Intro QuantitativeGenetics 2024 Part1

Introduction to Quantitative Genetics
Nicolas Salamin
Department of Computational Biology
nicolas.salamin@unil.ch; tel: 4154; office: Génopode 2025.3
March, 2024
Link to the Moodle course: click here

Teams channel: click here
What is quantitative genetics?
from www.globalbiofest.com
Nicolas Salamin – Introduction to Quantitative Genetics / Partie 1 – p. 2

What is quantitative genetics?
Key topic in evolutionary biology

Theory of the statistical relationship between genotypic variation and
phenotypic variation
Main questions
1. what is the cause of phenotypic variation in natural populations?
2. what is the genetic architecture and molecular basis of phenotypic
variation in natural populations?

Level of study of traits
Patrick Phillips, NiMBIOS lecture 2016

A bit of history...
After the rediscovery of Mendel’s work, heated debate between two

“schools”:
Mendelians Biometricians
▶ discrete traits inherited and ▶ supporters of Darwin and
associated to genotypes founders of modern statistics
▶ evolution moves by major leaps ▶ important variation in evolution
due to new mutations did not follow Mendel’s rule
▶ merging of phenotype and ▶ e.g. height, weight, BMI, skin
color
genotype in continuous traits
▶ vary continuously
▶ if affected by environment, then ▶ blending inheritance
not inherited ▶ respond to environment
Modern synthesis: fusion of Darwin’s evolution by natural selection with

Mendelian inheritance.

From Mendel and Pearson to now
Patrick Phillips, NiMBIOS lecture 2016

Genotype vs phenotype
Genotype
▶ genetic makeup of an organism
▶ specific set of alleles inherited at a locus
Phenotype
▶ any measurable characteristic of an individual, e.g. height, hair color,
disease status
▶ selection acts on the phenotype
▶ modified by genetic and environmental background
▶ monogenic traits (rare)
▶ discrete binary characters
▶ polygenic traits (common)
▶ discrete (number of bristle), continuous (body mass) or binary (disease
status)

Increasing the number of loci
leads to a continuous phenotype frequency

▶ with 1 locus → 2 homozygous, 1 heterozygous
▶ to many loci → continuous distribution
cubocube.com

Quantitative genetics model
Writing down the model for 1 locus

( AA = +0.95 )
phenotype =µ+ Aa = +0.99 +E
aa = +0.76
to multiple loci
( AA = +0.95 ) ( BB = +0.01 ) ( CC = −0.60 )
phenotype = µ+ Aa = +0.99 + Bb = −0.05 + Cc = +0.35 +E
aa = +0.76 bb = −0.02 cc = +0.06

Phenotype distribution
Effect of many loci

▶ overall mean = 0

Phenotype distribution
Effect of many loci

▶ overall mean = 0
▶ locus mean = 0.90
▶ all others vary around
overall mean, but
effects will add up

Genotype effects on phenotype

Reaction norm
Distribution of phenotypes
▶ distribution of environments reflected as a distribution of phenotypes
▶ transformation of environmental distribution into phenotype
distribution is determined by the norm of reaction
from book: Griffiths et al 1996 Freeman and Company

Galton’s regression to the mean
https://select-statistics.co.uk/blog/regression-to-the-mean-as-relevant-today-as-it-was-in-the-1900s/

How to obtain it? Try and explain
k<-100; n<-1000 #k=num loci, n=num parent/offspring

p<-0.5 #allele frequency
d<-data.frame(midPar=array(dim=n),offVal=array(dim=n), dad=array(dim=n), mum=array(dim
for(i in 1:n) {
#genotypes
dad<-rbinom(k,2,p); mum<-rbinom(k,2,p)
kid<-rbinom(k,1,dad/2) + rbinom(k,1,mum/2)
#phenotypes / sd=5 is arbitrary

z_dad<-rnorm(1,sum(dad),5); z_mum<-rnorm(1,sum(mum),5)
z_kid<-rnorm(1,sum(kid),5)
d$dad[i]<-z_dad; d$mum[i]<-z_mum
d$midPar[i]<-mean(c(z_dad,z_mum))
d$offVal[i]<-z_kid
}
plot(d$midPar, d$offVal, xlab="Mid-Parent trait",

ylab="Child trait")

The wrong blending inheritance
Half of variation removed in each generation

Blending inheritance of continuous traits
σ 2 (zf ) σ 2 (zm ) σ 2 (z)

2 2 zf + zm
σ (zo ) = σ = + =
2 22 22 2
with zo is the offspring value, zf and zm are the maternal and paternal
values and trait variance is the same in females and males
(i.e. σ 2 (zm ) + σ 2 (zf ) = 2 × σ 2 (z)). It leads over time t to
t
1
σ 2 (zt ) = σ 2 (z0 )
2
Mendelian inheritance
Transmission of alternative alleles in gametes of heterozygous parents
restores genetic variance → solve the issue and is integrated in the modern
synthesis

Partitioning phenotypic value
Basic model to use
P =G +E
where
▶ P is the phenotypic value measured on individuals
▶ G is the mean phenotypic value of those carrying the same genotype
▶ E is the deviation due to the environment, assumed with mean = 0
G and E are artificial constructs that need to be estimated using statistical

methods
Genotypic values are functions of the environments experiences (and we left

aside the G × E interactions)

Single locus influence
How does it influence a phenotype

▶ G is expected phenotype contribution (for a given set of genotypes)
resulting from the joint expression of all of the genes underlying the
trait
▶ for multilocus trait, G can be very complex
▶ what if a single autosomal locus affect the phenotype? (weird, but
easier to show the process and hold for many loci)
Genotypic value

 2a if genotype is AA
Genotypic value = (1 + k)a if genotype is Aa
0 if genotype is aa


Dominance and additivity
k and a values

 2a if genotype is AA
Genotypic value = (1 + k)a if genotype is Aa
0 if genotype is aa

▶ a is the additive genotypic value

▶ 2a = difference in mean phenotype for AA and aa
▶ k is the scaled measure of dominance
▶ k = 0 → alleles A and a are additive
▶ k > 0 → A has dominance over a (reverse for k < 0)
▶ k = 1 → complete dominance
▶ k > 1 → overdominance since mean phenotype of heterozygotes
exceeds both homozygotes
▶ k < −1 → underdominance

Example
Fecundity in Merino sheep

▶ litter size is polygenic, but mainly driven by Booroola gene in Merino
sheep (Piper and Bindon, 1988)
▶ for three genotypes, mean litter size for 685 records
Genotype Mean litter size

bb 1.48 (sd = 0.09)
Bb 2.17 (sd = 0.08)
BB 2.66 (sd = 0.09)
Small exercice (send me the answers)

▶ what is the dominance value k for this locus?
▶ is there significant dominance effect?

Other way to represent
Change the relative value

Genotype value relative to the average mean genotype for the two
homozygotes

 a if genotype is AA
Genotypic value = d if genotype is Aa
−a if genotype is aa

Answer the following question

▶ what is the value of d to cover all cases shown above (i.e. additivity,
dominance, . . .)?
▶ tip: add a to all scales and let d = ak
▶ k = d/a, which is why it is called the scaled measure of dominance

Representing genotypic values
Genotype aa Aa AA
Genotypic value −a d a
0
total difference: 2a
An example to illustrate
Calculate, with the following example
▶ the dominance effect d
▶ the additive genotypic value a
aa Aa AA
weight (g) 6 12 14

Decomposing genotypic values

Decomposing the genotypic values
G is a complex function across loci

Decompose G into additive and non-additive components
Gij = GijA + δij = µG + αi + αj + δij
for individuals with alleles i and j at a locus.
The function has the following components

▶ Gij is the mean genotypic value
▶ µG is the genotypic mean in the population (a fonction of P)
▶ αi and αj are the mean additive effects for each allele
▶ µG + αi + αj is the predicted genotypic value over all genotypes of
allele i and j
▶ δij is a dominance effect, i.e. difference between true and predicted
value from sum of average effects

Average effect of each allele
Decomposing the genotypic effect

Again, assume a trait locus with two alleles i = A and j = a. We then have

 µG + 2αi if genotype is AA
GijA = µG + αi + αj if genotype is Aa
µG + 2αj if genotype is aa

The goal is to calculate the average effect of each allele for a phenotype
▶ genotype values relative to the average of the mean genotypic value for
the two homozygotes
▶ help the interpretation of the additive effects for the alleles
▶ assume that A increases the phenotypic value (see graph in previous
slide)

Mean genotypic value
Assuming Hardy-Weinberg equilibrium

▶ frequency of A and a are p and q
▶ what is the mean genotypic value µG on this scale?
µG = a(p 2 ) + d(2pq) − aq 2
= a(p 2 − q 2 ) + d(2pq)
= a(p + q)(p − q) + d(2pq)
= a(p − q) + d(2pq)

Population mean genotype value
Contribution of a locus to the population mean

▶ two terms are defining it
▶ a(p − q), which only depends on the homozygotes
▶ d(2pq), which only depends on the heterozygotes
▶ under no dominance, mean genotypic value proportional to allele
frequency µG = a(1 − 2q) (or a(2p − 1))
▶ with complete dominance of the A allele (d = a, or d = −a for
dominance of a), mean proportional to the square of the allele
frequency µG = a(1 − 2q 2 )
Questions
▶ total range of values attributed to this locus is 2a
▶ what would be the contribution of this locus to the phenotype if the
population is monomorphic A? What if monomorphic a?

Mean allelic effect
Different from mean genotypic effect

▶ average effect linked with an allele carried by an individual (i.e. αi )
▶ important to characterize because parents transmit one of their alleles
at a locus to their offsprings, not their genotypes
▶ breeding value is the sum of the additive effects of the alleles carried by
an individual and that will be given to its offsprings

 µG + 2αi if genotype is AA
GijA = µ + αi + αj if genotype is Aa
 G
µG + 2αj if genotype is aa

Mean allelic effect, cont.
How to estimate αi ?
▶ αi is the mean effect of allele i = A
▶ mean deviation from population of individuals with allele A when the
other allele is drawn at random from the population
▶ assume as always that A and a have frequencies p and q
▶ genotypic value of AA is a, Aa is d and aa is −a
What is the average effect of the genotypes that are created if A is

randomly paired with gametes in the population?

Mean allelic effect, cont.
Estimation of αi
a × P(A pairs with another A) + d × P(A pairs with a a)
Then, average effects of genotypes with A is ap + qd
It follows that
αi = pa + qd − µG = q[a + d(q − p)]
Estimation of αj
Similarly,
αj = −qa + pd − µG = −p[a + d(q − p)]

Average effect of allele substitution
When we have two alleles

▶ suppose that we could change at random a alleles into A
▶ what would be the resulting change in genotypic value?
▶ mean change produced is the average effect of allele subsitution
How would this work out if a alleles are chosen at random

▶ proportion p are in Aa genotypes, which change into AA
▶ genoytpic value change from d to a → with an effect of a − d
▶ proportion q are in aa genotypes, which change into Aa

▶ genotypic value change from −a to d → with d + a effect
What is the average allele effect of allele substitution?

Average effect of allele substitution, cont.
Combining the two components

▶ average effect of substitution α is
α = p(a − d) + q(d + a) = a + d(q − p) = αi − αj
▶ this is the difference between the average effects of the two alleles
i = A and j = a
It turns out that

▶ αi = qα
▶ αj = −pα

Additive genetic value (A) or breeding value
Key concept
The αi values are the average effects of an allele.
Used to estimate the Breeding value or the additive genetic value

▶ key concept : parents only pass single alleles at each locus to their
offspring
▶ different offspring from the same parents will differ depending on the
allele that they receive from their parents
▶ parents pass the A part of their genotypic value G
▶ for 2 alleles, A = αi + αj
▶ for n alleles, A = nk=1 (α(k) (k)
P
i + αj )
▶ offspring A will be the average of the two parents A’s

Representing it graphically
GAA ◦
Genotypic value
GAa ◦
Gaa ◦
0 1 2 Copies of allele A
aa Aa AA Genotypes
adapted from Bruce Walsh’s lecture

GAA ◦
Genotypic value
GAa ◦
Gaa ◦
aa Aa AA Genotypes

•
GAA ◦
Genotypic value
GAa ◦
•
•
Gaa ◦
aa Aa AA Genotypes

• µG + 2αA
GAA ◦
Genotypic value
GAa ◦
• µG + αA + αa
µG + 2αa
•
Gaa ◦
aa Aa AA Genotypes

• µG + 2αA
GAA ◦
Genotypic value
GAa ◦
• µG + αA + αa
µG + 2αa
α Slope = α = αa − αA
1
•
Gaa ◦
aa Aa AA Genotypes

• µG + 2αA
GAA ◦ δAA
Genotypic value
GAa ◦
δAa
• µG + αA + αa
µG + 2αa
α Slope = α = αa − αA
1
•
Gaa ◦ δaa
aa Aa AA Genotypes

Population level data
Linear regression model

•
◦
◦
GAA ◦
◦
◦
Genotypic value
GAa ◦
◦
•
•
◦
◦
Gaa ◦
aa Aa AA Genotypes

Putting it into a linear regression
Adapting the representation

If we assume a biallelic locus
▶ let’s X1ij and X2ij be the number of alleles of type A and a, respectively,
(i.e. 0, 1 or 2), in genotype Gij
▶ as X1ij = 2 − X2ij , Gij becomes
Gij = β0 + β1 X1ij + δij
where
▶ β0 = µG + 2αj is the intercept
▶ β1 = αPj − αi is the average effect of allele substitution and the slope
▶ µG = (Gij × freqij )
▶ slope will change depending on the allelic effects, even with identical
genotypic values
▶ can be estimated in a linear regression of traits vs genotypes

Multi-locus traits
Polygenic traits, most common case

▶ alleles of these loci contribute to the genotypic mean (and thus the
phenotype)
▶ assume that the loci are unlinked (no epistasis, i.e. no interaction)
▶ population mean of the trait affected by L loci is simply
L
X L
X
µG = ai (pi − qi ) + 2 di pi qi
i=1 i=1
where, at loci i
▶ ai = genotypic value for the homozygotes with larger value
▶ di = genotypic value for the heterozygotes
▶ pi and qi are the two allele frequencies
Easily framed into a multiple linear regression too (see Zoltan’s course for
details)!

Exercices (from Falconer and Mackay, 1989)
Exercice 1
A locus is overdominant with the following genotypic values:
AA Aa aa
120 150 90
Find the allele frequency giving the maximum mean value. What is this
mean value? Tips: use a graph to plot the results and find the maximum
Exercice 2
What are the breeding values of the three genotypes above?

Exercices, cont.
Exercice 3
Use R to estimate the average effect of allele substitution and both allelic
effects in this example:
genotype<-c("aa","AA","Aa","AA","Aa","aa","AA",
"AA","AA","aa","aa","AA","Aa","AA","AA","aa",
"Aa","Aa","Aa","Aa","aa")
phenotype<-c(1.79,23.83,12.30,23.27,13.25,1.59,
23.14,23.70,25.09,1.82,2.40,22.94,12.51,24.13,
22.60,4.92,12.43,11.39,12.93,13.57,2.03)
Tips: transform the genotype and use lm() to get the intercept and slope.
Interpret the estimates as described in the course.
Assuming that the allele frequencies are fa = 0.43 and fA = 0.57, calculate
the allelic effects.

Further reading to do
Read Falconer and Mackay, 1989

▶ Chapter 7 – pages 111 to 124
▶ here’s the pdf
▶ ask questions through Teams

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Introduction to Quantitative Genetics

nicolas.salamin@unil.ch; tel: 4154; office: Génopode 2025.3

Link to the Moodle course: click here

Nicolas Salamin – Introduction to Quantitative Genetics / Partie 1 – p. 2

Key topic in evolutionary biology

Nicolas Salamin – Introduction to Quantitative Genetics / Partie 1 – p. 3

Patrick Phillips, NiMBIOS lecture 2016

Nicolas Salamin – Introduction to Quantitative Genetics / Partie 1 – p. 4

After the rediscovery of Mendel’s work, heated debate between two

Modern synthesis: fusion of Darwin’s evolution by natural selection with

Nicolas Salamin – Introduction to Quantitative Genetics / Partie 1 – p. 5

Patrick Phillips, NiMBIOS lecture 2016

Nicolas Salamin – Introduction to Quantitative Genetics / Partie 1 – p. 6

Nicolas Salamin – Introduction to Quantitative Genetics / Partie 1 – p. 7

leads to a continuous phenotype frequency

Nicolas Salamin – Introduction to Quantitative Genetics / Partie 1 – p. 8

Writing down the model for 1 locus

Nicolas Salamin – Introduction to Quantitative Genetics / Partie 1 – p. 9

Effect of many loci

Nicolas Salamin – Introduction to Quantitative Genetics / Partie 1 – p. 10

Effect of many loci

Nicolas Salamin – Introduction to Quantitative Genetics / Partie 1 – p. 11

Nicolas Salamin – Introduction to Quantitative Genetics / Partie 1 – p. 12

from book: Griffiths et al 1996 Freeman and Company

Nicolas Salamin – Introduction to Quantitative Genetics / Partie 1 – p. 13

Nicolas Salamin – Introduction to Quantitative Genetics / Partie 1 – p. 14

k<-100; n<-1000 #k=num loci, n=num parent/offspring

d<-data.frame(midPar=array(dim=n),offVal=array(dim=n), dad=array(dim=n), mum=array(dim

#phenotypes / sd=5 is arbitrary

plot(d$midPar, d$offVal, xlab="Mid-Parent trait",

Nicolas Salamin – Introduction to Quantitative Genetics / Partie 1 – p. 15

Half of variation removed in each generation

σ 2 (zf ) σ 2 (zm ) σ 2 (z)

Nicolas Salamin – Introduction to Quantitative Genetics / Partie 1 – p. 16

Basic model to use

G and E are artificial constructs that need to be estimated using statistical

Genotypic values are functions of the environments experiences (and we left

Nicolas Salamin – Introduction to Quantitative Genetics / Partie 1 – p. 17

How does it influence a phenotype

Nicolas Salamin – Introduction to Quantitative Genetics / Partie 1 – p. 18

▶ a is the additive genotypic value

Nicolas Salamin – Introduction to Quantitative Genetics / Partie 1 – p. 19

Fecundity in Merino sheep

Genotype Mean litter size

Small exercice (send me the answers)

Nicolas Salamin – Introduction to Quantitative Genetics / Partie 1 – p. 20

Change the relative value

Answer the following question

Nicolas Salamin – Introduction to Quantitative Genetics / Partie 1 – p. 21

Nicolas Salamin – Introduction to Quantitative Genetics / Partie 1 – p. 22

Nicolas Salamin – Introduction to Quantitative Genetics / Partie 1 – p. 23

G is a complex function across loci

Gij = GijA + δij = µG + αi + αj + δij

for individuals with alleles i and j at a locus.

The function has the following components

Nicolas Salamin – Introduction to Quantitative Genetics / Partie 1 – p. 24

Decomposing the genotypic effect

Nicolas Salamin – Introduction to Quantitative Genetics / Partie 1 – p. 25

Assuming Hardy-Weinberg equilibrium

Nicolas Salamin – Introduction to Quantitative Genetics / Partie 1 – p. 26

Contribution of a locus to the population mean

Nicolas Salamin – Introduction to Quantitative Genetics / Partie 1 – p. 27

Different from mean genotypic effect