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MICHAEL HEMANN: Good, so why are we here?
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Well, genetics, right?
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So that is true specific, literally,
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and is true cosmically.
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But genetics in a large overview essentially
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is the connection between genotype and phenotype.
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So genotype meaning the genetic status, the DNA sequence,
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the gene content of us or the organisms
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that we study, and phenotype, meaning what we see,
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what is around us.
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The movement from phenotype to genotype essentially
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underlies the first half of this course.
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And the converse movement from genotype to phenotype
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represents, to some extent, the second half of this course.
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But essentially everything that I'm going to talk about
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involves the connection between our gene content
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and the biology that we see.
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So this movement from phenotype to genotype, we term
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forward genetics.
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So forward genetics, moving from a phenotype
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to genotype, why do you want to do that?
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Well, you see something, right?
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You have some characteristic and you
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want to understand the genetic etiology of it.
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You're working on an organism, you
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want to know why does it look that way.
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You want to know why do we look the way that we look like.
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Why do we have the genetic predispositions?
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Why do we have the biological conditions,
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the medical conditions?
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We want to trace those down to a genetic etiology.
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And we do that essentially by a process called mapping.
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So we look at inheritance.
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We perform crosses.
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We look at DNA marker analysis, all in an attempt
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to move us from very broad phenotypes to very
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specific genes, and, specifically,
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particular sequence variations that
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exist in those genes, that explain
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the underlying etiology.
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This allows us to predict patterns of inheritance,
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to give good counseling if we're genetic counselors.
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They allow us to understand a biology that's
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governing a process so that perhaps we
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have therapeutic interventions that we
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can use to actually alter phenotypes or better understand
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the basis of those phenotypes.
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So there's a lot of work in a lot of organisms
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that we'll talk about that allows us to do this mapping.
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So how do you do mapping?
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How do you go from the very big idea to the very specific gene?
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The reverse direction, from genotype to phenotype, we term
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reverse genetics.
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So how do you go from genotype to phenotype?
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Well, essentially, you break things.
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And breaking, in a genetic sense, is mutation.
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So you have a gene and you wonder what it does.
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Well, you introduce a mutation.
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Or you mutate all of the genes in a strain
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to look at what are the consequent phenotypes following
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perturbation of this gene.
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So, again, it allows us to explore,
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using engineering, the possible functions of a particular gene
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of interest.
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So let's talk a little bit about phenotypes.
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Well, phenotypes are all around us.
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We all have a host of really interesting, very
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cool phenotypes.
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Does anybody-- I don't know if everybody's had cilantro.
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But does cilantro tastes like soap to anybody?
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I've got cilantro here.
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It's actually kind of old cilantro.
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I don't know, but it tastes OK, maybe not great.
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But it doesn't taste like soap to me.
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So we have 80 responders, 81 responders.
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And for six of them, it actually tastes like soap.
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It's, again, an interesting phenotype.
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So you can actually start with this very broad phenotype.
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You can map that phenotype.
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And you can map it back to a specific difference
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in their nucleotide sequence, in a gene called OR6A2.
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So what is that?
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It's an olfactory receptor, essentially a smell receptor.
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So if you have a difference in the gene
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sequence in this olfactory receptor,
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cilantro essentially tastes like soap.
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Now, you can actually deal with this.
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You can actually sort of learn to live with this
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and sort of overcome it.
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I don't know if it's worth it for cilantro.
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But if you're really committed to it, you can.
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But amazingly, again, just a very simple distinction,
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genetic distinction, between us, can
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lead to a very peculiar distinction between us.
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The phenotype is not peculiar.
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It's just peculiar that some of us have it and some of us
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don't.
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What about this one?
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Do any of you sneeze when you go from the dark into sunlight?
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So you're in a movie theater and you walk outside.
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Maybe you don't know that you do it.
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You should try it.
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I mean, February is not a good time to try it.
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But go from the dark and into the sunlight.
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It's estimated about a quarter of the population actually has
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this phenotype.
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And the phenotype is referred to as ACHOO syndrome,
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or autosomal dominant compelling helio-ophthalmic outburst.
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ACHOO syndrome is a more simple way of saying it.
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But this is due to a genetic polymorphism
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adjacent to a gene called Zeb2.
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It's actually unclear whether it actually
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has anything to do with Zeb2 itself.
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But there's a proximal distinction in a nucleotide
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sequence between people that have this syndrome and people
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that don't.
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It's really unclear whether there's
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any other problem with anybody that
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has this condition, other than their propensity to sneeze.
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But it's just representative of the really cool variation
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that exists between lots of different people
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and populations.
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This is a dominant condition.
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The cilantro condition is likely a recessive condition.
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And we'll talk about what those mean next time.
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But these are phenotypes.
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And we can map these phenotypes and understand
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the genetic etiology by doing mapping studies, which
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we'll talk a lot about.
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So what about going the opposite direction?
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What about going from genotype to phenotype?
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Well, here, as I mentioned before, what we generally do
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is breaking things.
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And so if you think about an equivalent
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of this breaking process, it's like asking
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what a car part does if you actually pull it out
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of the car, all right, so looking
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at the overall phenotype of that car
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once you actually take out a specific piece.
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This is classic genetics approaches.
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And so what happens if you actually take a car part out?
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Well, here are two phenotypes, right?
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Car won't start.
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Car won't stop.
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These are kind of big phenotypes.
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Which one do you think is the most, or the more specific,
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phenotype?
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The car won't start is a pretty broad phenotype.
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So there are lots of things you can think about that
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would cause a car not to start.
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So you don't have a key.
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You don't have an ignition.
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You don't have a motor.
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You don't have a transmission.
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There are lots of problems, lots of things that give you
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the same phenotype in the end.
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Car won't stop has a pretty specific etiology, right?
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You got a problem with your brakes.
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And so when we're doing genetics,
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we like to have very specific phenotypes.
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We want to have informative phenotypes that tell us
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that a gene that we're perturbing
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is very specifically involved in a particular process.
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And the more specific that phenotype
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can be, the more informative that screen is going to be,
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the more informative our perturbation of this gene
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is going to be.
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So that's something to bear in mind
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as we think about how we do this kind of broad reverse genetics.
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A lot of you have probably done this kind of thing
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before in a genetic screen.
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And again, you want to have a phenotype that really tells you
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something very specific about what you're doing.
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