An introduction to simple and complex traits in humans, and how to study them in mice.

An Introduction to
Simple and Complex Traits in Humans,
and How to Study Them in Mice.
Steve Munger
The Jackson Laboratory

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Questions to Answer
• What are the differences between simple
and complex traits?
• How do we study the genetic basis of
complex traits in humans?
• Why and how do we study complex traits
in mice?
• What is “21st Century Mouse Genetics”?

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What is a trait?
Trait - n. a distinguishing feature of your personal nature.
In science, trait refers to a characteristic that is caused by
genetics. A disease can be considered a trait.
Traits can be classified by their inheritance pattern.
Simple trait – Arises from mutations in a single gene.
= “Mendelian” trait
= “Binary” trait
Complex trait – Affected by many genes.
= “Quantitative” trait
= “Multifactorial” trait

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Simple or ”Mendelian” traits arise from
mutations in a single gene.

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Red hair is an example of a simple trait.

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Red hair is caused (primarily)
by mutations in a single gene.
23andMe.com

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Red hair is an example of a recessive trait.
23andMe.com My redhaired daughter
?

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For a simple trait, you either have it or
you don’t -- aka Binary phenotype.
“Widow’s Peak”

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Your genome has about 3 billion bases of DNA.
Changing only one of those bases can cause severe disease.

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1 base change in the DNA →
1 amino acid change in the protein
Glutamic Acid ⇢ Valine

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1 amino acid change → clumped hemoglobin
→ Red blood cells with a “sickled” phenotype

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“Sickled” cells clump and block blood vessels…
Sickle Cell
Normal
Red Blood Cell
… and cause Sickle Cell Anemia

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But traits aren’t always simple.
Most traits are complex.

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Proportion
Most human traits are not binary and simple,
but rather continuous and complex.
These quantitative traits derive from the interplay
of many genes (“polygenic”) and the environment.

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Height is a good example of a
complex, quantitative trait.

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Your height is determined by a
complex interplay of your genetics
and your environment.
Genome
+
Environment
Let’s dig into genetic networks a little more

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No gene
is an island.

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All genes act within networks, and
all genetic networks are complex
-- even for a simple trait.
Muller-Linow et al 2008

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The effects of a single gene mutation can disrupt
the network enough to cause disease.
Disease

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In other people, that mutation may be buffered by
variation in other genes.
Healthy

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Wait a second, if it is that complex
for a simple trait, what does it look like
for a complex trait?!?

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Complex traits are even more
complex…
Person 1
Healthy

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Person 2
Healthy

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Person 3
Mild
Disease

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Person 4
Severe
Disease

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= Critical gene for that cell type
Oh, and by the way, not every gene variant
acts in the same cell type…

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Oh, and by the way, not every gene variant acts in
the same cell type… or at the same time.

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And the environment affects everything.
Maternal Diet
Air/Water Quality
Stress
Nutrition
Pregnancy Length
Drug Use

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But how do we
study a trait or
disease that is
so complex?
HEIGHT

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Probability
How do we even figure out which genes are
causing variation in a complex trait?

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Example: Height is a
quantitative trait
Height (Inches)
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55
60
65
70
75
80
Observed Theoretical Normal

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Height (Inches)
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Male Female

View Slide

Your height is largely determined
by your genes.
Height (Inches)
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Sex
Effect

View Slide

Most traits have a genetic
component. “Heritability”
Sex Effect

View Slide

Finding SNPs associated with height
Height (Inches)
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View Slide

Height (Inches)
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60
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AA AG GG
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Finding SNPs associated with height

View Slide

We can test every SNP for its
association with height.
Significance
“Manhattan Plot”

View Slide

But what does that tell us? The Arby’s example.

View Slide

But what does that tell us? The Arby’s example.
I originally made this example for students at Bates College in
Lewiston, Maine. The scenario is this: You are really craving an
Arby’s Beef ‘n Cheddar sandwich, but you don’t know where
the Arby’s is located in Lewiston-Auburn, and you don’t have a
car. How could you figure out where the Arby’s is located using
the Citylink bus routes (and without seeing the actual Arby’s
restaurant)?

View Slide

At each bus stop, count the number of
Arby’s wrappers in the trash.

View Slide

Could you predict which bus stop
is closest to Arby’s?
23
1
2
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1
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5
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0
1
0
0
0
0

View Slide

Height (Inches)
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55
60
65
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75
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AA AG GG
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55
60
65
70
75
80
There’s an Arby’s (gene regulating height)
near this bus stop (SNP marker).

View Slide

Finding “Arby’s” in the genome
Significance

View Slide

Our ability to detect an association depends on
the variant’s frequency in the population.
Height (Inches)
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60
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70
75
80
AA AG GG

View Slide

Rare variants are problematic
Solution: Increase your sample size
Height (Inches)
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55
60
65
70
75
80
AA AG GG

View Slide

UK Biobank data
Current Genome-Wide Association Study
(GWAS) results for height

View Slide

Some traits turn out to be pretty simple.

View Slide

If you can measure it, you can run a GWAS on it.
But buyer beware (of confounding variables).
None of these genes/variants are known to be associated with food or alcohol intake. But
in the UK Biobank, this trait is positively correlated with "Average total household income
before tax" and inversely correlated with "Job involves heavy manual or physical work”.

View Slide

Let’s dig into an example of a complex
disease: Type 2 Diabetes (T2D)

View Slide

In Type 2 Diabetes, the body stops using
and making insulin properly.
https://ghr.nlm.nih.gov/condition/type-2-diabetes

View Slide

Type 2 Diabetes is a complex disease caused by
genetic and environmental factors.
GWAS has identified hundreds of genetic variants associated with T2D.
The vast majority are found in non-coding regions of the genome.

View Slide

View Slide

So we can use GWAS to identify genetic variants
associated with T2D.
Maternal Diet
Air/Water Quality
Stress
Nutrition
Pregnancy Length
Drug Use
But how do we go from genes → mechanisms → therapeutics?

View Slide

Humans are terrible genetic models
Novembre et al 2008
• Population stratification can
cause false positives in
association studies.
• They take too long to breed,
and live way too long.
• Environmental variance can
mask genetic influence.
• Many adult traits originate
during development.

View Slide

Emerging themes
Most traits and diseases are complex and polygenic.
No gene is an island
- The function of any gene depends on the genetic background it is a
part of.
- The effects of a mutation in one gene may be amplified or buffered
(ie, modified) by variation in another gene (modifier).
- A disease-causing mutation may lead to severe pathology in some
people but mild or no pathology in others.
We can identify these modifier variants in humans using
Genome-Wide Association Studies.
We’re limited to what we can study (and more specifically,
how we can study it) in humans themselves.

View Slide

Bring on the mouse!
(Full Disclosure: I love mouse genetics)
(Yes, this is my license plate) (Not to scale)

View Slide

Mice are exceptional animal models
• Physiologically and anatomically similar to humans.
• Breed early and often. Access to tissues at all stages of
development and adulthood.
• Can be inbred and genetically modified.
• Highly characterized (genome sequence, curated
databases)
• Can be used to map modifiers and build networks.
• No, they are not little humans, but…

View Slide

No, mice are not humans, but the mouse
and human genomes are very similar.
Griffiths et al. 2002

View Slide

Let’s dig into mouse genetics - Laboratory mice
are derived from three major sub-species

View Slide

Classical inbred laboratory strains are genetically
closely related.

View Slide

What is an inbred strain?
• Genetically identical
• Animals that result from
the process of brother-sister
mating for at least 20
sequential generations

View Slide

Consequences of Inbreeding
Up to 20 Generations
Silver 1995
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
0 5 10 15 20
Generations of inbreeding
Individual homozygosity at
current generation
Portion of genome that is fixed
between two breeding sibs chosen
for producing next generation
98.6%

View Slide

Sanger: Resequencing 36 inbred strains (http://www.sanger.ac.uk/resources/mouse/genomes/)

View Slide

Inbred mice are useful models of disease

View Slide

For example, there are many inbred strains that
model one or more aspects of diabetes

View Slide

Mouse Phenome Database http://www.jax.org/phenome
A wealth of historic data exists
for inbred strains.

View Slide

Mouse Genetic
Crosses/Strains
Visual Summary
Crosses
Backcross (N2)
Intercross (F2)
Strains
Consomic
Congenic
Advanced Intercross
Recombinant Inbred (RI)
Recombinant Congenic (RC)
Recombinant Inbred
Intercross (RIX)
Image courtesy of
Wayne Frankel, JAX
Slide stolen from Greg Cox

View Slide

Intercross
P1 X P2
F1 X F1
F2
~25 recombinations
per F2 animal

View Slide

Backcross
P1 X P2
P1 X F1
BC1
~15 recombination events
per mouse

View Slide

QTL Mapping Genome Scan
Lander and Botstein, Genetics 1989
Few hundred F2 or BC progeny
100-200 markers genotyped

View Slide

A QTL interval may contain hundreds of
genes – Difficult to find the causal gene.

View Slide

Two-parent QTL Crosses
• Easy to map significant QTLs. Straightforward analysis.
• Fewer mice required.
– Even recessive alleles will be homozygous in ¼ of progeny.
• All mice need to be genotyped ($).
• Number of recombination events per mouse is low. Less
recombination = lower mapping resolution = more mice ($).
• Confidence intervals tend to be broad and resolving the
causative gene may require heroic follow-up experiments.

View Slide

Variations on a theme:
Recombinant Inbred Lines (RILs)
Rob Williams
Ashbrook et al. 2019
BXD Lines Genenetwork.org
Each BXD line is inbred, replicable, and
fully genotyped, and is associated with
a lot of historic data

View Slide

Expand to analyze many lab strains and RILs –
Hybrid Mouse Diversity Panel
Jake Lusis

View Slide

Common
laboratory strains
are only showing
us part of the
genetic story.
Yang et al., 2011
Nature Genetics

View Slide

But is the mouse really a good model of human
biology and disease?

View Slide

Is an inbred mouse a good model for the
genetically diverse human population?

View Slide

View Slide

Why didn’t I see this adverse effect in my mouse model?

View Slide

Transitioning from a reductionist
approach to one that integrates
and embraces genetic diversity:
“21st Century Mouse Genetics”

View Slide

Genetically diverse mouse models may
improve translational relevance

View Slide

Multi-parent crosses
Use 8 inbred founder lines
Select founder lines to
increase genetic diversity
CAST
129S1
WSB NZO
A/J
B6
NOD
PWK

View Slide

Founder strain genomes are fully sequenced
and annotated
Mouse Genomes Project, Keane et al. 2011
https://www.sanger.ac.uk/sanger/Mouse_SnpViewer/rel-1505

View Slide

Diversity Outbred and Collaborative Cross mice
Powerful orthogonal resources for gene discovery and validation
• Balanced population structure
• 400+ recombinations per animal
• High heterozygosity
• Each animal is unique
5 common lab + 3 wild-derived strains
52 million+ SNVs, 2 million+ indels
• Reproducible genomes
• High genetic diversity
• Fewer recombinations per line

View Slide

The Collaborative Cross (CC) are replicable, diverse inbred
strains for disease research and genetic mapping.
*CC strains can also be used to validate observations/predictions from the DO.

View Slide

CC strains have emerged as powerful
tools for infectious disease research

View Slide

Recombinant inbred intercrosses (CC-RIX)
Availability of replicable hybrid genomes enables more precise measurement of traits.
Higher measurement precision improves genetic mapping.

View Slide

Diversity Outbred (DO) mice are each genetically unique,
highly heterozygous, and optimized for genetic mapping.

View Slide

Balanced allele frequencies in the DO
Svenson et.al. Genetics, 2011
A/J
C57BL/6J
129S1/SvImJ
NOD/ShiLtJ
NZO/LtJ
CAST/EiJ
PWK/PhJ
WSB/EiJ
*Nearly every gene in the genome has genetic variants
segregating in the DO that are potentially functional

View Slide

50
40
30
20
10
Body weight (gm)
7/11/2014 7/31/2014 8/20/2014
date
50
40
30
20
10
Body weight (gm)
7/11/2014 7/31/2014 8/20/2014
date
female DO mice male DO mice
DO mice are genetically and phenotypically diverse
Alan Attie &
Mark Keller
Female DO mice Male DO mice

View Slide

Diversity Outbred mice exhibit phenotypes far exceeding the
range observed in the founder inbred strains.

View Slide

Some combinations of genetic variants
produce very long-lived mice.
This Diversity Outbred female lived to be 4 years 8 months old.

View Slide

None of the founder inbred strains live past 2.5 years.
How is it possible that mixing their genomes up can result in
a mouse that lives almost twice as long?

View Slide

DO Genomes: 28 possible heterozygous and 8
homozygous genotype states at every locus.
A/J
A
BL6
B
129
C
NOD
D
NZO
E
CAST
F
PWK
G
WSB
H
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
A A A A A A A A B B B B B B B C C C C C C D D D D D E E E E F F F G G H
A B C D E F G H B C D E F G H C D E F G H D E F G H E F G H F G H G H H
Founder strains – 8 possible genotypes
Diversity Outbred – 36 Possible Genotype states

View Slide

Genetic Mapping in DO Mice
Genotyping Arrays Hidden Markov Model Genome Reconstruction
i
i
k
k
ik
c
j
j
ij
i
g
x
y e
g
b
a +
+
+
= å
å
=
=
8
1
1
Linkage and Association:

View Slide

Example of the power of the DO:
Benzene Genotoxicity

View Slide

Benzene Inhalation Study
0 ppm
Day 0 7 14 21 28
1 ppm
10
ppm
100
ppm
6 hrs per day
5 days per week
1 2 Total
75 75 150
75 75 150
75 75 150
75 75 150
300 300 600
French, et al., Environmental Health Perspectives, 2015

View Slide

Benzene Study Endpoints
Pre- and post-exposure blood
Post-exposure bone marrow
Proportion of micronucleated reticulocytes (MN-RET)
o Measure of chromosomal damage
French, et al., Environmental Health Perspectives, 2015

View Slide

Bone Marrow MN-RET
DNA
Damage
French et.al., EHP, 2015

View Slide

QTL Plot of Bone Marrow MN-RET

View Slide

The CAST allele on Chr 10 is protective
against genome damage.
Chr 10
DNA
Damage

View Slide

The CAST allele is dominant
Prop. MN-RET
Genotype
Dan Gatti

View Slide

We can impute all known SNPs onto
each DO genome and perform
association mapping

View Slide

Sult3a1 and Gm4794 are sulfotransferases

View Slide

Sult3a1 and Gm4794 have high expression
in CAST livers

View Slide

Sult3a1 has a strong cis-eQTL in DO livers
CAST allele is highly expressed

View Slide

CAST/EiJ has a copy number gain of
sulfotransferases
http://www.sanger.ac.uk/sanger/Mouse_SnpViewer/rel-1303
http://ensembl.org
Gm4794
Sult3a1

View Slide

Regulatory variants (eQTL) are abundant in the DO
(but you have to be very careful in your RNA-seq analysis…)
CC/DO Founder Strain samples

View Slide

The founder origin of each allele is tagged and
provides direct estimates of allelic abundance.
The local eQTL for the lincRNA Gm12976 is cis-acting.
DO samples N=277
N=554 allele-specific estimates.

View Slide

Differential allelic expression is the rule
rather than the exception.

View Slide

Unique power + unique challenges
Multi-parent, multi-generation crosses like the DO offer
high genetic diversity (45M SNPs) and fine
recombination block structure.
Increased complexity requires specialized methods for
haplotype reconstruction and mapping.
QTL confidence intervals can be very small, but require
more samples for mapping.
Founder sequences can help to identify causal variants.
Word of caution: If your phenotype is affected by many
variants with small effects segregating in the DO, you will
need ++++ mice to map them.

View Slide

Summary
• Most common diseases are polygenic and stem from
complex interactions between one’s genetic background
and their environment.
• No gene is an island. Genes interact within networks
and pathways.
• We can apply genetic mapping in human cohorts to
identify risk variants associated with complex
traits/diseases.
• We can leverage the power of the mouse model and
emerging diversity resources to refine and expand our
understanding of complex human diseases.

View Slide

Questions to Answer
• What are the differences between simple
and complex traits?
• How do we study the genetic basis of
complex traits in humans?
• Why and how do we study complex traits
in mice?
• What is “21st Century Mouse Genetics”?

View Slide

Thank you!
Alex Stanton
Questions?
Email [email protected]

View Slide

An introduction to simple and complex traits in humans, and how to study them in mice.

An introduction to simple and complex traits in humans, and how to study them in mice.

Steve Munger

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