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 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 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 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 What’s milk got? ❖ ‘milk sugar’ = lactose =

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

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

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

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

13 Smoking & non-smoking guns LNP sequences LP sequences

14 Whodunnit? Smoking guns

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

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

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 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 Domestication europe-a 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: ❖ 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:

22 Resources ❖ HHMI: lactase movie ❖