Does milk make you gassy? Why/why not?

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

2. 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

3. 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’ √

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

5. 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?

6. Promoter Go! 6 What’s in a gene? Controls ‘regulatory region’ Product instructions ‘coding sequence’ • A ‘gene’ is… • instructions for what to make (‘coding sequence’ • instructions about where, when, howmuch to make (specified by the regulatoryregions) • Changes in anyof thesecan give rise to changes in appearance--phenotype

7. 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

8. 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 expressionseveral times • This will entail allowing researchers to stare at people’s genes *Wikipedia’s descriptor

9. 9 Summary: lactose in humans • 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. 10 Whence milk-induced gases? • How did humans ‘discover’ (genetically) how to drink milk? • How many times was this discovery made? • Where? When?

11. 11 Caveat! • 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. 12 Whodunnit? Smoking guns Shown: DNA sequences with points of variability marked

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

14. 14 Whodunnit? Smoking guns

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

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

17. 17 And it goes like this... “This result would justify the hypothesis that the European T13910 and East African G13907 LP alleles might have arisen because of a common domestication event of the cattle whereas the C3712- G13915 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