CS 563

Lecture 4
Oct. 04, 2018
Properties of Genes Affecting Quantitative Traits

Assigned Reading for lecture:

Falconer & Mackay Chapter 6; pp. 108-109; pp. 131-135.

Quantitative genetics is also called statistical genetics. It is concerned with the

inheritance of phenotypic measurements.
There are two types of phenotypic variation among populations
- Discrete or Mendelian (qualitative differences in phenotype between individuals)
- Continuous or polygenic (also quantitative or metric traits) because they are
concerned with measurement of traits and not counting)
Genetic principles underlying the inheritance of quantitative traits have their foundation
in population genetic theory.

Properties of a polygenic trait

Does not follow Mendelian genetics
Segregation of genes cannot be followed
The variation is continuous and not discrete
Variation approximates normal distribution
Trait controlled by many genes each contributing a small effect
Trait is sensitive to the environment

Quantitative variation is ubiquitous and may include traits such as:

Anatomical dimensions and proportions,
Aspects of physiology and behavior,
And ‘intermediate’ phenotypes such as transcript abundance,
Enzyme activity,
Disease susceptibility,

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Metabolite levels

Variation in quantitative traits is typically continuously distributed in populations, such

that it is generally not possible to infer an individual’s genotype for a quantitative trait
from knowledge of the phenotypic measurement. This is because the effects of allelic
variation at a single gene affecting a quantitative trait are usually (but not always) small,
many loci act together to affect the phenotype, and the effects of alleles are sensitive to
the environment in which the individual is reared. The underlying genetic
polymorphisms affecting variation for quantitative traits do obey the Mendelian rules of
inheritance; therefore, we need to develop a framework to relate Mendelian genetic
variation at multiple loci with quantitative genetic variation in phenotypes.
Understanding quantitative variation is important for the progress in:
Agriculture
Medicine
Adaptation / evolution
Genetics / genomics

Gene Action at a locus

Additivity and dominance

We begin by considering a single autosomal locus, A, with two alleles (A1 and A2) that
affect a particular complex trait (i.e., there is a difference in phenotype between
individuals that have different genotypes at this locus). For any quantitative trait, we can
convert the average of the phenotypic measures of each of the three genotypes to
genotypic values on an arbitrary scale as follows:

A2A2 A1A2 A1A1

–a 0 d +a

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The mean value of the A1A1 homozygote (by convention, the homozygous genotype
increasing the trait measurement) is +a, and of the A2A2 homozygote is –a, where the
unit of measurement of a is the same as for the trait. The difference (interval) in mean
trait value between the two homozygous genotypes is

2a, i.e., +a – (-a) = 2a

Thus, we can estimate a as a = (A1A1 – A2A2)/2. a is also called the additive effect. It is
sometimes standardized by the phenotypic standard deviation units of the trait (a/sP) to
facilitate comparisons among traits. Values of a/sP > 3 will cause a bimodal or trimodal
distribution of the trait in the population, where individuals can be unambiguously
assigned to two or three genotypes and the variant can be scored as a Mendelian allele.
Single genes with minor effects affecting quantitative traits more typically have effects in
the range of 0.25 – 1.0 a/sP.

The value of the heterozygote on this scale is d, which is the mean value of the
heterozygous genotype expressed as a deviation of the heterozygote from the mean of
the two homozygotes: d = A1A2 – (A1A1 + A2A2)/2. Thus, the mid-point of the arbitrary
scale is 0 (the mid-parent). Since the value of d depends on the degree of dominance, d
is also called the dominance effect. If d = 0, the mean value of the heterozygote
genotype is exactly intermediate between the two homozygous genotypes. In this case,
we say that gene action is additive. If d ≠ 0, there is non-additive interaction between
alleles at the locus such that an allele displays some form of dominance over other
alleles. If d = –a, the A2 allele is completely dominant; conversely, if d = +a, the A1 allele
is completely dominant. If d < 0 but d > –a, the A2 allele is partly dominant. If d > 0 but d
< +a, the A1 allele is partly dominant. Finally, if d > +a (or d <–a) then there is over
(under) dominance. The degree of dominance is often expressed as d/a. On this scale,
d/a = 0 indicates additive gene action, d/a = 1 or –1 means the A1 (A2) allele is
completely dominant, –1 < d/a < 1 indicates partial dominance, and –1 > d/a > 1
indicates over (under) dominance. In classical genetics, dominance and recessivity are
common, and the term co-dominant is used to refer to any category of gene action

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in which the heterozygous genotype is intermediate between the two
homozygous genotypes. Quantitative genetics thus allows for a greater spectrum of
gene action than Mendelian genetics where only discrete effects are observed.
Genotype Value

+a

-a

A2A2 A1A2 A1A1

d = -a; A2 dominant Genotype

d = 0; additive
d = +a; A1 dominant
d > +a; overdominance

Example:

Mutations in the myostatin (MSTN) gene cause a double muscle phenotype in several
mammalian species. Recently, a two base pair deletion in the third exon of MSTN that
leads to a premature stop codon (UAA, UAG, UGA) at amino acid 313 was found to
give rise to a double muscle phenotype in the whippet dog breed. Homozygotes for the
mutation (mh/mh) are double muscled type called ‘bully’ whippets (Mosher et al., 2007,
PLoS Genetics 5: e79), while heterozyogtes (mh/+) are more muscular than wild type
(+/+) whippets (normal muscle). The mean neck girths (cm) of individuals of the three
genotypes were:
Genotype Neck girth
mh/mh 38.48
mh/+ 30.63
+/+ 29.26
We can thus compute the additive and dominance effects as:
a = (38.48 – 29.26)/2 = 4.61
d = 30.63 – (38.48 + 29.26)/2 = –3.24

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 d/a = –3.24/4.61 = –0.70
The dominance ratio is negative; thus the mh mutation has partially recessive effects on
neck girth.

Gene action at many loci

Epistasis
If two loci, A and B, each with two alleles (A1, A2; B1, B2) both control a trait, we need to
consider the effects of all possible genotypes:

Table 1. Possible Linear and Non-linear interactions between locus A and locus B

Genotype A1A1 A1A2 A2A2

B1B1 aA + aB + aaAB dA + aB + daAB –aA + aB – aaAB

B1B2 aA + dB + adAB dA + dB + ddAB –aA + dB – adAB

B2B2 aA – aB – aaAB dA – aB – daAB –aA – aB + aaAB

Here, the aaAB, adAB, daAB and ddAB terms represent the different possible kinds of non-
linear interactions between A and B (= epistasis). Epistasis is therefore the interaction
of genes that are not alleles and are at different loci. If all of these terms are equal to
zero, then we have additive interactions between loci. Thus, the term additive is used to
refer to both intra- and inter-locus interactions. Epistasis occurs when the additive
and/or dominance effects at one locus are dependent on the genotype of a second
locus affecting the trait. In classical genetics, epistasis is used to denote masking of
effects of one locus by another, and is detected by modifications in the expected 9:3:3:1
phenotypic ratio in the F2 of a cross of homozygous dominant mutations at two
independent loci (i.e., A1A1B2B2  A2A2B1B1, where A1 and B1 are dominant alleles).
Examples of modified Mendelian ratios are 9:3:4; 9:6:1; 9:7; 12:3:1; 13:3 and 15:1. The
quantitative genetic perspective on epistasis refers to a broader range of interactions,
whereby any interaction between two loci that is not additive is epistatic. Note that

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dominance (an interaction between alleles at a single locus) and epistasis (an
interaction between alleles at different loci) are independent; one can have dominance
at a locus but no epistasis between loci, and epistasis between loci with no dominance
at the individual loci. Epistasis is important, since it occurs when two loci genetically
interact, and can be used to infer genetic pathways or networks.

(A) No dominance, no epistasis (B) Dominance, no epistasis

B1B1 +a B1B1
+a B1B2

Genotype Value
Genotype Value

B1B2

0 B2B2
0 B2B2

-a -a

A2A2 A1A2 A1A1 A2A2 A1A2 A1A1

Genotype Genotype

B1B1
+a B1B2 +a B2B2
Genotype Value

Genotype Value

0 0 B1B2

-a B2B2 -a B1B1

A2A2 A1A2 A1A1 A2A2 A1A2 A1A1

Genotype Genotype

(C) Dominance, epistasis (D) Epistasis

Pleiotropy

Pleiotropy refers to the effect of a gene on more than one trait. In the narrow sense,
pleiotropy can be restricted to a particular allele.

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Example:
Whippet dogs that race are grouped into four racing grades (A, B, C, D in order from
fastest to slowest). Is racing grade (phenotype) associated with presence of the mh
mutation (Mosher et al., 2007, PLoS Genetics 5: e79)? That is, if mh gene affects both
neck girth and racing traits, then we have pleiotropy.

Genotype
No. of dogs distributed across racing
grades
Racing
+/+ +/mh mh/mh % mh
grade
A 12 8 1 42.8 = 9/21 *100
B 18 3 0 14.3 = 3/21 *100
C 25 0 0 0.0 = 0/25 *100
D 17 1 0 5.6 = 1/18 *100
Total 72 12 1 15.3 = 13/85 *100

Clearly, far more individuals with a copy of the mh mutation are in the fastest racing
grade, given the overall frequency of individuals with at least one mh copy in the
population sampled (P = 0.0003). Therefore, the mh mutation is pleiotropic. It affects
musculature and racing speed.

In a broader sense, pleiotropy refers to effects of different alleles at the same gene on
different traits. For example, null (non-functional) alleles of the Drosophila gene scribble
are embryonic lethal, but a hypomorphic (mutation causing a partial loss of gene
function) viable allele caused by a P transposable element insertion in the promoter
region affects adult olfactory behavior (Ganguly et al., 2003, Genetics 164: 1447-1457).
As we will see in a later lecture, the pleiotropic effect of a mutation on fitness is a major
factor affecting its frequency within and between populations.

Environmental Effects

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Quantitative traits are exquisitely sensitive to variation in the environment, including but
not limited to differences in nutrition, temperature, humidity, time of day, lighting, age of
the individual, and maternal and social environment. Therefore, measurements of the
same trait for individuals that have the same genotype will not be identical, even if the
individuals are reared under highly controlled environmental conditions.

The figure illustrates measures of aggressive behavior for two different Drosophila strains, B and Oregon.
Individuals of each strain are genetically identical and reared under the same constant environmental
conditions. The range of phenotypic variation in aggressive behavior within each strain is due to environmental
variation; the difference in mean level of aggression between the strains is due to genetic differences between
the strains. (A. Edwards and T. F. C. Mackay, unpublished data.)

Combined Effect of Genes and Environment

Because both genes and environment affect quantitative traits, we can express the
mean phenotypic value (P) of a group of identical individuals reared under the same
environmental conditions as P = G + E. G, the genotypic value is due to the individual's
unique genotype at all loci controlling the trait, and the total value of all the alleles on the
expression of the trait. For a single locus, G = a (A1A1), –a (A2A2) or d (A1A2). For two
loci, the values of G are given in Table 1 (above). E, the environmental deviation, arises
from environmental influences on the genotype (all non-genetic causes). E includes real
environmental differences, as well as any measurement error. Thus, the phenotype of
any individual is caused by the genes it carries and the environment in which it was
raised. Even a genetically large mouse will be small if starved. We assume that in the
population as a whole the environmental fluctuations cancel out, so MP = MG (ME = 0). It
is possible to measure the mean genotypic (phenotypic) value only when we have a

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large number of individuals with the same genotype, or if clonal propagation is possible.
Typically, the genotypic value of an individual in an outbred population is not directly
measurable.

Genotype by Environment Correlation and Interaction

A genotype - environment correlation can occur if better phenotypes are given better
environments. For example, "better" (pedigree and performance of parents) racehorses
go to better trainers and are ridden by better jockeys.

Truly continuous variation arises from environmental causes. Each genotype does not
have a single phenotypic expression but a norm of reaction that covers a range of
phenotypes. The plot of phenotypic values across an environmental gradient is the
reaction norm (or norm of reaction) of a genotype. This is also called the environmental
sensitivity of a genotype. Each line is a norm of reaction for a different genotype. The
same genotype may have different phenotypes according to the environment, and
different genotypes can have different patterns of environmental sensitivity.
Independence of genotype and environment also implies that a specific difference in
environment has the same effect on different genotypes. A particular environmental
deviation can be associated with a specific difference in environment, irrespective of the
genotype on which it acts. When this assumption is violated, there is genotype by
environment interaction (GEI). GEI can arise if specific differences in the environment
have greater effects on some genotypes than others (changes in variance), or if there is
a change in order of merit of a series of genotypes measured under different
environments (changes in rank). GEI thus occurs if the environmental sensitivities are
not the same for different genotypes. GEI is common for quantitative traits.

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 +a A1A1 +a A1A1 +a A1A1

Genotype Value
Genotype Value

A1A2
Genotype Value

A1A2
0 A2A2 0 0 A1A2

A2A2

-a -a -a A2A2

A B A B A B

Environment Environment Environment

(A) No GEI (B) Conditional neutrality (C) Antagonistic pleiotropy

A. Different phenotypes in A, proportional sensitivity leading to corresponding phenotypes in environment B.
B.Same phenotype in environment A. Different sensitivity and different phenotypes in environment B.
C. Different phenotypes and sensitivities in environment A and B

Example:

Crabbe et al. (1999, Science 284: 1670-1672) tested eight different inbred strains of
mice in six behavioral assays (1. Locomotor activity in an open field, 2. The elevated
plus maze anxiety test, 3. Walking and balancing on a rotating rod, 4. Learning to swim
to a visible platform, 5. Locomotor activity after cocaine injection, and 6. Preference for
drinking ethanol versus tap water); in three different locations (Portland, Edmonton and
Albany). Despite efforts to use exactly the same strains and apparati, there were
differences in performance of the different stains between sites. For example,
129/SvEvTac mice tested in Albany were very inactive compared to their counterparts in
other labs. Similar results were seen for sensitivity to cocaine stimulation: B6D2F2 mice

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were very responsive (and A/J mice quite insensitive) to cocaine in Portland, but not at
other sites.

There are often differences between the mean value of a quantitative trait between
males and females of the same genotype, called sexual dimorphism. A special case of
GEI is variation in the amount of sexual dimorphism between different genotypes; here
sex is considered as two different environments.

Example:

Variation for avoidance response to benzaldehyde among isogenic chromosome 3 substitution lines in Drosophila. The
male and female avoidance scores of each line are connected (Mackay et al., 1996, Genetics 144: 727-735). Twenty-four
lines were tested.

Penetrance and Expressivity

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Quantitative genetics allows for a range of phenotypes to be expressed by a single
genotype, due to environmental sensitivity, epistatic interactions with other loci, and/or
GEI. In human genetics, the terms penetrance and expressivity are used to indicate that
the relationship between genotype at a locus and trait phenotype is not perfect.
Penetrance refers to the proportion of the individuals with a given genotype that display
the phenotype associated with that genotype. Expressivity refers to quantitative
variation in expression of a phenotype among individuals of the same genotype. In both
cases the cause of the phenomenon could be epistasis (modifying loci) or
environmental.

The dark blue circles represent individuals with the same hypothetical homozygous
genotype that affects spotting (small teal circles). Individuals can vary for presence and
absence of spots (variable penetrance), number of spots (variable expressivity) or both.
For variable penetrance, individuals with blue circles must have the phenotype that
carries the teal circles. In the above figure, only three individuals have the phenotype
displayed by this genotype and three do not have. So the penetrance here is variable.

With expressivity, while blue circled individuals must have one teal circle, some
phenotypes are showing two/three teal circles, so we have variable expressivity. The
product of variable alone and penetrance alone should give the corresponding
penetrance and expressivity values. However, we see that the penetrance and
expressivity above is variable in the fourth column.

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