Molecular Evolution
What is molecular evolution?
Change measured by scale of DNA, RNA, proteins
Hereditary variations is the medium of evolution – result of underlying changes at
DNA level
- DNA sequence evolution: changes to DNA over time
- Molecular basis of adaptive phenotypes
Molecular evolution of single genes and molecular clock/adaptive
evolution/duplicated genes
Molecular evolution stems from mutations (which are random)
Some mutations affect gene function – typically changing the amino acid = non-
synonymous substitution
- If deleterious – removed by purifying selection
- If advantageous – fixed by positive selection
- Epas1 gene has an allele that confers advantages at high altitudes by increasing
production of RBCs – has been selected in Tibetan population
Most mutations have no effect on gene function – no change in amino acid sequence
= silent substitutions, or synonymous substitutions
- Silent substitutions have no fitness effect – evolve neutrally, through genetic
drift
Neutral Theory and Molecular Evolution
(Kimura, 1968) – suggested that most polymorphisms observed at the molecular level
are selectively neutral, so that their frequency dynamics in a population are
determined primarily by random genetic drift
When theory was first developed – data consisted of protein polymorphism data
Neutral theory is important in generating rigorous null hypotheses
- When the theory is rejected: reasons include heterogeneity in mutation process,
mis-specification of the sampling process, hidden population structure and
migration, natural selection
Original formulation of the theory focused on mutations are strictly selectively
neutral so fate is determined purely through random genetic drift
- Mutations could have effects of fitness, but were postulated that mutations
would either be deleterious and rapidly eliminated, or much more rarely,
favourable and rapidly fixed
, - As deleterious mutations are removed quickly, effect would be as though the
neutral mutation rate were simply lower by an amount equal to proportion of
mutations that are deleterious
In all models – random drift occurs when N adult individuals produce an infinite pol
of gametes from which 2N are chosen at random to create N zygotes of the next
generation
- Under genetic drift, rate of fixation of silent substitutions should be steady
through time (proportional to rate of mutation)
- µ: mutation rate per gene per generation
- N: population size (number of individuals contributing to the next generation)
- No, of chromosomes in population = 2N for diploid
- No, of new mutations per generation = 2Nµ
- Probability that any new mutation will be fixed in populations = 1/2N
- Rate of substitution (tick rate of clock) = 2Nµ x 1/2N = µ
Predicts steady change through time =
Molecular clock
- Sampling individual at each generation,
longer the divergence time, larger the
differences
- Mutations will also be different for
each individual
Evidence for the Neutral Theory
Rate of silent substitutions is higher than rate of non-synonymous substitutions
Among non-synonymous substitutions, changes to amino acids with similar
biochemical properties is common than changes with greater effect on protein
function
Non-coding sequences such as introns and pseudogenes evolve at high rate, similar
to silent sites
The Molecular Clock
Tick-rate of clock varies
by nucleotide type
- High tick-rate in
pseudogenes – as most
of them neutral and
genes don’t serve any
known function
Tick-rate varies by gene type
- Functional constraints: magnitude of effect of mutation
, - Genes with higher functional constraints evolve more slowly – fewer mutations
are neutral
(Rabosky et al., 2012) – molecular clock and silent DNA substitutions can be used to
infer phylogenetic relationships, speciation
rates, divergence rates
- Measure genetic distance between species
- Use number of genetic changes per unit
changes per unit time to convert genetic
distance to divergence time
- Calibrate with known divergence time (fossil
record, biogeography) – but is it reliable?
- Positive gradient – diversity decreasing over
time, negative slope, no. of species increasing
over time
Assumptions of the molecular clock
1. Genetic drift is constant – but selection is
weaker is smaller
- Genetic drift is stronger if you have fewer
chromosomes
2. Mutation rate is constant
- But mutation rate is affected by metabolic rate – higher metabolism causes
more oxidative damage to DNA = faster tick rate
- Generation time: faster generation time increases number of meiotic divisions
per year = faster tick rate
3. Selection is constant
- But adaptive bursts happen (eg. adaptation to a new food source) – eg.
Hawthorne to domestic apple preference by Rhagoletis
- Gene duplication can change selective force
By knowing the sources of variation,
molecular clock can be modelled and
corrected for
The Hawaiian Molecular clock
Divergence of species matches
geographical separation seen
Hawaiian islands formed as a
result of volcanic activity
What is molecular evolution?
Change measured by scale of DNA, RNA, proteins
Hereditary variations is the medium of evolution – result of underlying changes at
DNA level
- DNA sequence evolution: changes to DNA over time
- Molecular basis of adaptive phenotypes
Molecular evolution of single genes and molecular clock/adaptive
evolution/duplicated genes
Molecular evolution stems from mutations (which are random)
Some mutations affect gene function – typically changing the amino acid = non-
synonymous substitution
- If deleterious – removed by purifying selection
- If advantageous – fixed by positive selection
- Epas1 gene has an allele that confers advantages at high altitudes by increasing
production of RBCs – has been selected in Tibetan population
Most mutations have no effect on gene function – no change in amino acid sequence
= silent substitutions, or synonymous substitutions
- Silent substitutions have no fitness effect – evolve neutrally, through genetic
drift
Neutral Theory and Molecular Evolution
(Kimura, 1968) – suggested that most polymorphisms observed at the molecular level
are selectively neutral, so that their frequency dynamics in a population are
determined primarily by random genetic drift
When theory was first developed – data consisted of protein polymorphism data
Neutral theory is important in generating rigorous null hypotheses
- When the theory is rejected: reasons include heterogeneity in mutation process,
mis-specification of the sampling process, hidden population structure and
migration, natural selection
Original formulation of the theory focused on mutations are strictly selectively
neutral so fate is determined purely through random genetic drift
- Mutations could have effects of fitness, but were postulated that mutations
would either be deleterious and rapidly eliminated, or much more rarely,
favourable and rapidly fixed
, - As deleterious mutations are removed quickly, effect would be as though the
neutral mutation rate were simply lower by an amount equal to proportion of
mutations that are deleterious
In all models – random drift occurs when N adult individuals produce an infinite pol
of gametes from which 2N are chosen at random to create N zygotes of the next
generation
- Under genetic drift, rate of fixation of silent substitutions should be steady
through time (proportional to rate of mutation)
- µ: mutation rate per gene per generation
- N: population size (number of individuals contributing to the next generation)
- No, of chromosomes in population = 2N for diploid
- No, of new mutations per generation = 2Nµ
- Probability that any new mutation will be fixed in populations = 1/2N
- Rate of substitution (tick rate of clock) = 2Nµ x 1/2N = µ
Predicts steady change through time =
Molecular clock
- Sampling individual at each generation,
longer the divergence time, larger the
differences
- Mutations will also be different for
each individual
Evidence for the Neutral Theory
Rate of silent substitutions is higher than rate of non-synonymous substitutions
Among non-synonymous substitutions, changes to amino acids with similar
biochemical properties is common than changes with greater effect on protein
function
Non-coding sequences such as introns and pseudogenes evolve at high rate, similar
to silent sites
The Molecular Clock
Tick-rate of clock varies
by nucleotide type
- High tick-rate in
pseudogenes – as most
of them neutral and
genes don’t serve any
known function
Tick-rate varies by gene type
- Functional constraints: magnitude of effect of mutation
, - Genes with higher functional constraints evolve more slowly – fewer mutations
are neutral
(Rabosky et al., 2012) – molecular clock and silent DNA substitutions can be used to
infer phylogenetic relationships, speciation
rates, divergence rates
- Measure genetic distance between species
- Use number of genetic changes per unit
changes per unit time to convert genetic
distance to divergence time
- Calibrate with known divergence time (fossil
record, biogeography) – but is it reliable?
- Positive gradient – diversity decreasing over
time, negative slope, no. of species increasing
over time
Assumptions of the molecular clock
1. Genetic drift is constant – but selection is
weaker is smaller
- Genetic drift is stronger if you have fewer
chromosomes
2. Mutation rate is constant
- But mutation rate is affected by metabolic rate – higher metabolism causes
more oxidative damage to DNA = faster tick rate
- Generation time: faster generation time increases number of meiotic divisions
per year = faster tick rate
3. Selection is constant
- But adaptive bursts happen (eg. adaptation to a new food source) – eg.
Hawthorne to domestic apple preference by Rhagoletis
- Gene duplication can change selective force
By knowing the sources of variation,
molecular clock can be modelled and
corrected for
The Hawaiian Molecular clock
Divergence of species matches
geographical separation seen
Hawaiian islands formed as a
result of volcanic activity
