term consequences of gene duplication
• Provision of second copy (or multiple copies) of
  gene where large amounts of transcript required
• 2. Forms basis of gene families
• 3. Increase in genome size
• 4. Increase in protein complexity (e.g.
  subunits) and subtlety (e.g. enzymes with small
  differences in specificity)
• 5. Development of completely new functions

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• BUT sometimes gene duplication may meet a
  pre-existing need/opportunity.
• e.g.
• A protein already has two functions (e.g. GH in
  primates?)
• subunits are already associating
• snow goose haemoglobin
• multiple hormone receptors

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Cytokine receptors