Does milk make you Does milk make you gassy?gassy?

Why/why not?Why/why not?

What’s normal? Which the ‘discovery’?What’s normal? Which the ‘discovery’?

1

I see dead people: DNA is historical record

❖ You got your genes at the Parent’s storeYou got your genes at the Parent’s store

❖ So did theySo did they

❖ ad infinitumad infinitum

❖ Conclude:Conclude: Your genes are not your own. They are a Your genes are not your own. They are a copy of a copy of a copy of a copy…copy of a copy of a copy of a copy…

❖ They contain a record of who (what) you wereThey contain a record of who (what) you were

2

Information => Thinking❖ Consider Tamiflu predictionsConsider Tamiflu predictions

❖ IF resistance IF resistance precedesprecedes stability, resistance should be stability, resistance should be olderolder

❖ should be ‘deeper branch’ + several subsets are should be ‘deeper branch’ + several subsets are stablestable

❖ IF stability IF stability precedesprecedes resistance… resistance…

❖ stability should be the deeper branch w/ resistance stability should be the deeper branch w/ resistance ‘branchlets’‘branchlets’

3

√

What’s milk got?

❖ ‘‘milk sugar’ = lactose = milk sugar’ = lactose =

4

http://commons.wikimedia.org/wiki/File:Alpha-lactose-from-xtal-3D-balls.png

E. coli & lactose

❖ In In Escherichia coli Escherichia coli ((E. coliE. coli, the gut bacterium), lactose , the gut bacterium), lactose ‘decisions’ are an hour-to-hour thing‘decisions’ are an hour-to-hour thing

❖ How/why does it make these decisions?How/why does it make these decisions?

5

What’s in a gene?

❖ A ‘gene’ is…A ‘gene’ is…

❖ instructions for instructions for whatwhat to make (‘coding sequence’ to make (‘coding sequence’

❖ instructions about instructions about wherewhere, , whenwhen, , howhow muchmuch to make to make (specified by the (specified by the regulatoryregulatory regionsregions))

❖ Changes in Changes in anyany of theseof these can give rise to changes in can give rise to changes in appearance--appearance--phenotypephenotype

6

Controls‘regulatory

region’Product

instructions‘coding

sequence’

Go!Go!

Promoter

Imagine a normal mammal...

❖ notnot some bizarro cross-species-suckling human! some bizarro cross-species-suckling human!

❖ ......wherewhere do you get milk? do you get milk?

❖ ......whenwhen do you get milk? do you get milk?

❖ when do you when do you no longerno longer get milk? get milk?

❖ Is it pointful to build milk-processing bioMachines Is it pointful to build milk-processing bioMachines (enzymes) for entire lifespan(enzymes) for entire lifespan

7

You & lactose❖ For millennia it was a sensible For millennia it was a sensible infancy vs. adulthoodinfancy vs. adulthood thing thing

❖ Ability to digest milk was Ability to digest milk was wastefulwasteful in adults!!! in adults!!!

❖ If you don’t digest it… gut bacteria in your colon will!If you don’t digest it… gut bacteria in your colon will!

❖ result: ‘result: ‘copious amountscopious amounts’’** of gas (CO2, methane, H2) of gas (CO2, methane, H2)

❖ I will now argue that humans evolved I will now argue that humans evolved extended lactase extended lactase expressionexpression several timesseveral times

❖ This will entail allowing researchers to stare at people’s This will entail allowing researchers to stare at people’s genesgenes

8

*Wikipedia’s descriptor

Summary: lactose in humans

9

❖ Heard of ‘lactose intolerance’? It’s the old normal!Heard of ‘lactose intolerance’? It’s the old normal!

❖ Alternative = ‘lactAlternative = ‘lactasease persistence’: production of lactose- persistence’: production of lactose-digesting enzymes digesting enzymes into adulthoodinto adulthood

❖ Ancestral: only babies need digest lactose b/c primary source is Ancestral: only babies need digest lactose b/c primary source is mother’s milkmother’s milk

❖ ‘‘Derived’ state: hey! I think I’ll suck on a cow/camel (ewww!)Derived’ state: hey! I think I’ll suck on a cow/camel (ewww!)

❖ So: who’s the mutant?So: who’s the mutant?

Whence milk-induced Whence milk-induced gases?gases?

How did humans ‘discover’ (genetically) how to drink milk?How did humans ‘discover’ (genetically) how to drink milk?How many times was this discovery made?How many times was this discovery made?

Where? When?Where? When?

10

Caveat!11

❖ This is ongoing researchThis is ongoing research

❖ So we’re discussing preliminary results based on initial So we’re discussing preliminary results based on initial datasetsdatasets

❖ TERMS:TERMS:

❖ LNP LNP nonnon-Persistence (LNP, the ‘ancestral’ state)-Persistence (LNP, the ‘ancestral’ state)

❖ Lactase Persistence (LP, the ‘derived’ state)Lactase Persistence (LP, the ‘derived’ state)

Whodunnit? Smoking guns

12

Shown: DNA sequences with points of variability marked

Smoking & non-smoking guns

13

LNP sequenc

es

LP sequenc

es

Which mutations could be causal: lead to LNP phenotype?

Whodunnit? Smoking guns

14

Contrasting hypotheses15

Cause of change will Cause of change will be common to all be common to all

sequencessequences

Occam:Occam:Simplest = Simplest = most likelymost likely

Single Single originorigin

All lac-expressors All lac-expressors will have same will have same

change(s)change(s)

Multiple Multiple originsorigins

All lac-expressors All lac-expressors will will NOT NOT have same have same

change(s)change(s)

Camel or cow milk? Yes.16

(chimpanzee sequence)

Human

Blue: nte, position

Circle: large group of people

Red: causes LP

Green: digesters

And it goes like this...17

“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.”

Concept: mutation clock18

❖ Things fall apartThings fall apart

❖ Some things are irrelevantSome things are irrelevant

❖ Those things can be reasonably be presumed to fall Those things can be reasonably be presumed to fall apart at constant rateapart at constant rate

❖ Calibrate to reliable externals: fossil record, Calibrate to reliable externals: fossil record, ancestries, migrations… and you get the mutation ancestries, migrations… and you get the mutation clockclock

Do wild animals resemble cats, dogs, cattle?

❖ OK, maybe cats...OK, maybe cats...

❖ Where did these docile, man-serving little blessings Where did these docile, man-serving little blessings come from?come from?

❖ The same place as corn, broccoli, tomatoes…The same place as corn, broccoli, tomatoes…

❖ We made thatWe made that

19

Domestication 20

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

References (not trivial!)❖ Blue eyesBlue eyes

❖ ““Blue eye cool in humans may be caused by a perfectly Blue eye cool in humans may be caused by a perfectly associated founder mutation in a regulatory element located associated founder mutation in a regulatory element located within the HERC2 gene inhibiting OCA2 expression”within the HERC2 gene inhibiting OCA2 expression”

❖ Human GeneticsHuman Genetics 123:177 2008 123:177 2008

❖ MilkMilk

❖ ““Independent Introduction of Two Lactase-Persistence Alleles Independent Introduction of Two Lactase-Persistence Alleles into Human Populations Reflects Different History of into Human Populations Reflects Different History of Adaptation to Milk Culture”Adaptation to Milk Culture”

❖ American Journal of Human GeneticsAmerican Journal of Human Genetics 82: 52-72 2008 82: 52-72 2008

21

Resources

❖ HHMI: lactase movieHHMI: lactase movie

❖ http://www.hhmi.org/biointeractive/evolution/http://www.hhmi.org/biointeractive/evolution/Lactase_Regulation/01.htmlLactase_Regulation/01.html

22