1. Molecular Clock

2. 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

3. 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

4. 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

5. 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

6. 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

7. A B A B A B Molecular distance from A to B is the same in all cases equal A slower B slower

8. 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 BOutgroup (O)

9. Testing the Molecular Clock 1.Compare lineages: is there a “Local clock”? 2.Hypotheses and mechanisms of clock disruption

10. 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

11. 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

12. 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

13. Sharks versus mammals Sharks appear to be evolving 7-8 times slower than mammals Metabolic rate hypothesis

14. Hypotheses for rate variation DNA repair efficiency Generation time effect Metabolic rate hypothesis

15. 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

16. 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

17. 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 : 

18. 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

19. Estimates of  Higher primates:  = 4.2 – 6.3 Mice & rats:  = ~2 Strong support for male-driven evolution But …

20. 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

21. 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

22. 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.

23. Metabolic Rate Hypothesis Sharks appear to be evolving 7-8 times slower than mammals Metabolic rate hypothesis

24. 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