Population Genetics

So far we have looked at how individual phenotypes are built by

genes/genotypes, and how those genes are transmitted from parent to
offspring.

‘Population Genetics’: is not concerned so much with individuals, but

with populations of organisms, and in particular, populations of
genes/alleles. It is from these large allele pools that alleles are chosen
and individuals produced. In this way individuals are the output of a
larger genetic process, with genes transmitted from generation to
generation.

Further, the frequency of different alleles in a population, and therefore

the types of individual organisms that can be made, changes from
generation to generation. Population genetics is concerned with the rise
and fall of allele frequencies in the population.
Allele frequency…
Alleles and Allele Frequency
Case 1. Suppose you have a gene that comes in only one allelic form,
i.e., one sequence. The frequency of that allele is then 1, everyone in
the population has it, there are no other options.
Case 2. Suppose a gene comes in two allelic forms. The frequency in
the population could be 50% one form and 50% the other form. In which
case you have two equal options, like flipping a coin.
Case 3. But the allelic forms do not have to be equal in frequency. One
might be present at a frequency of 90% and the other at 10%, making it
more likely that you would have the one with the frequency of 90% and
less likely the other.
Case 4. And genes may come in many allelic forms with a range of
frequencies. The frequencies must add up to 1, or 100%. The chance of
getting any particular form is based on the frequency of that allele in the
population.
Of course you can only get what your parents have, but in the terms of
the population as a whole, alleles are distributed according to their
frequencies.
Allele frequencies must total 1, or 100%

If you have allele 1 at a frequency of 70%, and allele 2 at 25%,

this adds to 95%. That doesn’t make sense, you either have
some more alleles to account for the missing 5% or, if there are
really only two alleles, they cannot be at 70-25, they have to be
at some proportion that adds to 100%, like 72-28. If they add up
to more than 100% (>1) there is also a problem; you have to
renormalize.

That is, all of the parts of something that we have set at a value
of 100, or 1, have to be a fraction of that 100% or that 1 so that
all the parts added up make a complete 100%.
Of course, 44% = 0.44, so it doesn’t matter which way we use,
but usually we see 0.44 and a designation of proportions on an
out of 1 basis.
Genotype Frequencies and Allele Frequencies

How to determine genotype frequencies in a population

1. Collect organisms (you go out and set traps for instance, like
maybe this weekend)
2. Separate organisms according to their genotype AA, Aa, aa.
(obviously you have to be able to tell them apart somehow, either
visually or by molecular/sequencing techniques)
3. Divide the number of each genotype by the total collected

Example: AA is 78
Aa is 20
aa is 2
Frequency (AA) is 78/100 = 0.78
Frequency (Aa) is 20/100 = 0.20
Frequency (aa) is 2/100 = 0.02
Genotype Frequencies and Allele Frequencies

1. How to determine allele frequencies in a population

Example Numbers:
AA is 293 Aa is 604 Aa is 103
Total is 1000 organisms, but number of alleles would be X2 since each
organism is diploid
Let p = frequency (A)
Let q = frequency (a)
p = [(2 X #AA) + #Aa] / 2 X total
p = [(2 X 293) + 603] / 2000 = 0.595
q = [(2 X #aa) + #Aa] / 2 X total
q = [(2 X 103) + 603] / 2000 = 0.405
Note that 0.595 + 0.405 = 1
p+q=1 total of all alleles in population is 1 (100%), divided into
individual frequencies for each allele type, here p and q
Genotype Frequencies and Allele Frequencies

2. How to determine allele frequencies in a population

Frequency of A allele = frequency of AA + ½ frequency of Aa

= 0.293 + ½ (0.604)
= 0.595
Frequency of a allele = 1 - frequency of A allele
= 1 – 0.595 = 0.405

Note: The number of alleles is less than number of genotypes

Here alleles = 2 (A and a) genotypes = 3 (AA, Aa, aa)

Note: for X-linked genes keep in mind that females have twice the
number of alleles than males (2X vs. 1X)
 Alleles differ in abundance; adding
them gives a total amount that is
set at one.
In population genetics alleles are
Allele Allele Allele
distributed as if you put your hand
Allele
A1 A2 A3 A4 in the bowl and pick one out.
Case with two alleles:
A? chance is p Parent one contributes A, parent
a? chance is q two gives A or a
Parent one contributes a, parent
a AA a A a AA a A two gives A or a
A a A AA A a A AA
a a aA a a a aA a
A A
Male get AA? p x p = p2 Female
get Aa? p x q = pq
2pq
get aA? q x p = pq
get aa? q x q = q2
Hardy-Weinberg Equilibrium

For 2 alleles with frequencies p and q in the population

The frequencies will stay constant and the genotypes of individuals will
occur with frequencies given by….

p2 + 2pq + q2 = 1

Where frequency of AA genotype is given by p2

frequency of Aa genotype is given by 2pq
frequency of aa genotype is given by q2
A population where the Hardy-Weinberg equation describes the distribution
of genotypes from the allele frequencies p and q is said to be in
Hardy Weinberg Equilibrium
Hardy-Weinberg Equilibrium

Hardy Weinberg is a mathematical description of allele and genotype

frequencies in populations and it makes the following assumptions….
1. Population is infinitely BIG
2. Matings are random (that is, matings do not depend on whether the
organism is AA, Aa, or aa)
3. Mutations of the A gene do not alter the frequencies of A alleles
4. There is no migration of individuals into or out of the population
5. There is no selection for A or a (that is, there is no preferential
transmission of A or a)
Under these conditions the Hardy Weinberg Equilibrium says that allele
frequencies will not change from generation to generation and it says that
genotype frequencies of individuals in the population will be given by
AA = p2 Aa = 2pq aa = q2

Of course these conditions are never true, but its close enough.
Graph of
genotype
frequencies
relative to
allele
frequencies
for Hardy
Weinberg
Gives a visual
sense of
relative AA,
Aa, and aa
genotype
frequencies
Example Problem

Case where you can determine the number of homozygotes:

(e.g. cystic fibrosis; autosomal recessive)

Use HW to estimate heterozygote frequency…

If 1/2500 people have cystic fibrosis (among people of European

descent), this turns out to be 0.0004 of the population

Assuming HW, q2 = 0.0004

q = 0.02

p=1–q
p = 0.98

2pq = 2 (0.98)(0.02)
2pq = 0.04 (4 %) carriers

Allele frequencies for X-linked genes
Figure shows expected
change in frequency of X-
linked gene if it started
from frequency of 1 in
females and 0 in males.
In the first generation, the
female offspring would
have frequency of 0.5,
since they will all get an X
from father. In contrast the
males will all get X from
mother so their frequency
of the X-linked gene will
rise from 0 to 1.
And so on…
Try it yourself for the first
few generations to see.
Notes on alleles for X-linked traits

For females, X-linked traits follow…

p2 (XA XA) 2pq (XA XB) q2 (XB XB)

For males the frequencies are different and are…

p (XA) and q (XB) (the other chromosome is Y)

EXAMPLE:

color blindness gene with allele frequency 0.039

females affected = q2 = (0.039)2 = 0.0015

males affected = q = 0.039

Differences between genomes (alleles) can be identified by molecular
techniques. Shown is a restriction fragment length polymorphism (RFLP).
This is a sequence difference between genomes that affects a restriction
enzyme site. Some animals have two copies, some one, some none.
Hardy Weinberg and multiple alleles
Frequencies for multiple alleles can also be determined if you can tell
them apart (e.g. A1A1, A1A2, A1A3, A2A2, A2A3, A3A3…….)

In the case of three alleles, p+q+r=1

and the genotype frequencies are given by

p2 + q2 + r2 + 2pq + 2pr + 2qr = 1

EXAMPLE PROBLEM:
Given: Frequency of blood types in some population is
A is 0.53
B is 0.13
O is 0.26

First question: Those blood group frequencies don’t add up to 1. What’s

left? AB

AB = 1 – 0.53 – 0.13 – 0.26

= 0.08
Second Question: What are the allele frequencies?
Three alleles: p, q, r
let p = IA, q = IB, r = O (O instead of i here)

p2 + q2 + r2 + 2pq + 2pr + 2qr = 1

A B O AB A B

Letting r represent the frequency of the recessive allele O

type O people are OO and OO frequency is 0.26, so r2 = 0.26
allele frequency r = 0.51 (here O designates the i allele)

proportion of type A is 0.53

type A people are produced from combinations IA/IA and IA/O
in the equation those people are given by
p2 + 2pr = 0.53

rearranges to
p2 + 2pr – 0.53 = 0
solve it………uhhhh….how do you solve it? (quadratic formula?)
A cute way…..
p2 + 2pr + r2 = 0.53 + 0.26
(p + r)2 = 0.79
p + r = .89
p = 0.89 – r = 0.89 – 0.51 = 0.38
Then what is q? q is whats left…

p+q+r=1
q = 1 – (p +r)
q = 1 – 0.89
= 0.11

Conclusion
A population of 53% A, 13% B, 26% O, and 8% AB that is in Hardy-
Weinberg Equilibrium will have allele frequencies

IA (0.38)

IB (0.11)

O (0.51)
Example: Is a population in HW equilibrium?
Clethrionomys gapperi (a vole)
A vole is a small mouse-like rodent with a stout body, a short hairy tail and small
ears and eyes.

Transferrin Gene
Two alleles, M and J
Three genotypes MM, MJ, JJ

captured 12 MM, 53 MJ, 12 JJ

allele frequencies
p (M) = (2 X 12) + 53
2 X 77
= 0.5

q (J) = 1 – p = 1 – 0.5 = 0.5

These frequencies are measured

not calculated
Using HW we can calculate expected numbers
X 77 Observed
p x p = MM = 0.25 19.3 12
2pq = MJ = 0.5 38.5 53
q x q = JJ = 0.25 19.3 12

Chi-square analysis (not shown) indicates that the difference between the observed
and the expected numbers are ‘too high’.

We conclude the population is NOT in HW equilibrium.

The results say that you can count up the frequency p of the M allele and the
frequency q of the J allele, but that when you try to plug the numbers you get
back into the HW equation, you don’t get the correct genotype frequencies

Huh? That seems weird. How can you calculate the allele frequencies and
then get the wrong numbers for the types of organisms (genotypes)? Don’t
the allele frequencies have to predict the genotype frequencies?

YES THEY DO, but they don’t have to do so using the Hardy-Weinberg
equation. That equation is an oversimplification of real populations that
makes certain assumptions like large populations, random matings, no
mutations, no migration, no selection.
How Can Allele/Genotype Frequencies not be Hardy Weinberg?
Any time one of the HW assumptions does not hold true (is way off)
Of course technically that means all the time since populations are not
infinitely big, etc, but here we mean way off.

Example: Regional/Geographic differences

p1, q1

p2, q2

p3, q3

p4, q4

Mountains Prairie

Example: Population age differences

OLD VOLES p1, q1 (past allele distribution)
MIDDLE AGED VOLES p2, q2
PARENT VOLES p3, q3
ADOLESCENT VOLES p4, q4
BABY VOLES p5, q5 (future allele distribution)
Mutations

Mutations are the source of genetic variation. This is where alleles

(differences between genes) come from in the first place

Consider a nucleotide change occuring at some forward and backward rate

nt change (rate µ)
allele (gene) A Æ allele (gene) a
Å
nt change (rate ν)

if total A alleles is 100,000, if µ is 10-5, then in one generation

1AÆa

That’s not very fast.

But, in humans there are of course about 3 billion sites available for mutation.
Mutations

The rate at which DNA mutations occur is important, and is

determined by things like……

--intrinsic chemical properties of DNA

--exposure to DNA damaging agents

--the efficiency of DNA repair mechanisms

--the accuracy (fidelity) of DNA replication

Note: Mutations cause genetic variation to percolate up into the

population. If the rate is too high, genes will accumulate defects and the
species will become progressively ‘broken’. If the rate is too low, the
species will not be able to adapt.
 Some important questions in genetics. About mutations

Why are there BAD genes at all?

‘Bad’ (defective) alleles are a subset within the total pool of alleles. They, like
all alleles, arise as a consequence of mutagenesis, it just happens. The point of
such diversity normally is to produce unique individuals. The process works
but there is this dark side.

‘Bad’ alleles can stay hidden due to the fact that we are diploid.

In addition, some alleles, although harmful when homozygous, are beneficial

when heterozygous. For instance, alleles of globin genes that cause sickle cell
anemia when present in two copies, may confer some resistance to malaria if
present in one copy.

Or, bad alleles may be linked to nearby favorable genes and get preferentially
transmitted over time because of that linkage.

Bad alleles are sometimes high in populations that are small or isolated or
inbred. If the allele frequency is high enough then inbreeding will more
frequently generate homozygous recessive individuals.
 Some important questions in genetics.

Why don’t BAD genes go away?

Consider a recessive lethal.

Once established at some frequency say by accumulation of mutations, linkage

to an advantageous adjacent gene, etc. a lethal recessive allele takes a long
time to be eliminated from the gene pool because the heterozygote carriers
show no affect.

Homozygous recessive may die, removing two lethal alleles from the population,
but there are still a lot of unaffected carriers that retain the allele.

Would being haploid or triploid be better?

Some organisms, e.g. yeast, pass through a haploid stage. Does this mean they
are genetically healthier because they pass through a haploid ‘filter’?
Some ways in which allele frequencies change over time

Mutation
introduces new alleles but by itself probably not a major contributor to
changes in allele frequency (unless there is also selection which we will
discuss later)

Genetic drift
Statistical variations that occur as a result of population size. These
variations can be large in small populations, and small but still important in
large populations

Imagine flipping a coin 10 times, 30 times, 100 times, 500 times. Informally
speaking, we expect that the larger the sample is the more likely the results
will approximate 50-50. Smaller samples may show wider variation.
Experiment
two alleles in a fly population,
bw75 and bw

start with flies that have bw75 at

frequency of about 0.5

put 8 females and 8 males into 107

different bottles
let them reproduce

collect 8 female and 8 male offspring

from each bottle
put them in new bottles
let them reproduce…….and so on…..

at each generation measure frequency of

bw75allele

alleles/populations get FIXED

bw75 gone in some and bw gone in
some
 More about how allele frequencies in a population
change over time

Bottleneck

(something really bad happens)…for example, everyone gets sick with

flu, a nearby volcano erupts, a typhoon hits

Results in diminished genetic diversity. Important in conservation

biology

Founder Effect

population originates from relatively few ‘founder’ individuals

Example: islands populated by shipwrecked families Tristan da Cunha
(living there is kind of like being on the moon?)
Changes in allele frequency: Migration
movement of organisms between populations

consider allele A

population X Æ population Y
px (A) = 0.8 py (A) = 0.5

after migration, population Y has been altered by the addition of

organisms that have a different allele frequency for A
the p(A) frequency in the new, combined population is

p’y = m px + (1 - m) py

where m is the proportion of the new population made up by the X

organisms and (1 - m) is the proportion of the new population made up by
the original y organisms
Changes in allele frequency: Migration
Very Simple Example:

If population Y consists of 90 animals,

And 10 animals from population X move in

Population Y makes up 0.9 fraction of the new total

Population X makes up 0.1 fraction of the new total

then the final allele frequency for A, p(A), will be

New p(A) = 0.1(0.8) + (1 – 0.1)0.5

= 0.53

(which means allele frequency p increased in new population)

Migration

Combining three
populations
would work
similarly only
there would be
another
box/more terms
to deal with.

And, be careful
about applying
HW afterwards.
HW assumes no
migration.
Changes in allele frequency: Fitness

Basic Point: Individuals do not have exactly the same number of

offspring. After that its just arithmetic.

Organisms that have more offspring contribute more alleles to the

future population than organisms that have no or few offspring.

Fitness here is defined as how many offspring you have.

fitness = w

genotype G1G1 G1G2 G2G2

avg offspring 8 4 2
fitness w = 1 (8/8) w = 0.5 (4/8) w = 0.25 (2/8)

Of course if none of the 8 G1G1 offspring reproduced then the fitness

would eventually be 0 for the G1G1, but we simplify the concept by
saying it is the number of offspring.
Various scenarios describe the relative fitness of 2 alleles 1 and 2

w(11) = w(12) = w(22) = 1 Equal fitness, no selection

w(11) = w(12) < 1 w(22) = 1 Selection against dom. allele

w(22) < 1 w(11) = w(12) = 1 Selection against rec. allele

w(22) < w(12) w(11) = 1 Recessive also affects hetero

w(11) < 1 w(22) < 1 w(12) = 1 Selection for hetero

w(12) < 1 w(11) = w(22) = 1 Selection against hetero

Loss of allele a starting from freq 0.5 Dominant: fitness of AA, Aa,
under various fitness constraints. aa of 1, 0.5, 0.5

Note especially the curve labeled Additive: fitness of AA, Aa,

recessive. aa of 1, 0.75, 0.5

Recessive: fitness of AA, Aa,

aa of 1, 1, 0.5

Graph shows decline in

frequency of a allele from q =
0.5 for each case, dominant,
additive, and recessive over
10 generations

1. Its hard to get rid of an

allele if it only has an effect
when homozygous recessive.

2. And, the rate of loss slows

down as the allele frequency
drops.
Now on to some other interesting topics
 Inbred Organisms (plants, mice)

Inbreeding results in genetic homozygosity. That is, individuals

from a complex, heterozygous outbred population with many alleles
serve as founders to generate a new homozygous inbred
population. Individuals are homozygous at all genes. The particular
allele chosen at any given gene depends on those that were present
in the original population, you don’t get to choose. Such organisms
are clones of one another basically.

This is useful in scientific experiments because all the animals are

genetically the same. Variation in data (e.g. ability to metabolize
some drug) from inbred animals is less likely to be due to inter-
individual differences. Also, experiments in one lab should match
experiments in another lab. Of course, experiments using different
strains of inbred animals would result in different data.
 Problems with inbred organisms

A disadvantage of inbreeding in agriculture is that you reduce the

genetic diversity.

And sometimes inbreeding accidentally makes deleterious alleles

homozygous, not just wild type normal alleles, ‘inbreeding
depression’, wherein the population becomes genetically sicker.

This is the same concept that underlies laws about sibling matings.

And it is why inbred dogs are be susceptible to certain diseases.

And why certain genetic diseases are high in certain populations

(bad allele concentration is high compared to wider population).
Commercial Production
of Chickens Takes Toll on
Genetic Diversity
By HENRY FOUNTAIN
Published: November 3,
2008
To the connoisseur of fine food, chicken may seem depressingly monotonous no
matter how it’s prepared. But scientists worry about a more basic degree of
sameness — a lack of genetic diversity in the birds that are raised for meat and
eggs. An analysis of commercial chicken populations around the world by William M.
Muir of Purdue University and colleagues has revealed the extent of the problem.
Fifty percent or more of the diversity of ancestral breeds has been lost, they report in
The Proceedings of the National Academy of Sciences. That could make chicken
production more susceptible to disease outbreaks for which resistant genes have
disappeared.
Sampling about 2,500 birds, the researchers looked at several thousand instances of
genetic variation and used that to estimate what a hypothetical ancestral population
looked like genetically. “Then we were able to say what is missing” in commercial
birds, Dr. Muir said.
Their findings indicate that most of the diversity was lost with the advent of wide-
scale commercial production in the 1950s. Only a handful of hundreds of breeds
have been crossed to produce broilers and layers.
 The physical/behavioral characteristics of a line of inbred mice
depends on what allele combination was produced during breeding.

STRAIN: C57BL/6
black fur. aggressive mice. low testosterone levels. high alcohol preference.
high activity on the exercise wheel. learn quickly in response to shock. high
locomoter activity. resistant to seizures induced by loud sound. mammary
tumors are rare. high thyroid activity. high tail temperature. low body
temperature. resistant to electroconvulsive seizures. small kidneys.
STRAIN: BALB/c
white fur (albino). visual problems. breeds well. low exploratory activity.
low wheel activity. poor shock avoidance learning. low alcohol preference.
high blood pressure. low heart rate. sleeps a lot. low body temperature.
large brain weight. sensitive to X-ray irradiation damage. low
responsiveness to amphetamines. resistant to induction of diabetes.
relatively high frequency of leukemia.
STRAIN: DBA/2
pale brown fur. low alcohol preference. high wheel activity. males compete
poorly for females. high incidence of mammary cancer. susceptible to
seizures induced by loud noise. poor learner. ok memory. high metabolic
rate. large testes. small brain weight. poor breeding performance.
susceptible to liver parasites. resistant to induction of skin cancer by coal
tar. sleeps a long time after anasthesia.
 Inbreeding
Inbreeding causes heterozygosity in founder individuals, e.g. outbred
mice or plants, to be fixed into homozygosity.

Consider a plant with genotype Aa. A self cross produces genotypes

AA, Aa, Aa, or aa. If these genotypes cause obvious characteristics
we could just pick AA or aa. The plant is now inbred/true-
breeding/homozygous, at that locus. But, for most loci we cannot
visually select for homozygosity. And for a complete organism we are
talking some 25,000 genes.
Lets suppose as an example a founder plant is Bb at the B gene (it
could be BB or bb too, we actually don’t know, but suppose its Bb). A
self cross would produce offspring of types BB, Bb, Bb, bb. We can’t
tell which is which. So, we pick one offspring, any one. If we are
unlucky, we pick Bb; this puts us back at the starting point. The
chance of this is 50%. But, we also have a 50% chance of accidentally
getting BB or bb. Such an organism is homozygous and from that
point on will only produce BB or bb offspring.
 Inbreeding

The point of the previous procedure is that by inbreeding (selfing) we

have a 50% chance, a coin flip chance, of locking in either of the two
homozygous states AA or aa.
The same thing happens at the same time across all the other genes.
If an organism starts with 30,000 genes, all heterozygous, round 1 of a
self cross will generate about 15,000 homozygous loci and 15,000
heterozygous loci. This already locks in about 50% of the genes in
homozygous form.
To lock in the remaining 15,000 we have to continue our self crosses.
Round 2 locks in 7,500 more.
After enough generations we will have obtained homozygosity at
every locus.
The procedure, if repeated, would generate an inbred plant with a
different collection of alleles as was obtained the first time.
Hybrid seed?
 Hybrid Seed

True breeding strain A X True breeding strain B

F1 seeds are A/B hybrids. This seed is sold to me and you.

It turns out the hybrid is useful because it will often possess the
characteristic advantages of both parents, germination time, time to
produce fruit, disease/blight resistance, fruit/vegetable size, color,
whatever.
But you have to buy these seeds from a company. The company
knows what the parents are and it goes to the trouble of generating
the seed for you. It also markets the seeds and tries to convince you
how much better the plants will be by showing a terrific (read:
unrealistic) picture on the package.
 Hybrid Seed
Question: If you grow the F1 hybrids, collect the seeds at the end of
the season, and replant next year, can you bypass the company (not
buy any more seed)?

Answer: The F1 hybrid is heterozygous for strain A alleles and strain

B alleles. During meiosis the paternal and maternal genomes (A and
B) are all mixed up so that the gametes all get some randomized
assortment of both. That gamete must in turn be fertilized by another
haploid gamete that is also a randomization of the A and B genomes.
The resulting F1 X F1 seeds will display an enormous range of
phenotypes, and so the F2 will likely not get the set of A and B alleles
that gave the original hybrid its superior characteristics. Basically
you get a lot of variety, inconsistency, junk.

If interested, look up ‘heirloom’ plant to see what those are.