Genetic

and Environmental
Basis of Complex Traits
 Genetic and Environmental Basis of Complex Traits

Learning Goal: Appreciate gene and environment interactions

After the pre-class assignments you should be able to:

• Define the terms SNP and genetic marker
• Describe how nondisjunction can cause variation in chromosome number between gametes
• Explain and discuss how various factors might influence the relationship between genotype and
phenotype, and explain how these phenomena can complicate pedigree analysis
• Describe how variation can be measured, and what can be done to distinguish genetic and
environmental sources of variation
• Explain how continuous traits produce phenotypes

By the time you take the first midterm you should also be able to:
• Evaluate whether a specific SNP or VNTR is associated with a specific disease
• Interpret experiments to determine the relative influences of genes and the environment on a given
phenotype
• Evaluate how genes and the environment can interact to produce a phenotype
• Relate trait values of offspring to parents to identify heritability of traits
• Predict how chromosome numbers in a gamete may vary depending on non-disjunction during meiosis
Start Monday
Case 3 and 15.3
 You from A to T:
Your Personal Genome
How do genetic markers help us study diseases?
Are diseases like cancer heritable?
 SNPs, RFLPs,
VNTRs can all
act as genetic
markers
 Marfan syndrome is a connective tissue disorder with an autosomal dominant
inheritance pattern. The affected gene (FBN1) is very large, so sequencing the gene
to look for mutations is not practical. Instead, you have identified two VNTR regions
(A and B) very close to the FBN1 gene that can be readily analyzed using PCR. You
test the two VNTR regions to see if there are any alleles that are linked to mutant
alleles of the FBN1 gene. Your results are shown below.

Discuss these results with your neighbor:

1. What are the VNTR genotypes of the individuals in the pedigree?
2. Could any of the VNTR alleles be used as a marker for mutant FBN1?

I-1 I-2 II-1 II-2 II-3 III-1 III-2

I
1 2
B1
A1
II
1 2 3 A2

III B2
1 2
Text
 Marfan syndrome is a connective tissue disorder with an autosomal dominant
inheritance pattern. The affected gene (FBN1) is very large, so sequencing the gene
to look for mutations is not practical. Instead, you have identified two VNTR regions
(A and B) very close to the FBN1 gene that can be readily analyzed using PCR. You
test the two VNTR regions to see if there are any alleles that are linked to mutant
alleles of the FBN1 gene. Your results are shown below.

Which allele, if any, would you use as a genetic marker to test for the
presence of mutated FBN1?
A. A1 B. A2 C. B1 D. B2 E. None of these
The affected should have the same alleles!
I-1 I-2 II-1 II-2 II-3 III-1 III-2
I
1 2
B1
A1
II
1 2 3 A2

III B2
1 2
 Individuals II-1 and II-2 are expecting their third child. They visit a
genetic counselor, who conducts a VNTR analysis on the fetus, the
couple, and their children. The VNTR analysis is shown below. Is the
fetus predicted to be affected by Marfan syndrome?

A. Yes B. No
The fetus does not have A2; does not appear the child have the marker; already discussed that A2 is marker
Not always true because of cross-over
II-1 II-2 III-1 III-2 fetus
I
1 2
B1
A1
II
1 2 3 A2

III B2
1 2
Individuals II-1 and II-2 have their third child and he has
Marfan syndrome. How could this have happened?
Discuss with your neighbor.
Marker chosen is the close to the gene!

II-1 II-2 III-1 III-2 III-3

I
1 2
B1
A1
II
1 2 3 A2

III B2
1 2 3
Single Nucleotide Polymorphisms (SNPs)
can be used as genetic markers

Individual 1

Individual 2
The pedigree below shows the inheritance of
an autosomal dominant trait linked to a SNP.

Which SNP allele is a

marker for the
dominant trait?

A. T
B. G
C. Cannot be
Pretty good marker but not 100% because of that T/G determined
Cross-over!
The pedigree below shows the inheritance of
an autosomal dominant trait linked to a SNP.

Which individual labeled

on the pedigree indicates
a recombination event
between the marker allele
and the dominant trait?

A B C D E
Answer: D
 The Genetics of Cancer

Can cancer be genetically

inherited?
Yes, depends on which cancer.
LS7A Review: What is Cancer?
just sit there; not really danger
if one of those leave from the (doesn’t follow apoptotic condition)
group, it undergoes apoptosis

benign cancer ex. cororectal cancer

Accumulation of
somatic mutations in
proto-oncogenes and
tumor suppressors
can lead to cancer
 Cancer can be sporadic or heritable
The “two hit hypothesis” model
(could have 2 random mutations)

Person with TWO

functional alleles Cancer
of tumor Progression!
suppressor gene (Sporadic)

Person with ONE

inherited mutant Cancer
allele of tumor Progression!
suppressor gene (Familial)
Remember BRCA1?
• 5% of breast cancer is
associated with an inherited
mutation in BRCA1
• BRCA1 is a tumor suppressor
involved in double-strand DNA
break repair
• Inheriting a BRCA1 mutation
increases the risk of getting
breast or ovarian cancer
• The BRCA1 gene was first
identified by Mary-Claire King
How did Mary-Claire King
determine that BRCA1 mutations
are a risk factor for breast cancer?
Breast cancer can be inherited.
The pedigree below is from one family with a high incidence
of breast cancer. The “dx” denotes the age at which the
individual was first diagnosed with breast cancer, or the age
at death if deceased. The letters (A-H) represent eight
different alleles of VNTR marker “D17S74”

Discuss with your neighbor:

1. What trends do you notice
in this pedigree?
2. Could D17S74 be a marker
for breast cancer? If so, are
any of the alleles linked to
the mutant allele causing
this disease?
Can use the allele E as a marker!

Note: A diagonal line through square or

circle denotes individual is deceased
The pedigree below is from one family with a high incidence
of breast cancer. The “dx” denotes the age at which the
individual was first diagnosed with breast cancer, or the age
at death if deceased. The letters (A-H) represent eight
different alleles of VNTR marker “D17S74”

Which D17S74 allele, if any,

appears to be linked to the breast
cancer trait in this family?
A. The B allele
B. The D allele
C. The E allele
D. The H allele
E. None; this marker is not linked
to the breast cancer trait
The pedigree below is from one family with a high incidence
of breast cancer. The “dx” denotes the age at which the
individual was first diagnosed with breast cancer, or the age
at death if deceased. The letters (A-H) represent eight
different alleles of VNTR marker “D17S74”

Which D17S74 allele, if any, appears to

be linked to the breast cancer trait in
this family?
A. The A allele
B. The B allele
C. The D allele
D. The E allele
E. None; this marker is not linked to
the breast cancer trait
 This pedigree analysis allowed
Mary-Claire King and her
colleagues to conclude that the
breast cancer disease gene was
located somewhere on
chromosome 17q but they still
didn’t know where!

Eventually they determined

that BRCA1 is the disease gene.
 From the news: After discovering she carried
one mutant allele of the BRCA1 gene,
From your reading: Claudia Gilmore’s Angelina Jolie decided to undergo a double
paternal grandmother developed mastectomy and have her ovaries removed.
breast and ovarian cancer. Her father
tested positive for a BRCA1 mutation, Discuss with a neighbor: what issues
so Claudia got a genetic test and
found that she too was a carrier. might you want to consider to make
Ultimately, she decided to undergo a the decisions that Claudia Gilmore
double mastectomy at the age of 23. and Angelina Jolie made? Would you
get tested for a genetic risk factor?
 Take a moment to read through
the two case studies about
Angelina Jolie and Edward Brooke.
Case #1. Angelina Jolie’s mother and maternal grandmother
died of ovarian cancer. Her maternal aunt died of breast
cancer. Angelina Jolie opted to have a blood test to see if she
had a BRCA1 mutation. DNA was extracted from a sample of
white blood cells and the two copies of the BRCA1 gene were
sequenced. One copy of the gene was wild-type (+). The other
copy had a nonsense mutation (-) that would cause the
production of a nonfunctional protein.

Case #2. United States Senator Edward Brooke died of

breast cancer in 2015. For the sake of this case study,
imagine that sequencing of his BRCA1 gene from white
blood cells revealed both copies to be wild type;
sequencing of his BRCA1 gene from his breast tumor
cells revealed both copies to be mutant. The BRCA1
mutations in each copy of the gene were similar to the
type of BRCA1 mutation found in the Jolie family.
 How would you characterize
these two cancers?
A. Both are heritable
B. Both are sporadic
C. Angelina Jolie’s is heritable; Edward
Brooke’s is sporadic
D. Angelina Jolie’s is sporadic; Edward
Brooke’s is heritable
How would you characterize
these two cancers?
 What is the probability that any one of
Angelina Jolie’s children inherited a mutated
copy of BRCA1? (You may assume that the
BRCA1 mutation is rare in the population.)
A. 0
B. 1/8
C. 1/4
D. 1/2
E. 1
 What is the probability that any one of
Edward Brooke’s children inherited a mutated
copy of BRCA1? (You may assume that the
BRCA1 mutation is rare in the population.)
radom muts

A. 0
B. 1/8
C. 1/4
D. 1/2
E. 1
 Mark A for True or B for False:

If Angelina Jolie had not undergone

a double mastectomy, she would
have definitely developed breast
cancer at some point in the future.
Where can mutations
come from?
Genetics Isn’t the Whole Story:
Environmental Risk Factors
• Non-genetic factors
like diet, pollution,
smoking, and
exercise can also
have an impact on
the development of
cancers and other
diseases
• Environmental
factors also impact
a number of
complex traits!
Mutations can also happen at the
chromosomal level
How do non-disjunctions occur?
 How do non-disjunctions occur?

If one gamete is getting two copies of one chromosome, what is

happening in the other gamete?
 When a nondisjunction occurs at meiosis I, two out of four cells
produced end up with an incorrect number of chromosome. The
figure below shows the results of a nondisjunction in meiosis I.

How is this as an
If instead of the scenario shown om the alternative?
figure, no nondisjunction occurred in meiosis
I but a nondisjunction occurred in one cell at
meiosis II, how many gametes would have an
incorrect number of chromosomes?
Text

A. 0
B. 1
C. 2
D. 3
E. 4
 When a nondisjunction occurs at meiosis I, all of the
gametes produced end up with an incorrect number of
chromosomes (see figure below). If a nondisjunction
occurred in one cell at meiosis II instead, how many
cells will have an incorrect number of chromosomes?

A. 0
B. 1
C. 2
D. 3
E. 4
 When a nondisjunction occurs at meiosis I, all of the
gametes produced end up with an incorrect number of
chromosomes (see figure below). If a nondisjunction
occurred in one cell at meiosis II instead, how many
gametes will appear like the gamete outlined below?

A. 0
B. 1
C. 2
D. 3
E. 4
Turner Syndrome Karyotype
Consider the pedigree below from a human family. The affected male
has Klinefelter syndrome, a genetic condition that results when a
child is born with XXY chromosomes. In each, A and B refer to
codominant alleles of the X-linked G6PD gene. The phenotypes of
each individual (A, B, or AB) are shown in the pedigree.

Based on the pedigree,

nondisjunction must have
occurred:
A. In meiosis 1 of the mother
B. In meiosis 1 of the father
C. In meiosis 2 of the mother
D. In meiosis 2 of the father
Consider the pedigree below from a human family. The affected male
has Klinefelter syndrome, a genetic condition that results when a
child is born with XXY chromosomes. In each, A and B refer to
codominant alleles of the X-linked G6PD gene. The phenotypes of
each individual (A, B, or AB) are shown in the pedigree.

Based on the pedigree,

nondisjunction must have
occurred:
A. In meiosis 1 of the mother
B. In meiosis 1 of the father
C. In meiosis 2 of the mother
D. In meiosis 2 of the father
Consider the pedigree below from a human family. The affected male
has Klinefelter syndrome, a genetic condition that results when a
child is born with XXY chromosomes. In each, A and B refer to
codominant alleles of the X-linked G6PD gene. The phenotypes of
each individual (A, B, or AB) are shown in the pedigree.

What might this look like on the exam?

Based on the pedigree, where could
nondisjunction have occurred? For
each of the following questions mark A
for True or B for False.
1. In meiosis 1 of the mother
2. In meiosis 1 of the father
3. In meiosis 2 of the mother
4. In meiosis 2 of the father
Start on/after
Wednesday
18.1-18.2
Complex traits
 Variation exists in all populations
• Genetic variation:
Based on the copy of the allele for that gene

Complex traits are affected by multiple genes

Examples: blood pressure, obesity, depression

• Environmental variation:
Due to differences in environment
Examples:
• sun exposure
• moisture levels
• access to food
Genes vs. Environment
Which of the following genotypes
show differential responses to
changes in the environment?

A. Genotype A
B. Genotype B
Phenotype

C. Both Genotype
A and B

Environment
 What if the line is flat? Discuss with
your neighbor what this may indicate
about the genotype and phenotype?
Phenotype

as environment changes, no change in the phenotype

Environment
 Mice with the same mutation in a
gene show variability in cholesterol
levels with differences in diet
Norm of Reaction: How environment affects phenotype
across a range of environmental
conditions, shows evidence of
phenotypic plasticity for a genotype
Example: Example:

Hydrangea color
determined by
pH of the soil
changes with the environment
Acidic = blue
Alkaline = pink
Most traits we see are not the result
of expression of a single gene
Regression Model Activity

Chapter 18
The Genetic and Environmental Basis
of Complex Traits
 Let’s consider the beak’s of finches

If finch beak size is a heritable trait, which

of the graphs below best illustrates the
relationship between parent and offspring
beak size?
Graph A Graph B Graph C
Beak depth of offspring

if parent beaks gets

bigger, the beaks of
offsprings should get
bigger

Beak depth of parents

A positive correlation between the beak size of
parents and their offspring suggests that it is a
heritable trait

Beak depth of offspring

Beak depth of parents

What would it mean if you had a cloud of points that
were concentrated in the green oval?

Beak depth of offspring

Beak depth of parents

 Heritability
Galton’s data

Galton’s observations are

what we now term
regression towards the mean

Addresses the question of

why offspring don’t look
exactly like their parents
Regression Plots and Heritability

blue line shows; it not a

drastic because of
regression toward to the

not heritable

Read section 18.2 for further explanation

There are examples in which the
mean height in a population has
changed over time, as for example in nutrition helps with gene expresion

Japan following the end of WW II. In

the case of Japan, it is thought that
this increase arose from a change in
nutrition, with a greater proportion of
meats, wheat flour, etc., available for
consumption after the war ended.
Note that the data in Figure 18.8 are
for a stable population, where
change in mean height is not if you have a stable population:
happening over time. An indicator of the 2 should intersect at the mean

this stable population mean is that

the parental and offspring lines
intersect exactly at the population
mean. In a case like Japan after WW
II, when the population height is
increasing, what would you expect to
be different about the point(s) of
intersection?
On your handout add
lines to show what you
think the plot of mean
height of offspring
would look like in the
scenario of a
population whose
mean height is A)
increasing over time
and B) decreasing
over time.
 slope C

In the graph above, which of the labeled lines would

best represent a trait with 100% heritability?
In the graph above, which of the labeled lines would
best represent a trait with 0% heritability?
In the graph shown above, which of the labeled lines
would best represent a trait that demonstrates Galton's
regression toward the mean?
In the graph above, which of the labeled lines would best
represent a trait that diverges from the mean rather than
regressing to it?
Add a new line to the graph above that would result if the offspring
of short parents were taller than the population mean and offspring
of tall parents were shorter than the population mean.
Regression towards the mean can
be a result of

A. Gene by gene interactions

B. Gene by environment
interactions
C. Both A and B
D. Neither A or B
Start on/after Friday

15.4
 A little bit of review and
some extensions of
Mendel before we move
onto evolution next week
What happens when multiple genes
affect the same phenotype?
What ratio of white to
brown (pigmented) chickens
would you expect to observe
in the F2 generation?

A. 15:1 white:brown
B. 12:4 white:brown
C. 13:3 white:brown
D. 9:7 white:brown
E. 1:1 white:brown
 ABO Blood Groups: Co-Dominance
Phenotype is determined by combination of three alleles:
IA (co-dominant), IB (co-dominant), and i (recessive)

Blood Group: A B AB O
(phenotype)

Genotype: IAIA IBIB IAIB ii

or or
IAi IBi
Suppose a child is blood group AB. Which
of the following pairs of individuals could
represent the parents of this child?

A. AB x O
B. A x O
C. A x AB
D. O x O
E. More codominant

than one
of the
above
Suppose a child is blood group O. Which
of the following pairs of individuals could
represent the parents of this child?

A. AB x O
B. A x O
C. A x AB
D. O x O
E. More
than one
of the
above
A human pedigree and the ABO blood groups
of some of the family members are shown
below. What is the genotype of individual I-1?

A. IAIB
B. IAi
C. IBi
D. ii
E. More than
one is
possible
A human pedigree and the ABO blood groups
of some of the family members are shown
below. What is the phenotype of III-2?

A. A
B. B
C. AB
D. O
E. More than
one is
possible
What if a single-gene trait has many alleles?
Hierarchy of dominance: C > ck > cd > ca

Black Sepia Cream Albino

CC ckck cdcd caca
What if a single-gene trait has many alleles?
Hierarchy of dominance: C > ck > cd > ca

A Black
CC
B Sepia
ckck C Cream
cdcd D Albino
caca

What is the color of a ckcd guinea pig?

 Suppose you cross a Ccd guinea pig
with a ckca guinea pig. What ratio of
color is the F1 guinea pig progeny?

A. 2 black: 1 sepia: 1 cream

B. 3 black: 1 sepia
C. 2 black: 2 cream
D. 1 black: 1 sepia: 1 cream: 1 albino
E. Can’t tell or don’t know

CC = black, ckck = sepia, cdcd = cream, caca = albino

Hierarchy of dominance: C > ck > cd > ca
Consider the guinea pig pedigree below. Recall the hierarchy
of dominance for the four coat color alleles is C > ck > cd > ca
and the colors of the homozygous genotypes are as follows:
CC = black, ckck = sepia, cdcd = cream, caca = albino
ck cd ck ca C ck ck ca

Work with a neighbor

to fill in as much
information about the
genotypes of these
ck - cd ca cd ca ck ca C ca ck - ck - guinea pigs as possible.

ca ca ck ca ca ca ck ca
Consider the guinea pig pedigree below. Recall the hierarchy
of dominance for the four coat color alleles is C > ck > cd > ca
and the colors of the homozygous genotypes are as follows:
CC = black, ckck = sepia, cdcd = cream, caca = albino

Suppose brother and

sister 6 and 7 are mated.
What is the probability
that their first pup will
be albino?
A. 1/4
B. 1/8
C. 1/16 addition rule

D. 1/32
E. Need more
information