Download Molecular Clock

Molecular Clock
Molecular Clock
• Rate of evolution of DNA
is constant over time and
across lineages
• Resolve history of
species
– Timing of events
– Relationship of species
• Early protein studies
showed approximately
constant rate of evolution
Different rates within a gene or genome
• Coding sequences evolve more slowly
than non-coding sequences
• Synonymous substitutions are often more
common than non-synonymous
• Some sequences are under functional
constraint
• Different genes evolve at different rates
Useless concept?
• There is no Universal Molecular Clock
• Still a very useful concept
• Possible to examine both short and long
term evolutionary processes by choosing
appropriate dataset
Rates
• How do we relate
molecular time to
geological time?
• Calibrate the clock
– Lineage divergences
in fossil record
– Major geological
events causing
isolation of populations
• Continental drift
(Panama Isthmus)
• Island or lake formation
Testing the Molecular Clock
• Estimate the number of divergences over
time
• Are these equal for the lineages of
interest?
• Problem: fossil dating of divergence times
is often inaccurate, and not possible for all
lineages
• Cannot measure absolute rates
equal
A
A slower
B
B slower
B
A
B
A
Molecular distance from A to B is the same in all cases
Relative Rate Test
Sarich & Wilson, 1973
• Test if molecular distance of A
to ancestor (circle) is same as
B to ancestor
• Measure molecular distance
from A-O; B-O (sequence
substitutions)
• Distance from A-O should
equal B-O
• Relative rate of evolution is
the same
A
B
Outgroup (O)
Testing the Molecular Clock
1. Compare lineages: is there a “Local
clock”?
2. Hypotheses and mechanisms of clock
disruption
Local Clocks
• Sea urchin species
separated by Panama
Isthmus
• mtDNA divergence
constant – obeys clock
• Colm O’hUigin (1992) –
rates are equal among
mouse, rat and hamster
lineages
• Constant rodent clock
Humans versus monkeys
• Slower rate in
hominoids
• Relative rate test
showed that Old
World monkey
lineage has evolved
1.5 times faster than
the human lineage
• Supported by: genes,
pseudogenes, introns,
and flanking regions
Rodents versus primates
• Laird et al., 1969
• Found higher rate of
nucleotide substitution
between mouse and rat than
between human and
chimpanzee
• Gu & Li (1993) – found 600 of
1000 amino acid changes
between human and rodent
occurred in the rodent lineage
• Hypothesise that this was due
to a Generation-time effect
Sharks versus mammals
• Sharks appear to be
evolving 7-8 times
slower than mammals
• Metabolic rate
hypothesis
Hypotheses for rate variation
• DNA repair efficiency
• Generation time effect
• Metabolic rate hypothesis
Generation time effect
• Generation time in
rodents is much shorter
than in humans
• Number of germline DNA
replication cycles per
generation is similar
• Rodents have more
replication cycles per
year
• Expect higher mutation
rate in short-lived
organisms
Generation time effect
• DNA replication is the major
source of mutation
• An organism with a shorter
generation time will undergo
more germ-line cell divisions
per year
• Males have more germ-line
cell divisions than females
• Expect more evolution in the
male lineage
Male-driven evolution
• Li et al., (2002) Current Opinion in Genetics and
Development 12:650-656
• Y chromosome is exclusively inherited paternally
• X chromosome 1/3 inherited paternally
• Compare rates of evolution of X-Y homologues
• Male to female ratio of mutation : 
Testing Male Driven Evolution
Hypothesis: Evolutionary approach
•
•
•
•
•
•
•
•
•
Miyata et al., (1987)
Ratio of Y/X mutation = 3/(2 + )
estimate 
But limited by available data
Possible to also use autosomes (A)
Y/A = 2/(1 + )
X/A = (2/3)(2 + )/(1 + )
Examine a large number of sites
Accumulation of mutations over long
evolutionary times
Estimates of 
• Higher primates:  = 4.2 – 6.3
• Mice & rats:  = ~2
• Strong support for male-driven evolution
• But …
Alternative hypothesis
• McVean & Hurst (1997)
• High  might be caused
by reduced mutation on
the X (not elevated on Y)
• Why?
• X chromosome is
hemizygous in males
• All deleterious mutations
are exposed to natural
selection
• Hypothesise:
advantageous to have a
low mutation rate on X
Testing the alternative
Birds
• Females are
heterogametic
• Males are homogametic
• Sex chromosome Z is
hemizygous in females,
not males
•  was estimated as 4-5
• Not an artefact of
selection
Generation-time effect and male-driven
evolution
• Age of the male should have an effect
• Kong et al. Nature (2012) – older fathers pass
on more mutations.
Metabolic Rate Hypothesis
• Sharks appear to be
evolving 7-8 times
slower than mammals
• Metabolic rate
hypothesis
Metabolic-rate hypothesis
• Martin & Palumbi (1993)
PNAS 90:4087-4091
• Strong correlation
between substitution rate
and body size
• Probably from correlation
with generation time and
metabolic rate
• Could explain why
whales have a slow
substitution rate relative
to primates despite their
shorter generation time