Download Introduction to Molecular Evolution

Models of Molecular
Evolution I
Level 3 Molecular Evolution and
Bioinformatics
Jim Provan
Page and Holmes: Sections 7.1 – 7.2
The a-globin molecular clock
Molecular divergence
time
600
Shark
0.75
Carp
Frog
0.50
Alligator
Chicken
0.25
Quoll
Cow
Baboon
500
400
300
200
100
Myr ago
Fossil divergence
time
Dayhoff distance (to humans)
1.00
The a-globin molecular clock
As relationships between species diverge, number of
amino acid differences appear to increase proportionally
Assuming the divergence time of one of the points is
known (humans and cows diverged 80 Myr ago), other
divergence times can be calculated:
17 of 149 amino acids (Dayhoff distance 0.131) differ between
humans and cows
47 differences (Dayhoff distance 0.445) between humans and
alligators
Suggests that humans and alligators diverged 3.4 times as long
ago as humans and cows (~270 Myr ago)
Fossil record suggests that humans and alligators diverged
~300 Myr ago: a-haemoglobin is behaving like a molecular clock
Processes of molecular evolution
Why should such a clock exist and how accurate is it?
Answer to this question will give insights into how
nucleotide and amino acid sequences evolve
Since the 1960s there have been two conflicting
models of how molecular evolution takes place:
One (neutralist) is dominated by the genetic drift of neutral
mutations
The other (selectionist) states that natural selection of
advantageous mutations is more important
Knowing which model best explains molecular evolution will
ultimately lead to development of more realistic models of
DNA substitution and thus allow the construction of more
accurate phylogenies
The classical and balance schools of
population genetics
Foundation of the neutralist-selectionist debate was laid in
the 1950s in the debate between the classical and
balance schools of population genetics:
The classical school believed that natural selection was
predominantly a purifying force, removing deleterious alleles, and
that there would be little genetic variation in populations
The balance school claimed that levels of genetic variation were
so high that most loci were polymorphic and that individuals were
heterozygous at a large number of loci – this scenario was
maintained by balancing (overdominant) selection
Both schools were agreed that natural selection was the
driving force in evolution but there was no evidence for
the divisive issue: how much genetic variation existed
within and between species?
Levels of variation in allozymes
Proportion of polymorphic loci
0.5
Drosophila
0.4
Invertebrates exc. insects
All invertebrates
Insects exc. Drosophila
0.3
European humans
Plants
Amphibians
Reptiles
0.2
Mammals
All vertebrates
Fish
Birds
0.1
0.0
0.00
0.05
0.10
Heterozygosity
0.15
The cost of natural selection and the
rise of the neutral theory
Technical advances had revealed that the balance
school was correct concerning levels of variation
These results posed a problem:
If natural selection had produced all this diversity, would it
not also be true that individuals with inferior alleles would be
selectively removed from the population?
The population could go extinct with all this “selective
death” - this is known as the cost of natural selection
Cost of natural selection is part of the overall genetic load –
the loss of overall fitness due to deleterious alleles:
—
—
Reason why classical school through there was low variation
This would be appropriate for substitutional load
Segregational load
Occurs when a polymorphism is maintained due to
overdominant selection
Classic example is human sickle-cell anaemia:
Individuals homozygous for HbA haemoglobin allele produce
normal haemoglobin
Individuals homozygous for HbS haemoglobin allele produce
mutant haemoglobin (sickle cell-anaemia: 80% fatal) but are
much less susceptible to malaria
Heterozygous individuals do not suffer from sickle-cell
anaemia and are much more resistant to malaria
Laws of Mendelian segregation show that individuals who
are susceptible to malaria (HbA /HbA) or to sickle-anaemia
(HbS /HbS) will still be produced
The neutral theory of molecular
evolution
High levels of genetic variation could be maintained
in populations without excessive selective death if
natural selection was not the driving force in
molecular evolution
Neutral mutations could be lost (usually) or fixed
(very occasionally) by genetic drift:
The neutral theory of molecular evolution suggests that
mutation and drift predominate
The selectionist school believed that selection was the
dominant force
Both agree that selection removes deleterious alleles
Central dogma of chance vs. necessity
Neutralist and selectionist models of
molecular evolution
Neutralist
Selectionist
Deleterious
Neutral
Advantageous
The neutralist-selectionist debate
Neutralist theory is not anti-Darwinist:
Claims that fixation through selection – the main process of
morphological evolution – occurs at low frequency
Effectively believes that most genes and proteins are already
almost-optimally adapted through selection
Current debate centres around four major predictions of
the neutral theory:
There is an inverse correlation between substitution rate and
degree of functional constraint acting on a gene
Patterns of base composition and codon usage reflect mutational
rather than selective processes
There is a constant rate (molecular clock) of sequence evolution
Level of within species variation is a product of only population
size and mutation rate
Functional constraint and amino acid
substitution
Rates of amino acid substitution are extremely
variable:
Fibrinopeptides evolve 900 times faster than histones
To neutralists, this difference is explainable by differences in
selective constraint, rather than positive selection
The more functionally constrained a gene is, the
higher the chance that a mutation will be deleterious
Correlation between functional constraint and
substitution rate is proposed as evidence for the
neutral theory
Functional constraint and amino acid
substitution
Functionally constrained
gene
Less functionally
constrained gene
Deleterious
Neutral
Non-coding DNA
Functional constraint at the
nucleotide level
Functional genes
Gene
Pseudogene
Position 1
Position 2
Position 3
Mouse ya3
Human ya1
Rabbit yb2
Goat ybx and yz
5.0
5.1
4.1
4.4
0.75
0.75
0.94
0.94
0.68
0.68
0.71
0.71
2.65
2.65
2.02
2.02
Average
4.7
0.85
0.70
2.34
Rates of nucleotide substitution per site, per year x 10-9