1. Does milk make you gassy? Why/why not? What’s normal? Which the ‘discovery’? 1

2. I see dead people: 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 2

3. Information => Thinking ❖ Consider Tamiflu predictions ❖ IF resistance precedes stability, resistance should be older ❖ should be ‘deeper branch’ + several subsets are stable ❖ IF stability precedes resistance… ❖ stability should be the deeper branch w/ resistance ‘branchlets’ 3 √

4. What’s milk got? ❖ ‘milk sugar’ = lactose = 4 http://commons.wikimedia.org/wiki/File:Alpha-lactose-from-xtal-3D-balls.png

5. E. coli & lactose ❖ In Escherichia coli (E. coli, the gut bacterium), lactose ‘decisions’ are an hour-to-hour thing ❖ How/why does it make these decisions? 5

6. 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 6 Controls ‘regulatory region’ Product instructions ‘coding sequence’ Go! Promote r

7. 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 entire lifespan 7

8. You & lactose ❖ For millennia it was a sensible infancy vs. adulthood thing ❖ Ability to digest milk was wasteful in adults!!! ❖ If you don’t digest it… gut bacteria in your colon will! ❖ result: ‘copious amounts’* of gas (CO2, methane, H2) ❖ I will now argue that humans evolved extended lactase expression several times ❖ This will entail allowing researchers to stare at people’s genes 8 *Wikipedia’s descriptor

9. Summary: lactose in humans 9 ❖ Heard of ‘lactose intolerance’? It’s the old normal! ❖ Alternative = ‘lactase persistence’: production of lactose-digesting enzymes into adulthood ❖ Ancestral: 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 (ewww!) ❖ So: who’s the mutant?

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

11. Caveat! 11 ❖ This is ongoing research ❖ So we’re discussing preliminary results based on initial datasets ❖ TERMS: ❖ LNP non-Persistence (LNP, the ‘ancestral’ state) ❖ Lactase Persistence (LP, the ‘derived’ state)

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

13. Smoking & non-smoking guns 13 LNP sequence s LP sequence s Which mutations could be causal: lead to LNP phenotype?

14. Whodunnit? Smoking guns 14

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

16. Camel or cow milk? Yes. 16 (chimpanzee sequence) Human Blue: nte, position Circle: large group of people Red: causes LP Green: digesters

17. And it goes like this... 17 “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. Concept: mutation clock 18 ❖ 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. 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 19

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

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 21

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 22