0:00

Hello and welcome back to Introduction to Genetics and Evolution.

In the previous set of videos, we talked about testing for

whether populations fit the assumptions of the Hardy-Weinberg equilibrium.

At the very end of the last set of videos, we looked particularly at one

deviation from the Hardy-Weinberg equilibrium, that of the Wahlund effect.

That is what happens when you sample two populations simultaneously

that differ in some of their allele frequencies, and

as a result of that, you see an under-representation of heterozygotes.

Let's recap that for just a moment, and

then we'll move into how we can actually leverage this Wahlund effect for

actually quantifying differences between populations in allele frequency.

0:45

Now what we did last time is we tried to calculate Hardy-Weinberg expectations and

fit the Hardy-Weinberg expectations for this MN blood type.

I showed you data from Navajo and Aborigines.

Here's the data from the Navajo.

So we first have our raw genome type counts,

from that we got the total number of individuals.

Using these two together,

we then were able to calculate the observed genotype frequencies.

From the observed genotype frequencies,

we calculate out the observed allele frequencies here.

And then from these observed allele frequencies, we look at the expected, or

predicted, Hardy-Weinberg genotype frequencies.

And these are down here.

1:36

Now what happens when we sample across two populations simultaneously.

Well, if we sample from Navajo and Aborigine together,

we follow the same overall procedure.

But in this case, now when we look at the predicted genotype frequencies,

they do not very well match the observed genotype frequencies.

And particularly we see this deficiency of heterozygotes in the observed

all through to the predicted.

The 0.488 predicted number is much greater than the observed, 2.246.

I attributed this to the Wahlund effect.

That is what happens when you have populations that differ in allele

frequencies even if each population individually is a Hardy-Weinberg.

If you put them together, you see a deficit of heterozygotes.

2:21

Now how is it that populations differ?

Well, I like to look at this in two ways.

One possible way is they may have different allele and genotype frequencies.

That is what we have been emphasizing so far.

We'll come back to that in just a moment.

But first, I wanted to entertain another possibility.

There may be alleles at some genes that are found in some populations but

not found in other populations.

You may have some alleles that are found, for example, in just East Asians, but

you will never see those particular alleles at other populations.

The genes will be there but the particular alleles would not.

This is especially likely under two particular conditions.

One is if it's a very recent new mutation that arose in an East Asian population,

for example, it hasn't spread to others.

Alternatively, if the populations are in complete isolation,

then that difference can persist for quite some time.

So let's talk just briefly about this latter group and

then we'll come back to the former.

3:14

Now differences can arise by mutation and spread.

So let's say in an ancestral population, everybody was aa, bb.

You can have over time, let's say for example the population splits,

so this is indicating a split between the population.

So in one population you're the one on the right, you have a mutation from b to B.

This B allele can spread, and eventually everybody here may be aa, BB.

In this other population, the one on the lef,t you can have a mutation from a to A.

The A allele can spread and eventually this population can be AA, bb.

So again, we have in this case a split between populations, and

we have differences that can then arise and potentially spread.

This is especially likely if you have complete isolation.

We'll come back to this section when we talk about speciation later on.

4:02

Now groups within species are different yet they are related.

That they may have some of these unique alleles that are not found in

other groups.

But it's probably more likely that most of them have very different genotype or

allele frequencies instead.

This shows approximate relationships from one calculation of

various human ethnic groups.

So for example, Melanesian and Papuan are more closely related to each other

than either is two populations from the Mediterranean or from Siberia, etc.

4:33

Well the easiest thing to quantify is if everybody in

one population differs from everybody else in another population at some allele.

This is referred to as a fixed difference, all right?

So for example, in Population 1 everybody's AA.

Population 2, everybody's aa.

So we're looking specifically at the aging in this case.

Everybody in one population differs from everybody in the other population.

We refer to this as a fixed difference.

So you go back to the ancestor, presumably they had the same alleles.

But something arose, at least in one population, and spread to make it so

it was completely different from the ancestor and from the others.

Now, this does happen, but it's not very common within a species.

And it's generally not true among modern human ethnic groups.

5:18

Instead as I said,

it's more common that you have frequency differences of alleles and genotypes.

For example A may have a frequency of 0.7 in East Asians, but

0.5 in Indian populations.

That's just as an example.

Now, what we're trying to do here, let me emphasize this,

is we're measuring differences between populations, not individuals.

We cannot say just because somebody has A,

oh therefore they are of Middle Eastern descent or something like that.

It's based on overall population.

The relative abundance of particular alleles

differs in one population as a whole relative to other populations as a whole.

Well this poses a challenge.

How do we quantify these slight differences in frequency between

populations?

6:03

Well, the deviation from Hardy-Weinberg that's associated with the Wahlund effect

that I've already introduced,

actually allows you to quantify allele frequency differences between population.

So, let's assume the two populations are at Hardy-Weinberg, and

that is an important assumption.

We'll come back to that later.

So, if you sample each population by itself you'll see them at Hardy-Weinberg.

So this would be similar to what we saw with the Aborigines and

the Navajo example I showed you earlier.

But if you sample both together, we see this deviation from Hardy-Weinberg.

And again, as you saw, that was the Wahlund effect.

Now how big this deviation is from Hardy-Weinberg when sampling these

populations simultaneously, will quantify the difference in allele frequencies.

That if you're fairly close, the allele frequencies must be similar.

If you're very different, then you'll see a very large Wahlund effect.

6:55

So the measure that we'll use is referred to as F ST.

So it's a F with subscript ST.

Now this measure ranges from 0 to 1.

If you have 0, then there is absolutely no frequency differences between

the populations you're studying.

If it's between 0 and 1, then the allele frequencies differ somewhat, and

if it's 1 you actually have this fixed sequence difference.

Such that for example everyone in this population is AA,

everybody in that population is aa.

They don't actually all have to be the same.

Maybe all of these would be a1 a1, or a1 a2, or a2 a2, and

over here in this other population they're all a3 a3 or a3 a4 or a4 a4.

Basically it just means you have no overlap in alleles between this population

and that population.

Now the measure is very simple.

So F ST can be estimated as the Hardy-Weinberg predicted 2pq.

Basically what would happen if you were at Hardy-Weinberg- %

observed heterozygotes / Hardy-Weinberg predicted 2pq.

Essentially it's the predicted- the observed / the predicted,

which is fairly common.

Let me show you an application of this, and

you'll see this is very straightforward.

8:03

So let's say that, there's an example as I mentioned to you of fixed difference.

Population 1 everybody's AA.

Population 2, everybody's aa.

So here's the totals.

Now let's imagine we're sampling these two populations together, and we have

to assume that we're sampling similar numbers here to calculate F ST correctly.

So here's our pooled population sample, 100, 0, 100.

Well, if we calculate this out the total genotype count is 200.

When we look at the genotype frequencies the observed would be 0.5, 0, and 0.5.

All right,

half the individuals we're sampling from this pooled population are AA.

Half of them are aa, none of them are Aa.

Here are our allele frequencies, 0.5 and 0.5.

All right, all straightforward so far.

9:05

This is the Hardy-Weinberg predicted, 0.5,- the observed,

0, / 0.5, and this gives you an F ST of 1.

As I mentioned, if you have an F ST of 1, that indicates a fixed difference.

Let's try one that's not quite so extreme.

9:21

Here's a set of populations.

Each population size here is 1,000.

So we have our total population size is 2,000.

This population is at Hardy-Weinberg.

This population is also at Hardy-Weinberg, but they differ in allele frequencies.

So, here's our pooled population, I just summed these numbers together.

250 + 90 is 340.

250 + 490 is 740, etc.

So again, what we do is we calculate the totals, get the genotype frequencies,

get the allele frequency.

So, here's our total, 2,000.

Here's our genotype frequencies, which is each of those numbers divided by 2000.

Here's our allele frequencies, actually comes out very nicely to 0.6 and 0.4.

So what is our Hardy-Weinburg predicted 2pq?

Well, it would be 2 times 0.6 time 0.4.

So 0.6 time 0.4 is 0.24, so

our predictive should be 0.48 if my math in my head is correct.

10:11

That is what we see.

In contrast to the observed, it's 0.46, so again we have a slight difference here.

It's not a huge difference in this case, but it is noticeable nonetheless.

Well now we can calculate a much smaller F ST than we did before.

Here's our number, here's our Hardy Weinberg predicted,

0.48- 0.46 which is the observed, / 0.48.

Again, it's always the predicted minus the observed over the predicted.

And this case our F ST measure comes out to 0.042.

And again in this case we have small differences in allele frequencies.

In the previous example we had a very large difference in allele frequencies,

and you can see that F ST ranges from 0 to 1, 0 being no difference,

1 being complete difference.

Let me give you one to try.

Here's a mixed data from the Aborigines and Navajo.

The numbers here aren't perfect because the sample sizes weren't exactly right,

but let's just pretend for a moment that they are.

Go ahead and calculate what you would see as F ST in this example for

Aborigine to Navajo.

11:15

Well, I hope that wasn't too difficult.

Let's go ahead and run through them.

Again, it's just to remind you what F ST is.

F ST is the Hardy-Weinberg predicted- the observed heterozygotes / the predicted.

So let's put in the numbers.

Here's our allele frequencies.

Here's our expected, or Hardy-Weinberg predicted.

We do see a deviation in this case.

There's our predicted is 0.488, our observed is 0.246.

So what should F ST be?

F ST would be in this case 0.488-

0.246 / 0.488.

Comes out not exactly but approximately 0.5.

So in this case we see a fairly large F ST.

And you'd expect this that there's been no historical gene flow between Aborigine and

Navajo.

12:08

Now again to recap, F ST is larger when you're

comparing populations that are more different in allele frequencies.

So again the Aborigine and Navajo were very different allele frequencies and

that's why we saw fairly large F ST there, 0.5.

If the frequencies were identical, F ST would be 0.

If they were fixed different, F ST would be 1.

Now let me give you a couple of values, so

you get an idea of what we actually see in human populations.

Obviously Aborigine and Navajo is an extreme example.

Among human populations, this is from a 2010 study.

They used a little bit over a million SNPs.

If you look at African Americans relative to Europeans, F ST was about 0.11, so

that's noticeable, but not tremendous.

African Americans to Chinese, F ST was 0.15.

Europeans to Chinese, F ST was about 0.11.

And if you look among the European populations, let's say for example,

you compare the Spanish to the Italians to the Germans, things like that.

F ST's typically, not always, but typically less than 0.01, very,

very low as you look at that sort of scale.

Let me show you a big table.

Here's a big table of F ST measures.

I'm not going to walk through all of these, but

you can see that there are some cases which are fairly high.

Like over here we have a couple that are over 0.2, like Papuan to Red Sea, etc.

Several of these are high.

Several of these are low.

But you see this range of values.

Now what is F ST in words?

13:29

Well, we can define F ST as the percent heterozygous of randomly chosen alleles

within populations, that's the observed aspect,

relative to what would be expected in the entire population, okay?

It's the percent heterozygous of randomly chosen alleles within populations,

relative to what would be expected if there was completely randomly

interbreeding.

And again, it's measuring this difference in allele frequencies.

So, why don't we see higher F ST among human populations?

We know there's a lot of non random mating out there, why isn't it bigger?

Well, there's a couple of reasons.

First, some of the assumptions of F ST are violated in humans, that this is supposed

to be applied to genes experiencing little or no natural selection.

You'll recall I mentioned earlier that F ST should be applied when each of

the individual populations is known to be at Hardy-Weinberg.

Now some of the SNPs,

for example, that were studied in that previous example, may not be neutral.

In fact, some of that variation may be under some sort of selection.

It's also susceptible to differences, and

historic changes in population size among groups.

But probably the biggest reason we don't see higher F ST values

is because we actually do have a fair amount of gene flow or

closer to random mating among population.

That'll be the subject for the next video.

Thank you.