MAST10016 Mathematics for Biomedicine

MAST10016 Mathematics for Biomedicine

Exercise Sheet 4

1. Suppose that a lethal recessive allele a is initially present in a population with an allele
frequency of pa (0) = 0.1.
(a) Calculate the allele frequencies at the end of generations 1 and 2.
(b) Write down an equation for the allele frequency pa (n) in terms of n.
Hint: You may use the solution for the lethal recessive case from lectures.
(c) Determine how many generations it will take for the allele frequency to drop to 0.1%.

2. A new biomedicine laboratory is founded, but it is soon noticed that a lethal recessive allele
is present in the lab’s population of lab rats. If the allele frequency at the end of the 10’th generation
of rats is found to be 0.075, determine the allele frequency in the initial generation.

3. For the difference equation mentioned in lectures

xn
xn+1 = n≥0
1 + xn
with initial condition x0 = 1:
1
(a) Verify that the sequence xn = n+1 satisfies the difference equation and initial condition.
(b) Let xn = 1/yn . Substitute this into the difference equation to obtain a (simpler) difference
equation for yn . Solve the new difference equation to find yn in terms of n. Hence find xn in
terms of n. You should end up with the same rule as in part (a).

4. Derive a difference equation for pa (n + 1) in terms of pa (n) and the fitness parameters
wAA , wAa , waa ,in the Fisher-Haldane-Wright model.

5. What does the Linear Stability Criterion tell us about the stability of the equilibrium of pa (n)
in the lethal recessive model?

6. For the case of a lethal recessive allele a,

(a) Derive a difference equation satisfied by pA (n) in two different ways:
i. by starting with the general Fisher-Haldane-Wright equation.
ii. by starting with the difference equation satisfied by pa (n).
You should get the same difference equation in each case.
(b) Calculate the first few iterates of the difference equation, and hence guess a formula for
p (n) in terms of n and y0 = pA (0).
A

(c) Verify that your formula from (b) is a solution of the difference equation.

7. Describe the evolution of genotype and allele frequencies in a population with a lethal domi-
nant allele.

8. Show that, if wAA = wAa = waa , then the Fisher-Haldane-Wright equation simplifies to
pA (n + 1) = pA (n).
What is the significance of this?

Exercise Sheet 4 1
MAST10016 Mathematics for Biomedicine

9. Consider a population with two alleles A, a, and with fitness constants wAA = 0.9,
wAa = 0.7, waa = 0.5. Suppose that the initial genotype frequencies are f AA (0) = 0.4, f Aa (0) = 0.5,
aa
f (0) = 0.1. Using the Fisher-Haldane-Wright model:
(a) Manually calculate (without using an applet) the zygote frequencies f AA (n), f Aa (n), f aa (n),
f (n) and f a (n), the mean fitness w(n) and the adult frequencies pAA (n), pAa (n), paa (n), pA (n)
A

and pa (n) in generations 0 and 1.

(b) Use an applet to calculate the allele and genotype frequencies amongst zygotes and adults
in generations 1-30.
(c) Using the applet, determine the first generation in which AA homozygotes make up more
than 99% of the adult population.
(d) Describe the long-term behaviour of the allele pool.

10. bAa and w

Calculate the relative fitnesses w baa , given that h = 0.2 and s = 0.7. Can you
AA Aa
calculate the absolute fitnesses w , w , w ? aa

11. bAa and w

In each of the following cases, calculate the relative fitnesses w baa , and the selection
pressure s and heterozygous effect h. Describe the type of selection acting on the A allele (eg. ‘directed
selection in favour of A’, ‘heterozygote advantage’) and (if possible) describe the dominance of the A
allele (eg. ‘A is recessive’, ’A is incompletely dominant’). Describe the long-term evolution of allele
frequencies.
(a) wAA = 0.6, wAa = 0.9 and waa = 0.2
(b) wAA = 0.8, wAa = 0.6, and waa = 0.4
(c) wAA = 0.4, wAa = 0.2 and waa = 0.3
(d) wAA = 1, wAa = 0.7 and waa = 0
(e) wAA = 0.9, wAa = 0.5 and waa = 0.4
(f) wAA = 0.7, wAa = 0.7 and waa = 0.7

12. bAa and w

Give two different sets of relative fitnesses w baa that would both result in an
A
equilibrium frequency of p = 0.8 in the Fisher-Haldane-Wright model.

13. Use the Linear Stability Criterion to verify that, in the case of heterozygote advantage,
p∗ = 0 and p∗ = 1 are unstable equilibria of the Fisher-Haldane-Wright equation.

14. Use an applet to investigate the effect of changing s while keeping h fixed. Try values of
h covering the three cases 0 < h < 1, h < 0 and h > 1, and try values of s in the range 0 < s < 1
including s = 0.9, s = 0.5 and s = 0.1.(Remember that to obtain valid frequencies we must have s ≤ 1
and hs ≤ 1). Summarise your findings.

1
15. In this exercise we will investigate the case of h = 2 in the Fisher-Haldane-Wright model.
Let h = 21 and s 6= 0.
1
(a) By substituting h = 2 into an appropriate form of the Fisher-Haldane-Wright equation,
show that
s
pn+1 = pn + pn qn .
2(1 − sqn )
spn (1 − pn )
(b) Hence show that pn+1 = pn + .
2(spn + 1 − s)
(c) Show that the only equilibria of this equation are p = 0 and p = 1.
(d) Use cobwebbing to investigate the stability of the equilibria, for various values of s.
(e) Draw a phase line diagram for pn (for 0 < s < 1).
(f) Use the Linear Stability Criterion to show that the equilibrium p = 0 is unstable and p = 1
is stable (for 0 < s < 1).
(g) Describe the long-term behaviour of the allele frequencies when h = 12 .

Exercise Sheet 4 2
MAST10016 Mathematics for Biomedicine

MAST10016 Mathematics for Biomedicine

Exercise Sheet 4 - Answers

1.
(a) pa (1) = 0.0909, pA (1) = 0.9091; pa (2) = 0.0833, pA (2) = 0.9167
0.1
(b) pa (n) = 1+0.1n
(c) 990 generations

x0
2. 0.3 Hint: Use the formula from lectures for a lethal recessive: xn = 1+nx0

3.
1 1
xn n+1 n+1 1
(a) RHS = 1+xn = 1
1+ n+1
= n+2 = n+2 = xn+1 = LHS, so the sequence satisfies the difference
n+1
1
equation. x0 = 0+1 = 1 so it also satisfies the initial condition.
1 1
xn 1 yn yn 1
(b) xn+1 = 1+xn so yn+1 = 1+ y1
= 1+yn = 1+yn , giving yn+1 = 1 + yn . The solution of this
n yn
1 1
constant coefficient linear first-order difference equation is yn = n + 1. Hence xn = yn = n+1 .

waa pa (n)2 + wAa pa (n)[1 − pa (n)]

4. pa (n + 1) =
waa pa (n)2 + 2wAa pa (n)[1 − pa (n)] + wAA [1 − pa (n)]2
Hint: Follow the derivation of the FHW equation from lectures but replace A with a.
p (n) a
x
5. The difference equation for pa (n) is pa (n + 1) = 1+p a (n) , so the function is g(x) = 1+x . The

only solution of x = g(x) is x = 0, so 0 is the only equilibrium. The derivative is g 0 (x) = (1+x)1
2 , and
0
g (0) = 1, so the Linear Stability Criterion is inconclusive.

6.
1
(a) pA (n + 1) = 2−pA (n)
Hint: For i., substitute wAA = wAa = w, waa = 0 into the FHW equation. For ii., use
pA = 1 − pa .
2−y0
(b) 1
pA (0) = y0 ; pA (1) = 2−y 0
; pA (2) = 3−2y 0
; pA (3) = 3−2y 0
4−3y0 .
n−(n−1)y0
The general rule is pA (n) = (n+1)−ny0 .
(n + 1) − ny0
(c) LHS = pA (n + 1) = .
(n + 2) − (n + 1)y0
1 1 1 (n + 1) − ny0
RHS = = = 2(n+1)−2ny −n+(n−1)y = = LHS.
2 − pA (n) n−(n−1)y0
2 − (n+1)−ny0 0 0 (n + 2) − (n + 1)y0
(n+1)−ny0

7. Since any individuals which possess the dominant A allele will die without reproducing, only
aa homozygotes will reproduce, and all of their offspring will be aa. Thus after the initial generation
the population will consist only of aa homozygotes. So f A (n) = 0 and f a (n) = 1 for n ≥ 1.

8. Let wAA = wAa = waa = w and substitute into the Fisher-Haldane-Wright equation:

2
w pA (n) + wpA (n) 1 − pA (n)
 
A
p (n + 1) =
w (pA (n))2 + 2wpA (n) [1 − pA (n)] + w [1 − pA (n)]2
pA (n)2 + pA (n) − pA (n)2
=
pA (n)2 + 2pA (n) − 2pA (n)2 + 1 − 2pA (n) + pA (n)2
= pA (n) as required.
If the fitnesses are equal then the allele frequencies remain constant, as in Hardy-Weinberg equilibrium.

Exercise Sheet 4 - Answers 1

MAST10016 Mathematics for Biomedicine

9.
(a)
n f AA f Aa f aa fA fa w pAA pAa paa pA pa
0 0.4 0.5 0.1 0.65 0.35 0.76 0.4737 0.4605 0.0658 0.7039 0.2961
1 0.4955 0.4168 0.0876 0.7039 0.2961 0.7816 0.5706 0.3733 0.0561 0.7573 0.2427
(b) Applet use required.
(c) Generation 18
(d) The A allele will become fixed and a will become extinct.

10. bAa = 0.86, w

w baa = 0.3. We cannot calculate the absolute fitnesses without more information.

11.
(a) bAa = 1.5, w
w baa = 31 = 0.333, s = 23 = 0.667, h = −0.75. A and a are co-dominant. There
is a heterozygote advantage. The allele frequencies will approach the equilibrium pA = 0.7,
pa = 0.3.
(b) bAa = 0.75, w
w baa = 0.5, s = 0.5, h = 0.5. A is incompletely dominant. There is directed
selection in favour of A. The A allele will become fixed and a will disappear.
(c) bAa = 0.5, w
w baa = 0.75, s = 0.25, h = 2. A and a are co-dominant. There is a heterozygote
disadvantage. One of the two alleles will become fixed and the other will disappear; exactly
which depends on the initial conditions.
(d) bAa = 0.7, w
w baa = 0, s = 1, h = 0.3. The A allele is incompletely dominant. There is directed
selection in favour of A. The A allele will become fixed and a will disappear.
(e) bAa = 59 = 0.5556, w
w baa = 49 = 0.4444, s = 59 = 0.5556, h = 0.8. The A allele is incompletely
dominant. There is directed selection in favour of A. The A allele will become fixed and a will
disappear.
(f) bAa = 1, w
w baa = 1, s = 0. h is not relevant in this case. All genotypes have equal fitness,
so the population will be in Hardy-Weinberg equilibrium. There is no selection. A is neither
dominant nor recessive (all genotypes are the same).

12. bAa = 34 , w
Two possibilities are w bAa = 67 , w
baa = 0 and w baa = 12 but others are possible.
h−1
Hint: Start with P = 2h−1 = 0.8 and solve for h. Choose arbitrary values for s.

13. Hint: Use the case of directed selection from lectures as a guide. For p∗ = 0 you should get
s(1 − h)
g 0 (0) = 1 + .
1−s
The denominator is > 0 since 0 < s < 1. The numerator is > 0 as s > 0 and 1 − h > 1. Therefore
g 0 (0) > 1 so 0 is unstable. For p∗ = 1 you should get
g 0 (1) = 1 − hs > 1
as h < 0 so 1 is unstable.
14. Some things you should notice are:
• The value of s does not affect the limiting behaviour or equilibrium values of the allele fre-
quencies. The limit allele frequencies depend only on h.
• The value of s does affect the speed at which the frequencies approach equilibrium - the larger
the value of s, the faster the frequencies approach equilibrium.
• When h < 0, the value of s does affect the equilibrium adult genotype frequencies.

Exercise Sheet 4 - Answers 2

MAST10016 Mathematics for Biomedicine

15.
(a)
hspn + s(1 − h)qn
pn+1 = pn + pn qn FHW equation
p2n + 2(1 − hs)pn qn + (1 − s)qn2
1 1
2 spn + 2 sqn 1
= p n + p n qn substitute h =
p2n + 2(1 − 12 s)pn qn + (1 − s)qn2 2
1 1
2 spn + 2 sqn
= pn + p n qn 2 expand
pn + 2pn qn + qn2 − spn qn − sqn2
1
2 s(pn + qn )
= pn + p n qn factorise
(pn + qn )2 − sqn (pn + qn )
s
= p n + p n qn as pn + qn = 1.
2(1 − sqn )

(b) Hint: Substitute qn = 1 − pn and simplify.

(c) Let pn = pn+1 = p∗ and substitute into the equation from (b):
sp∗ (1 − p∗ )
p∗ = p∗ +
2(sp∗ + 1 − s)
sp∗ (1 − p∗ )
0=
2(sp∗ + 1 − s)
∗ ∗
sp (1 − p ) = 0
p∗ = 0 or p∗ = 1.
(d) A typical cobweb diagram is shown below, for s = 0.8.

s = 0.8 s = -0.8

(e) 0 1 0 1
(f) s > 0 get g 0 (0) = 1 + s . Deduce that s <s 0 > 0 (as 0 < s < 1) so g 0 (0) > 1.
Hint: you should 2(1−s) 2(1−s)
For x = 1 you should get g 0 (1) = 1 − 2s .
(g) The A allele will become fixed and a will become extinct.

Exercise Sheet 4 - Answers 3