Human Genetics Course 2018

1. Population and
Evolutionary
Genetics 1
Dr. Daniel Gaston
daniel.gaston@dal.ca
March 2018
https://goo.gl/E9LatX
https://www.slideshare.net/dangaston

2. What are Population and Evolutionary
Genetics?
“Population genetics is the study of genetic variation within and
between populations. It involves the examination and modelling of
changes in the frequencies of alleles in populations over space and
time. Concerned with genetic, environmental, and societal factors.”
“Evolutionary genetics is the study of how evolutionary forces and
population genetics lead to speciation and diversification of
organisms over time. Evolutionary genetics also studies the
evolution of genome architecture and other aspects of genetic
change.”

3. "Nothing in Biology Makes Sense Except in the
Light of Evolution"
-- Theodosius Dobzhansky

4. Human Genetics is Profoundly Shaped
by Billions of Years of Evolution We are here

5. Human Genetics is Profoundly Shaped by
Human Population Movements

6. Mutation vs Polymorphism vs Variant
● Genetic variant/variation is the broadest term
● Polymorphism refers to variants present in a population
○ Generally common, minor allele > 1% in population
○ May or may not be associated with disease
● Mutation has variable meaning depending on field of genetics
○ Synonymous with variant in evolutionary genetics
○ Often reserved for deleterious variation in medical/disease
genetics

7. Population and Evolutionary Genetics:
A Brief Interlude About Terminology
● Common and Rare: Are statistical properties of alleles
● Dominant and Recessive: Are genotypic properties of alleles
● Advantageous and Deleterious: Are phenotypic properties of
alleles
Any combination of these is possible!

8. What is Population Genetics?
● Inheritance of individual genes is typically governed by Mendelian
principles
● What factors influence the frequency of alleles in a population?
○ Population size
○ Selective pressure
○ Reproductive forces
○ Mutation
○ Migration
● What is a population?
○ A community of reproducing individuals inhabiting a geographic area
○ Sexually reproducing populations = Mendelian populations

9. Hardy-Weinberg
Equilibrium

10. Hardy-Weinberg Equilibrium
● Independently described by WH Hardy (British Statistician)
and Wilhelm Weinberg (German Physician) in 1908
● The genetic variation within a population will remain the same
from one generation to the next in the absence of disturbing
factors

11. Hardy-Weinberg Equilibrium and the
Hardy-Weinberg Equation
To the Editor of Science: I am reluctant to intrude in a discussion concerning matters
of which I have no expert knowledge, and I should have expected the very simple
point which I wish to make to have been familiar to biologists. However, some
remarks of Mr. Udny Yule, to which Mr. R. C. Punnett has called my attention,
suggest that it may still be worth making...

12. Assumptions of Hardy-Weinberg
Image Credit: https://evieiraapbio.blogspot.ca/

13. Large Population
Large population buffers
against allele changes due to
random events.
Think of the impact of an
earthquake on a large versus a
small population

14. The Hardy-Weinberg Equation:
Linking Allele and Genotype Frequencies
● In a population at Hardy-Weinberg Equilibrium we can relate allele
frequencies to genotype frequencies. Alleles pair randomly
○ Frequency of A allele is p
○ Frequency of a allele is q
○ p + q = 1
○ The genotype frequencies become (p + q)2
A (p) A (q)
A (p) AA (p2
) Aa (qp)
a (q) Aa (qp) Aa (q2
)p2
+ 2pq + q2
= 1

15. The Hardy-Weinberg Equation:
Linking Allele and Genotype Frequencies
p2
+ 2pq + q2
= 1

16. Generalizing Hardy-Weinberg to 3
Alleles
● For three alleles, instead of the binomial expansion of (p + q)2
it is the trinomial
expansion of (p + q + r)2
:
○ p2
+ q2
+ r2
+ 2pq + 2pr + 2qr

17. Hardy-Weinberg in Autosomal
Recessive Disorders
● Using Hardy-Weinberg to calculate carrier frequencies from population samples of
recessive phenotype
● Group all disease-causing alleles together as if they were really only one
disease-associated allele (q)
● Determine the frequency of the disease in the specified population, this is q2
● This allows us to calculate the allele frequency (q) and the carrier frequency (2pq)
● Example:
○ The frequency of the disease PKU in a specific population is 1/4500 (q2
= 1/4500
= 0.000222…)
○ q = 0.015, 2pq = 0.029 (Carrier frequency in population is ~3%)

18. Hardy-Weinberg in X-Linked Disorders:
Red-Green Colour Blindness
● Three possible female genotypes and 2 possible male genotypes for genes on the X
chromosome (outside pseudo-autosomal region)
Sex Genotype Phenotype Incidence (Approx)
Male X+
Normal p = 0.92
Xcb
Colour blind q = 0.08
Female X+
/X+
Normal (homozygote) p2
= (0.92)2
= 0.8464
X+
/Xcb
Normal (heterozygote) 2pq = 2(0.92)(0.08) = 0.1472
Normal (combined) p2
+ 2pq = 0.9936
Xcb
/Xcb
Colour blind q2
= (0.08)2
= 0.0064

19. If it applies mainly
to ideal
populations, how
else is it useful?
Deviations from Hardy-Weinberg Equilibria

20. Assumptions of Hardy-Weinberg
Image Credit: https://evieiraapbio.blogspot.ca/

21. Chi-Squared Significance for Deviation
from Hardy-Weinberg
Phenotype White-spotted
(AA)
Intermediate
(Aa)
Little spotting
(aa)
Total
Number 1469 138 5 1612
Assuming Hardy-Weinberg:

22. p = 0.954, q = 0.046, Exp(AA) = 1467.4, Exp(Aa) = 141.2, Exp(aa) = 3.4
Pearson’s chi-squared test (1 degree of freedom, 5% significance level 3.84):
Null Hypothesis: Not Rejected
Chi-Squared Significance for Deviation
from Hardy-Weinberg
Phenotype White-spotted
(AA)
Intermediate
(Aa)
Little spotting
(aa)
Total
Number 1469 138 5 1612

23. Nonrandom Mating Violates
Hardy-Weinberg
Population stratification
Assortative mating
Consanguinity

24. Population Stratification
● Subgroups with limited genetic
mixing for historical, cultural,
religious, or geographic reasons
● Can mislead case-control studies
when not accounted for
● Hardy-Weinberg, when naively
applied, will incorrectly estimate
disease frequencies from
genotype frequencies

25. Population Stratification Example
● Minority population (10% of total population)
● Allele frequency for mutant allele that causes a recessive
disease in the minority population (qmin
) is 0.05. Therefore pmin
is 0.95
● In the majority population (90%), mutant allele is essentially
absent (qmaj
~ 0, pmaj
~ 1)
● qpop
= 0.1 x 0.05 = 0.005
● Naive application of Hardy-Weinberg to estimate disease
frequency:
○ q2
pop
= (0.005)2
= 2.5 x 10-5
● If stratification: q2
min
= (0.05)2
= 0.0025
○ q2
pop
= 0.0025/10 = 2.5 x 10-4

26. Assortative Mating
● Non-random mating based on traits
● People tend to choose mates similar to
themselves
○ IQ (some evidence)
○ Educational attainment
○ Congenital conditions
■ Blindness
■ Deafness
■ Extreme short -stature
● Results in an increase in homozygous
genotypes
● Disassortative mating for MHC

27. Consanguinity and Inbreeding
● Also increases the incidence
of recessive disease by
increasing the frequency of
mating between carriers of
recessive traits
● Unlike assortative mating,
resulting recessive
disorders may be extremely
rare and unusual compared
to the population
● Similar to founder effects

28. Non-Constant Allele Frequencies
Violate Hardy-Weinberg
Mutation
Gene Flow
Selection
Genetic Drift

29. Mutation Adds New Alleles
● Much slower process than nonrandom
mating
● Less deviation from Hardy-Weinberg (at
least for recessive mutations)
● Rate of new mutation is typically <<
frequency of recessive disease causing
alleles
● Most deleterious mutations initially hidden
in asymptomatic heterozygotes, not
subject to selection
○ Not the case for X-linked or dominant

30. Gene Flow/Migration Introduces New
Alleles
● Conceptually similar to mutation,
introduction of new alleles to a
population
● Migration in the broad sense:
overcoming reproductive barriers
of any kind (geographic, cultural,
ethnic)

31. Gene Flow Example: CCR5

32. Ancient Migration

33. Gene Flow: Archaic Human Admixture
(Introgression)

35. Population Size and Random Events:
Genetic Drift

36. Population Size and Random Events:
Genetic Drift
Small Population
Larger Population

37. Population Bottlenecks Reduce
Diversity: Founder Effects