1. 1 Semester projects! ❖ Miraculin paper based! ❖ Find a partner with same TA (needn’t be same section) ❖ You will ❖ Be supplied with suspicious red tablets! ❖ Be expected to support/refute a claim from the paper ❖ Read & reference >= 1 reference from the Miraculin paper as well as the paper itself ❖ Be awarded 3 point bonus for improving on the Dr. Pepper!!!

2. 2 Midterm musings ❖ How are bases & amino acids suited to their tasks? ❖ How does hemoglobin function as a machine? ❖ pH triggers ❖ DPG--how & why; fetal changes ❖ Cooperativity ❖ Periodic table: clues & progress ❖ siRNA: send a thief to catch a thief ❖ tamiflu: tracing lineages through mutations ❖ Blue eyes & milk drinking: single vs. multiple origins (hemo?)

3. 3 Does milk make you gassy? Why/why not? What’s normal? What’s the discover? *According to dictionary.com: the necessary changes have been made

4. 4 Key concept: DNA is historical record ❖ You got your genes at the Parent’s store ❖ So did they ❖ ad infinitum ❖ Conclude: Your genes are not your own. They are a copy of a copy of a copy of a copy… ❖ They contain a record of who (what) you were

5. 5 What’s milk got? ❖ ‘milk sugar’ = lactose = http://commons.wikimedia.org/wiki/File:Alpha-lactose-from-xtal-3D-balls.png

6. 6 Imagine a normal mammal... ❖ not some bizarro cross-species-suckling human! ❖...where do you get milk? ❖...when do you get milk? ❖ when do you no longer get milk? ❖ Is it pointful to build milk-processing bioMachines (enzymes) for your entire life

7. 7 If you don’t digest it... ❖ gut bacteria in your colon will! ❖ result: ‘copious amounts’* of gas (CO2, methane, H2) *Wikipedia’s descriptor

8. 8 Lactose in humans ❖ Who’s a mutant: those of you that can digest lactose, or those that cannot? ❖ Better way to look at it is ‘lactase persistence’: the continued ability to produce lactose-digesting enzymes ❖ “Ancestral” state: only babies need digest lactose b/c primary source is mother’s milk ❖ “Derived” state: hey! I think I’ll suck on a cow/camel/goat teat! (ewww!) ❖ So: who’s the mutant?

9. 9 What’s in a gene? ❖ A ‘gene’ is… ❖ instructions for what to make (‘coding sequence’ ❖ instructions about where, when, how much to make (specified by the regulatory regions) ❖ Changes in any of these can give rise to changes in appearance--phenotype Controls ‘regulatory region’ Product instructions ‘coding sequence’ Go! Promoter

10. 10 Whence milk-induced gases? How did humans ‘learn’ (genetically) to drink milk? How many times was this discover made? Where? When?

11. 11 Caveat! ❖ This is ongoing research ❖ So we’re discussing preliminary results based on initial datasets

12. 12 Whodunnit? Smoking guns Shown: DNA sequences with points of variability marked

13. 13 Smoking & non-smoking guns LNP sequences LP sequences

14. 14 Whodunnit? Smoking guns

15. 15 Contrasting hypotheses Cause of change will be common to all sequences Occam: Simplest = most likely Single origin Multiple origins All lac- expressors will have same change(s) All lac- expressors will NOT have same change(s)

16. 16 Camel or cow milk? Yes. (chimpanzee sequence) Human

17. 17 And it goes like this... “This result would justify the hypothesis that the European T 13910 and East African G 13907 LP alleles might have arisen because of a common domestication event of the cattle whereas the C 3712 - G 13915 allele in Arabia most likely arose due to the separate domestication event of camels.”

18. 18 Concept: mutation clock ❖ Things fall apart ❖ Some things are irrelevant ❖ Those things can be reasonably be presumed to fall apart at constant rate ❖ Calibrate to reliable externals: fossil record, ancestries, migrations… and you get the mutation clock

19. 19 Do wild animals resemble cats, dogs, cattle? ❖ OK, maybe cats... ❖ Where did these docile, man-serving little blessings come from? ❖ The same place as corn, broccoli, tomatoes… ❖ We made that

20. 20 Domestication http://www.spiegel.de/international/zeitgeist/neolithic-immigration-how-middle-eastern-milk-drinkers-conquered- europe-a-723310.html

21. 21 References (not trivial!) ❖ Blue eyes ❖ “Blue eye cool in humans may be caused by a perfectly associated founder mutation in a regulatory element located within the HERC2 gene inhibiting OCA2 expression” ❖ Human Genetics 123:177 2008 ❖ Milk ❖ “Independent Introduction of Two Lactase-Persistence Alleles into Human Populations Reflects Different History of Adaptation to Milk Culture” ❖ American Journal of Human Genetics 82: 52-72 2008

22. 22 Resources ❖ HHMI: lactase movie ❖ http://www.hhmi.org/biointeractive/evolution/Lactase_Regulation/01.html http://www.hhmi.org/biointeractive/evolution/Lactase_Regulation/01.html