Chapter VI: Linkage dis-equilibrium

and Hardy-Weinberg equilibrium

Linkage disequilibrium
 Mendelian
Genetics –
3:1 ratios …
Traits must come
in discrete units
– now called genes
Thomas Hunt Morgan, the first native-born
American to win the Nobel Prize, founder of
modern genetics
 Morgan used drosophila melanogaster

From 1907, Morgan used Drosophila melanogaster (fruit fly) as a

model:
- easy to feed and breed
one generation = 2 weeks
- only four pairs of chromosomes:
3 autosome
pairs ♂X
♀XX Y

5
 Linkage dis-equilibrium

X Thomas Morgan
P: (1866-1945)
Genotype: BB bb
SS ss

Gametes: BS bs

F1: 100%

Genotype: Bb
Ss
 Gene recombination
BC (Backcross):
X

Genotype: Thomas Morgan

Bb bb (1866-1945)
Ss ss

Population BC:

Parental phenotype Recombinant phenotype

Proportion: 40% 40% 10% 10%

 Gene recombination
Population BC:

BS bs bS Bs
bs Bb bb bb Bb
Ss ss Ss ss

25% 25% 25% 25%

Gregor Mendel
 Gene recombination
Population BC:

BS bs bS Bs
bs Bb bb bb Bb
Ss ss Ss ss

40% 40% 10% 10%

 MORGAN’S PROPOSAL
• During meiosis alleles of • Parental phenotypes occur
some genes assort most frequently, while
together because they recombinants less.
are near each other on • Terminology
– Chiasma: site of crossover
the same chromosome. – Crossing over: reciprocal
• Recombination occurs exchange of homologous
chromatid segments
when genes are
– Crossing-over occurs at
exchanged between X prophase I in meiosis; each
chromosomes of the F1 event involves two of the four
chromatids. Any chromatids
females may be involved in crossing
over.
 Gene recombination
BC (Backcross):
X

b b
Alfred Sturtevant
B b (1891-1970)
s s
S s

DNA replication:

Meiosis:
Prophase 1

Gametes: B B b b b
S s S s s
40% 10% 10% 40% 100%
 Gene recombination

40% B 10% B 10% b 40% b

S s S s
Alfred Sturtevant
(1891-1970)
100% b 40% 10% 10% 40%
s

Proportion of recombination between these 2 genes = 10% + 10% = 20%

→ The genetic distance between these 2 genes = 20 cM (centiMorgan)

B S

D(B-S) = 20 cM
B R
D(B-R) = 30 cM
Mechanism of crossing-over
 Recombination frequency by crossing over

related to the distance between the two genes

rare between neighbor genes → strong linkage reaches

50% for genes located far apart

equivalent to the distribution de genes located on ≠ chr.

unit: 1 centimorgan = 1 Morgan unit = 1%

50 %
-
Gene locus (by
Frequency comparison with
other genes)

0-
Distance on the
chr. 1
4
 Gene mapping

Genes Recombinantion Order of genes??????????

A-B-C
frequency B-A-C
A-B 25% A-C-B

A-C 16%

B-C 19%

25 cM
A B

C?? 16 cM 16 cM
C??
 Exercise on gene mapping

Draw a map for these 4 genes:

Genes Recombinantion
frequency
A-B 20%
B-C 35%
B-D 30%
A-D 15%

B A D C
 Mutant phenotypes

Short Maroon Black Cinnabar Vestigial Down- Brown

aristae eyes body eyes wings curved eyes
wings

0 16.5 48.5 57.5 67.0 75.5 104.5

Long Red Gray Red Normal Normal Red

aristae eyes body eyes wings wings eyes

Wild-type
phenotypes 97
The first genetic maps were based on morphological traits
Genetic map of the
human chromosom 12

Woman: 168 cM
Man: 78 cM
 Exercise on genetic linkage
- 4 genotypic classes AB, Ab, aB et ab AB: 37
- Numbers: 100 individual Numbers of
Ab: 13
individual in each
aB: 10
classes:
Use statistical test (Chi square) to check if ab: 40
Aa and Bb are independently inherited.
(α=0.05 )

(37 - 25) 2
(13 - 25) 2
(10 - 25) 2
(40 - 25) 2
C2 = + + +
25 25 25 25

C 2 = 29,52
For 3dll et α=0.05
X2= 7.81

The hypothesis of independence of A and B is rejected

Tests of genetic linkage
 Haplotypes

• A haplotype stands for a set of linked SNPs on

the same chromosome.
– A haplotype can be simply considered as a binary
string since each SNP is binary.

-A C T T T G C T C- Haplotype 1 C T C

-A C T T A G C T T- Haplotype 2 C A T

-A A T T T G C T C- Haplotype 3 A T C

SNP1 SNP2 SNP3 SNP1 SNP2 SNP3

22
 Source of SNP

Observed genetic variations

SNPs

Common
Ancestor

time present
23
Positional cloning

Content:
• Classical positional cloning
• Modern positional cloning
Classical genetics (candidate gene approach) vs positional cloning!
 Positional cloning

A B
m0a m0b

m1a m1b
m2a m2b

1 2 3 4 5 6 7 8 9 10
m
A B A A A B B A A A
Gametes 0
m
A A B A B A B B B A
1
m0
m
A A B A B A B B B A
2
m1

m2

1 2 3 4 5 6 7 8 9 10
 Positional cloning

A B
m0a m0b

m1a m1b
m2a m2b

1 2 3 4 5 6 7 8 9 10
Ph
m m wt m wt m wt wt wt m
Gametes e
m
A B A A A B B A A A
0
m0
m
A A B A B A B B B A
1
m1
m
A A B A B A B B B A
2
m2

1 2 3 4 5 6 7 8 9 10
 Positional cloning

A B
m0a m0b

m1a m1b
m2a m2b
1 2 3 4 5 6 7 8 9 10
Ph
m m wt m wt m wt wt wt m
Gametes e
m
A B A A A B B A A A
0
m
m
0 1
A A B A B A B B B A
m m
1 A A B A B A B B B A
2
m The phenotype and therefore the gene is linked to
2 markers m1 and m2.
1 2 3 4 5 6 7 8 9 10
 Genome wide association study (GWAS)

An illustration of a Manhattan plot depicting several strongly associated risk loci.

Each dot represents a SNP, with the X-axis showing genomic location and Y-axis
showing association level.
Hardy-Weinberg
equilibrium
 Allele Frequencies in a Population

G.H. Hardy Dr. Wilhelm

English Weinberg
Mathematician German Physician

The Hardy-Weinberg equilibrium is a principle stating that the genetic

variation in a population will remain constant from one generation to the
next in the absence of disturbing factors. When mating is random in a large
population with no disruptive circumstances, the law predicts that both
genotype and allele frequencies will remain constant because they are in
equilibrium.
 Conclusions of the Hardy-Weinberg
principle

1. Allele frequencies will not change from generation to generation.

2. Genotype proportions determined by the “square law”.

• for two alleles = (p + q)2 = p2 + 2pq + q2

• for three alleles (p + q + r)2 = p2 + q2 + r2 + 2pq + 2pr +2qr
 The Equations
p+q=1
p2 + 2pq + q2 = 1
A gene has two alleles, A and a
The frequency of allele A is represented by p
The frequency of allele a is represented by q
The frequency of genotype AA = p2
The frequency of genotype aa = q2
The frequency of genotype Aa = 2pq
The Equations
 An Example…
Assume a population in which 36% of the
population are homozygous for a certain recessive
allele, a. Assume the population is at equilibrium.

Question #1: What is the frequency of the

recessive allele, a in this population?

q  0.36
2

q  0.36
q  0.60
 An Example…
Assume a population in which 36% of the
population are homozygous for a certain recessive
allele, a. Assume the population is at equilibrium.

Question #2: What is the frequency of the

dominant allele, A in this population?
q  0.60
p  0.60  1
p  0.40
 An Example…
Assume a population in which 36% of the
population are homozygous for a certain recessive
allele, a. Assume the population is at equilibrium.

Question #3: What percentage of the population are

homozygous for the dominant allele, A?

p  0.40
p  0.40
2 2

p  0.16 16%
2
 An Example…
Assume a population in which 36% of the
population are homozygous for a certain recessive
allele, a. Assume the population is at equilibrium.

Question #4: What percentage of the population are

heterozygous for this trait?

2 pq  2(0.40)(0.60)
2 pq  0.48  48%
5 Agents of evolutionary change
Mutation
Gene Flow Non-random mating

Chemical
Changes to DNA Migration Sexual Selection
Genetic Drift Selection

Natural Selection
Small population Differential Survival
 Exercises

• A sample population was observed to have 50

AA, 25 Aa, and 25 aa individuals. Is it in Hardy-
Weinberg equilibrium?
• If not, what is the genotype distribution of this
population in Hardy-Weinberg equilibrium.
Online tool to calculate Hardy Weinberg
https://wpcalc.com/en/equilibrium-hardy-weinberg/
 Exercises

• Using Chi-square test, check if this population

follow Hardy – Weinberg equilibrium:

GG TG TT
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