Chapter 15

Chapter 15
The Genetic Basis

of Complex Traits
Multifactorial Traits
• Traits determined by multiple genetic and
environmental factors acting together.
• Also referred to as complex traits or quantitative
traits.
• Most traits that vary in the population, including
common human diseases with the genetic
component, are complex traits.
• Genetic architecture of a complex trait: specific
effects and combined interactions of all genetic
and environmental factors.
Use of Inbred Lines for Analysis of
Quantitative Traits
A. All individuals in an
inbred allele are
homozygous for one
allele of each gene.
B. F1 progeny of two inbred
lines are heterozygous
for alleles of all genes.
Types of Quantitative Traits
• Continuous traits: Continuous gradation from
one phenotype to the next (height).
• Categorical traits: Phenotype is determined by
counting (e.g., number of hens’ eggs laid).
• Threshold traits: Only two, or a few phenotypic
classes, but their inheritance is determined by
multiple genes and environment (e.g., adult-
onset diabetes).
Distributions
• The proportion of individuals that have each of
the possible phenotypes of a trait
• Mean: The average of all phenotypic values
= ∑fixi/N
• Variance: The spread of distribution estimated
by squared deviation from the mean
σ2 = ∑fi(xi – x )/N – 1
• Standard deviation: Square root of the variance
s =√ σ2
An Example of a
Phenotypic Distribution
• Mean = 63.1 in.
• Variance = 7.24 in.2
• Standard deviation =
2.69 in.
Distribution can be described as 63.1 ± 2.69 in.

Features of a Normal Distribution
Phenotypic Variation
• Variation of a trait can be separated into genetic
and environmental components.
• Genotypic variance sg2: Variation in phenotype
caused by differences in genotype.
• Environmental variance se2: Variation in
phenotype caused by environment.
• Total variance sp2: Combined effects of genotypic
and environmental variance.
sp2 = sg2 + se2
Returning to Inbred Lines
• All phenotypic variation within a single
population of an inbred line must be
environmental variation.
• Phenotypic variation in the F2 progeny of two
inbred lines is due to a combination of genetic
and environmental variation.
• Measurement of the two can provide estimates
of σ2G and σ2E.
Genotype–Environment Interactions
• Genotype–environment (G-E) interaction:

Environmental effects on phenotype differ
according to genotype.
• Genotype-by-sex interaction: Same genotype
produces different phenotype in males and
females (e.g., distribution of height among
women and men).
An Example of G-E Interaction
in Maize
Data from W. A. Russell, Annual Corn & Sorghum Research Conference 29 (1974): 81.
Heritability
• Broad-sense heritability (H2): The proportion of
phenotypic variation in a population due to all
genetic effects combined:
– H2 = sg2 / sp2 = sg2 / (sg2 + se2)
• Narrow-sense heritability (h2): The proportion of
phenotypic variation in a population due to additive
effects of individual alleles:
– h2 = sa2 / sp2
Estimating H2 from Twin Studies
• Twin studies are often used to assess genetic
effects on variation in a trait.
• Identical twins arise from the splitting of a single
fertilized egg = genetically identical.
• Fraternal twins arise from two fertilized eggs =
only half of the genes are identical.
• Theoretically, the variance between identical
twins would be equivalent to se2, and between
fraternal twins – sg2/2 + se2.
Sources of Error in Twin Studies
• Genotype–environment interaction increases
the variance in fraternal twins but not identical
twins.
• Frequent sharing of embryonic membranes by
identical twins creates similar intrauterine
environment.
• Greater similarity in treatment of identical twins
results in decreased environmental variance.
• Different sexes can occur in fraternal but not
identical twins.
Estimating Heritability from
Artificial Selection
• M = Mean of starting
population = 70
• M* = Mean of selected
breeders = 81
• M' = mean of progeny = 77
• Selection differential (S) =
M* – M = 81 – 70 = 11
• Response to selection (R)
= M' – M = 77 – 70 = 7
• h2 = R/S = 7/11 = 0.636
Limits and Correlations
• Selection limit at which successive generations
show no further improvement can be reached
because either
– All alleles have been fixed or lost, or
– Natural selection counteracts artificial
selection due to indirect harmful effects of
selected traits (e.g., weight at birth versus
viability)
• Correlated response: Effect of selection for one
trait on a nonselected trait (e.g., number of eggs
and their size)
Inbreeding Depression and
Heterosis
• Inbreeding depression:
Decrease in fitness due
to harmful recessive
alleles that become
homozygous
• Heterosis (hybrid vigor):
Superior fitness of
heterozygote; often used
in agricultural crop
production
Data from N. P. Neal, Agron. J. 27 (1935): 666-670.
Data from N. P. Neal, Agron. J. 27 (1935): 666-670.

Correlation Between Relatives
• Genetic variation is revealed by correlations
between relatives.
– Covariance (Cov): The tendency for traits to vary
together
– Cov(x,y)=∑fi(xi – x)(yi – y)/N – 1
– Correlation coefficient: Statistical evaluation of
paired data (pairs of parents, twins, parent and
offspring)
r =Cov(x,y)/sxsy
• Covariance and correlation coefficients can be
used to estimate heritability.
An Example of Parent–Offspring
Regression
Hypothetical Parent–Offspring Regressions
Given Various Values of h2 (r)
Threshold Traits and Heritability
• Liability: Quantitative trait that presents a
genetic risk for a threshold trait.
• Individuals with a liability above threshold
develop the trait.
• The risk of manifesting a threshold trait has H2
and h2 that cannot be estimated directly but can
be inferred from the incidents of the trait among
individuals and their relatives.
Quantitative Trait Loci (QTLs)
• Genes that affect a quantitative trait
• Localized by determining associations between
phenotype and alleles of polymorphic DNA
markers (typically SNPs)
• Can be identified
– In pedigrees
– In populations (GWAS)
The Basics of Genome-Wide
Association Studies (GWAS)
• Sample a large population consisting of
unaffected and affected individuals.
• Determine genotypes at a large number (>
500,000) polymorphic markers (usually SNPs).
• Look for statistical correlations between
presence of SNP alleles and the phenotype in
question.
Summary of GWAS Results
• Most trait examined are
affected by a large
number of loci.
• Each individual locus
has a small effect.
• Identified loci typically
explain only 10–20% of
the total heritability of a
trait.
Data from J.-H. Park et al. Proc. Natl. Acad. Sci. USA 108 (2011): 18026–18031.
Why the “Missing Heritability”
• Epistatic effects not detected
– Physiological epistasis: Interactions between genes
that affect molecular, cellular, or organismal
phenotypes
– Statistical epistasis: Interactions between genes that
are dependent on allele frequencies in populations
• Rare variants are not represented in the sample
population.
• Effects of some variants are too small to be
detected.
Additional Challenges for GWAS
• Many QTLs have pleiotropic effects.
• The effects are dependent on
genotype–environment or genotype–sex
interactions.
• The effects can be population-specific.
• Very few QTLs have large phenotypic effects.
• A “QTL” often is a cluster of functionally related
genes.
• It is often difficult to associate a particular gene
associated with a QTL with a phenotype-related
function.
The “Candidate Gene” Approach
• Identify genes whose products have a
demonstrable role in determining the phenotype.
• Identify polymorphisms affecting the structure or
regulation of that gene.
• Determine whether different genotypes are
associated with phenotypic differences.

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Chapter 15

The Genetic Basis

Distribution can be described as 63.1 ± 2.69 in.

• Genotype–environment (G-E) interaction:

Data from N. P. Neal, Agron. J. 27 (1935): 666-670.

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