Original subtitles

MICHAEL HEMANN: Good, so why are we here?

Well, genetics, right?

So that is true specific, literally,

and is true cosmically.

But genetics in a large overview essentially

is the connection between genotype and phenotype.

So genotype meaning the genetic status, the DNA sequence,

the gene content of us or the organisms

that we study, and phenotype, meaning what we see,

what is around us.

The movement from phenotype to genotype essentially

underlies the first half of this course.

And the converse movement from genotype to phenotype

represents, to some extent, the second half of this course.

But essentially everything that I'm going to talk about

involves the connection between our gene content

and the biology that we see.

So this movement from phenotype to genotype, we term

forward genetics.

So forward genetics, moving from a phenotype

to genotype, why do you want to do that?

Well, you see something, right?

You have some characteristic and you

want to understand the genetic etiology of it.

You're working on an organism, you

want to know why does it look that way.

You want to know why do we look the way that we look like.

Why do we have the genetic predispositions?

Why do we have the biological conditions,

the medical conditions?

We want to trace those down to a genetic etiology.

And we do that essentially by a process called mapping.

So we look at inheritance.

We perform crosses.

We look at DNA marker analysis, all in an attempt

to move us from very broad phenotypes to very

specific genes, and, specifically,

particular sequence variations that

exist in those genes, that explain

the underlying etiology.

This allows us to predict patterns of inheritance,

to give good counseling if we're genetic counselors.

They allow us to understand a biology that's

governing a process so that perhaps we

have therapeutic interventions that we

can use to actually alter phenotypes or better understand

the basis of those phenotypes.

So there's a lot of work in a lot of organisms

that we'll talk about that allows us to do this mapping.

So how do you do mapping?

How do you go from the very big idea to the very specific gene?

The reverse direction, from genotype to phenotype, we term

reverse genetics.

So how do you go from genotype to phenotype?

Well, essentially, you break things.

And breaking, in a genetic sense, is mutation.

So you have a gene and you wonder what it does.

Well, you introduce a mutation.

Or you mutate all of the genes in a strain

to look at what are the consequent phenotypes following

perturbation of this gene.

So, again, it allows us to explore,

using engineering, the possible functions of a particular gene

of interest.

So let's talk a little bit about phenotypes.

Well, phenotypes are all around us.

We all have a host of really interesting, very

cool phenotypes.

Does anybody-- I don't know if everybody's had cilantro.

But does cilantro tastes like soap to anybody?

I've got cilantro here.

It's actually kind of old cilantro.

I don't know, but it tastes OK, maybe not great.

But it doesn't taste like soap to me.

So we have 80 responders, 81 responders.

And for six of them, it actually tastes like soap.

It's, again, an interesting phenotype.

So you can actually start with this very broad phenotype.

You can map that phenotype.

And you can map it back to a specific difference

in their nucleotide sequence, in a gene called OR6A2.

So what is that?

It's an olfactory receptor, essentially a smell receptor.

So if you have a difference in the gene

sequence in this olfactory receptor,

cilantro essentially tastes like soap.

Now, you can actually deal with this.

You can actually sort of learn to live with this

and sort of overcome it.

I don't know if it's worth it for cilantro.

But if you're really committed to it, you can.

But amazingly, again, just a very simple distinction,

genetic distinction, between us, can

lead to a very peculiar distinction between us.

The phenotype is not peculiar.

It's just peculiar that some of us have it and some of us

don't.

What about this one?

Do any of you sneeze when you go from the dark into sunlight?

So you're in a movie theater and you walk outside.

Maybe you don't know that you do it.

You should try it.

I mean, February is not a good time to try it.

But go from the dark and into the sunlight.

It's estimated about a quarter of the population actually has

this phenotype.

And the phenotype is referred to as ACHOO syndrome,

or autosomal dominant compelling helio-ophthalmic outburst.

ACHOO syndrome is a more simple way of saying it.

But this is due to a genetic polymorphism

adjacent to a gene called Zeb2.

It's actually unclear whether it actually

has anything to do with Zeb2 itself.

But there's a proximal distinction in a nucleotide

sequence between people that have this syndrome and people

that don't.

It's really unclear whether there's

any other problem with anybody that

has this condition, other than their propensity to sneeze.

But it's just representative of the really cool variation

that exists between lots of different people

and populations.

This is a dominant condition.

The cilantro condition is likely a recessive condition.

And we'll talk about what those mean next time.

But these are phenotypes.

And we can map these phenotypes and understand

the genetic etiology by doing mapping studies, which

we'll talk a lot about.

So what about going the opposite direction?

What about going from genotype to phenotype?

Well, here, as I mentioned before, what we generally do

is breaking things.

And so if you think about an equivalent

of this breaking process, it's like asking

what a car part does if you actually pull it out

of the car, all right, so looking

at the overall phenotype of that car

once you actually take out a specific piece.

This is classic genetics approaches.

And so what happens if you actually take a car part out?

Well, here are two phenotypes, right?

Car won't start.

Car won't stop.

These are kind of big phenotypes.

Which one do you think is the most, or the more specific,

phenotype?

The car won't start is a pretty broad phenotype.

So there are lots of things you can think about that

would cause a car not to start.

So you don't have a key.

You don't have an ignition.

You don't have a motor.

You don't have a transmission.

There are lots of problems, lots of things that give you

the same phenotype in the end.

Car won't stop has a pretty specific etiology, right?

You got a problem with your brakes.

And so when we're doing genetics,

we like to have very specific phenotypes.

We want to have informative phenotypes that tell us

that a gene that we're perturbing

is very specifically involved in a particular process.

And the more specific that phenotype

can be, the more informative that screen is going to be,

the more informative our perturbation of this gene

is going to be.

So that's something to bear in mind

as we think about how we do this kind of broad reverse genetics.

A lot of you have probably done this kind of thing

before in a genetic screen.

And again, you want to have a phenotype that really tells you

something very specific about what you're doing.