Ch04 Slides v01

GENETIC
AN I NTE G RATE D APPR OAC H
A N A LY S I S
Chapter 4
Gene Interaction
Slides adapted from lectures by

Lectures by Kathleen
Kathleen Fitzpatrick
Fitzpatrick
Simon Fraser University
Mark F. Sanders
John L. Bowman
Copyright 2012 Pearson Education Inc.
Genetic interactions
Interactions among alleles at a single locus- dominance
Dominance is one of the simplest types of genetic interaction.
Dominance of one allele over another may not be complete,
or heterozygous genotypes may give rise to phenotypes very
different from either homozygote.
Interactions among alleles at multiple loci- epistasis
Two or more genes may affect the same trait, either
additively or non-additively.
In addition, the expression of a trait may also depend on the
interaction of genes with non-genetic factors.
Genetics Analysis: An Integrated Approach
4.1 Dominance relations describe interactions

between alleles
Mendel chose to examine traits with just two alternative forms
in which one form was completely dominant over the other, i.e.
heterozygous individuals were phenotypically indistinguishable
from one of the homozygotes. This is known as simple (or
complete) dominance.
There are other forms of dominance, including incomplete

dominance, co-dominance, and over-dominance.
Incomplete Dominance
Often the dominance of one allele over the other is
not complete
This is why allele designations such as A1, A2 or B1,
B2 are often preferred over A, a or B, b
Incomplete dominance, or partial dominance heterozygous individuals display phenotypes

intermediate to either homozygous type
Co-dominance
Co-dominance - heterozygous individuals display
both homozygous phenotypes; both homozygous
phenotypes are fully and completely expressed in the
heterozygote
More than one pattern of dominance may exist
between different alleles of a single locus, e.g. ABO
blood type
Molecular basis of ABO dominance relations

The A and B antigens represent distinct modifications (additions
of different sugars) to a core five sugar molecule present on
erythrocytes called the H antigen; no extra sugar molecule
added produces type O.
Dominance Relationships of ABO Alleles

Because blood typing
tests for the presence of
the A and B antigens,
IA and IB alleles are
completely dominant over
the i allele but codominant to each other.
Note that if we used a
different type of assay, we
would find different
dominance relations.
Effects of Mutation
Mutant alleles can be classified as:
Loss-of-function, in which there is a decrease in
(hypomorphic or leaky) or complete loss of (null)
gene activity/function
Gain-of-function, in which the mutant allele acquires
increased (hypermorphic) activity or a completely novel
activity (neomorphic)
Dominant Negative Mutations

Multimeric proteins, composed of two or more
polypeptides that join together to form a functional
protein are particularly subject to dominant negative
mutations
These mutations are dominant due to loss of function
of the multimeric protein due to an amino acid change
in one subunit
These are negative mutations due to their spoiler
effect on the protein as a whole
Allelic Series
Some genes have many phenotypically distinct
alleles
A locus with more than two alleles is said to have
multiple alleles
An order of dominance among the alleles may form
a sequential series referred to as an allelic series
The C locus for mammalian coat color

Many genes are required to produce and distribute
pigment to hair follicles or skin cells, where they influence
skin or coat color
The C locus is responsible for coat color variation in
several mammals, including cats, rabbits, mice, and
others.
It produces an enzyme active in the production of melanin
Allelic Series of the C Gene
Dominance relationships in the allelic series

Crosses among different genotypes has revealed
the dominance relationship of the alleles
The C allele is dominant over all the others
The cch allele is incompletely dominant to ch

The c allele is recessive to all other alleles
Molecular basis of the C dominance relations

The C allele produces a Tyrosinase enzyme that is 100%
active, whereas that of the cch allele is less than 20% active
The ch allele enzyme is temperature-sensitive; functional at
lower temperatures (like the paws, ears and tail) and nonfunctional at higher temperatures (the trunk)
The c allele produces no functional enzyme
Note that cch and ch could be considered either incompletely
dominant or co-dominant depending on how the traits are
defined
Lethal Alleles
Some inherited mutations are lethal. Most lethal alleles are
recessive with respect to lethality, but may have less severe
effects in heterozygotes
The majority of lethal mutations in animals cause death at early
developmental stages
Early embryonic lethality can be difficult to detect. Lethal alleles
can be detected as distortions in segregation ratios caused by
one or more missing classes of progeny
Lethal Alleles: The Agouti Locus

In mice, wild type coat color is
agouti, produced by a
combination of yellow and black
pigments along each hair
A dominant allele of agouti, AY,
causes yellow pigment to be
deposited along the entire hair,
resulting in a yellow coat
The AY allele is recessive
embryonic lethal, so all yellow
mice are heterozygous
Molecular basis of the AY lethality

The AY mutation is caused by a deletion that connects the Raly
promoter to the Agouti gene, causing ectopic expression of
Agouti (yellow, dominant) and the loss of Raly (lethal,
recessive).
Sex-Limited Traits
The sex of an organism can influence gene expression
Sex-limited gene expression is a pattern of expression
limited to one sex or the other
The traits involved are called sex-limited traits; both sexes

carry the genes for such traits, but they are expressed in just
one sex
Examples include antlers, prostate cancer, and ovarian cancer
Sex-Influenced Traits
Sex-influenced traits are those in which the phenotype
corresponding to a genotype differs between sexes
Male pattern baldness is an example:

In males and females, BB individuals have full hair
bb individuals of both sexes experience hair loss, but it is
much more severe in males due to the effect of androgens
Bb males experience hair loss just like bb males, while Bb
females have full hair
4.2 Some genes produce variable phenotypes

Interpretation of genotypic and phenotypic ratios is based on
the assumption that there is a strict correlation between
phenotype and genotype
However in some cases different phenotypes can result from

the same phenotype
Incomplete penetrance and variable expressivity can
complicate interpretation of genotypic and phenotypic ratios
Incomplete Penetrance
Traits for which individuals routinely occur that have the
genotype corresponding to a trait, but do not express the
trait are said to display incomplete penetrance
Incomplete Penetrance: Polydactyly

Polydactyly is an autosomal dominant condition, in which
affected individuals have more than 5 fingers and toes
The dominant allele is nonpenetrant in about 25 30% of
individuals (we could also say it is about 70 75% penetrant)
Variable Expressivity
In variable expressivity, individuals who carry the alleles for
a trait show a phenotype but to a varying degree of severity
Waardenburg syndrome has four principle features
Each affected member of the below family shows a different
combination of symptoms
Gene-Environment Interactions
Genes alone are not responsible for all the variation
between organisms
Gene-environment interaction is the result of the
influence of the environment on the expression of
genes and on the phenotype of the organism
Environmental modification to prevent

hereditary disease
The human autosomal recessive condition, PKU
(phenylketonuria) is caused by the absence of an
enzyme involved in phenylalanine catabolism
Infants with PKU are normal at birth, but over time,
the inability to break down phenylalanine is toxic to
developing neurons
PKU is one of the hereditary disorders infants are
routinely screened for
Preventing symptoms of PKU

The key to preventing the most severe symptoms of PKU is to
restrict dietary phenylalanine
Thousands of people with PKU are living normal lives due to

the simple dietary modification that prevents the expression of
the PKU phenotype
Pleiotropy
Pleiotropy is the alteration of multiple distinct traits by a
mutation in a single gene (e.g. decapentaplegic in
Drosophila)
Pleiotropy in Sickle Cell Anemia

Sickle cell anemia is an autosomal recessive condition
caused by a mutation in the -globin gene
Many red blood cells of people with sickle cell anemia take
on a sickle shape and cause numerous physical problems
and complications
4.3 Genetic interactions alter Mendelian ratios

Single-gene trait describes an inherited variation of a gene
that can produce a mutant phenotype. However, this is not a
complete depiction of the underlying processes. Many genes
work together to build the complex structures and organ
systems of plants and animals.
A genetic interaction occurs when the phenotype caused
by a particular genotype of one locus is affected by the
genotype of another locus
e.g. Numerous genes contribute to the normal red eye color
of Drosophila, including those responsible for production of
eye pigments or transport proteins
Three Genes Involved in Drosophila Eye Color

The brown gene produces an enzyme in a pathway that
synthesizes a bright red pigment; mutant flies, bb, have brown
eyes
The vermillion genes produces an enzyme in a pathway that

synthesizes a brown pigment; mutant flies, vv, have bright red
eyes
The white gene encodes a transporter that carries pigment to
the eye; flies that do not produce this protein have white eyes
The One-Gene-One Enzyme Hypothesis

George Beadle and Edward Tatum were among the first to
investigate biosynthetic pathways, and laid the groundwork for
later examination of genetic pathways
They studied growth variants of the fungus, Neurospora crassa
Their proposal, the one-gene-one enzyme hypothesis came

out of their experiments
The Hypothesis Made a Connection Between

Genes, Proteins and Phenotypes
Each gene produces an enzyme and that each enzyme has a
specific role in a biosynthetic pathway that produces the
phenotype
Each mutant phenotype was attributable to the loss or
malfunction of a specific enzyme
Each enzyme defect was inherited at a single-gene defect
More Recent Adjustments to the Hypothesis

Some protein producing genes produce transport proteins,
structural or regulatory proteins, rather than enzymes
Some genes produce RNAs rather than proteins
Some proteins (e.g. -globin) must join with other proteins to
acquire a function
Genetic Dissection to Investigate Gene Action

Biosynthetic pathways consist of sequential steps
Completion of one step generates the substrate for the next
step in the pathway
Completion of every step is necessary to produce the end
product
Genetic dissection is an experimental approach taken to

investigate the steps of biosynthetic pathways
Horowitzs Experiments on Met- Mutants of

Neurospora
Horowitzs analysis aimed to:
Determine the number of intermediate steps in the
methionine synthesis pathway
Determine the order of the steps
Identify the step affected by each mutation
Results of Horowitzs Experiments

Whether or not a mutant strain grows on a medium containing
a component of the pathway allows determination of the step at
which the mutant is blocked
Mutants blocked at a step after the intermediate still cannot
grow
Mutants blocked at a step before the intermediate will grow
Epistasis
Epistasis: genetic interaction in which the alleles of one gene
modify the expression of alleles of another gene
For example, a mutation affecting an early step in a
biosynthetic pathway may prevent (or exacerbate) the
expression of a mutation affecting a later step in the same
pathway.
Gene interaction can lead to altered phenotypic ratios of wildtype and mutant progeny
Epistatic interactions
A minimum of two genes are required for epistatic
interactions; by definition, these participate in the same
genetic pathway
Epistasis is readily detected among progeny of dihybrid crosses
There are six ways epistasis could alter the predicted 9:3:3:1
dihybrid ratio
No Interaction (9:3:3:1 Ratio)

The expected 9:3:3:1 ratio is seen in the absence of
epistasis: when the genes do not interact to change
the expression of one another
When pure-breeding brown flies (b/b; v+/v+) are
crossed to pure-breeding vermillion flies (b+/b+; v/v),
the F1 all have wild-type red eyes (b+/b; v+/v)
Results of F1 x F1
When the F1 are interbred (b+/b; v+/v x b+/b; v+/v ),
the F2 are:
9/16 b+/-; v+/-, wild-type, red eyes
3/16 b/b; v+/-, brown eyes
3/16 b+/-; v/v, vermillion eyes
1/16 b/b; v/v, white eyes
The results show that the genes are not involved in

epistatic interaction with one another
Complementary Gene Interaction (9:7 Ratio)

Bateson and Punnett crossed two pure-breeding
strains of white flowered sweet peas
They found all the F1 were purple flowered; the F1 x
F1 cross yielded 9/16 purple and 7/16 white flowered
progeny
They recognized that the two genes interact to
produce the overall flower color; when genes work in
tandem to produce a single gene product, it is called
complementary gene interaction
Duplicate Gene Action (15:1 Ratio)

Two genes that duplicate each others activity
constitute a redundant system in which a dominant
allele at either locus gives rise to a wild type
phenotype
The genes in a redundant system have duplicate
gene action; they encode the same product, or they
encode products that have the same effect in a
pathway or compensatory pathways
Recessive Epistasis (9:3:4 Ratio)

In recessive epistasis, homozygosity for the
recessive alleles at one locus will mask the phenotypic
expression of the alleles at a second locus, giving a
9:3:4 ratio
E.g. in Labrador retrievers one gene is responsible for
eumelanin production, while a second is responsible
for the distribution of the pigment in the hairs
Dogs that cannot produce the eumelanin pigment have
a yellow coat color regardless of the genotype at the
deposition locus
Dominant Epistasis (12:3:1 Ratio)

In dominant epistasis, a dominant allele at one locus
will mask the phenotypic expression of the alleles at a
second locus, giving a 12:3:1 ratio
E.g. in foxglove flowers a dominant allele at one locus
restricts the deposition of pigment to a small area of
the flower
This allele masks the affect of the genotype at a
second locus that is responsible for producing the
pigment for flower color
Dominant Suppression (13:3 Ratio)

In dominant suppression, a dominant allele at one
locus completely suppresses the phenotypic
expression of the alleles at a second locus, giving a
13:3 ratio
In chickens, the C allele is responsible for pigmented
feathers and the c allele for white feathers
The dominant allele of a second gene, I, can suppress
the color producing effect of the C allele, leading to
white feathers in both C/- and c/c individuals
4.4 Complementation Analysis
When geneticists encounter organisms with the

same mutant phenotype, they ask two questions:
Do these organisms have mutations in the same or in
different genes?
How many genes are responsible for the phenotypes
observed?
Genetic Complementation
Genetic heterogeneity is when mutations in
different genes can produce the same or very
similar mutant phenotypes
Mating of two organisms with similar recessive
mutant phenotypes can lead to wild-type offspring, a
phenomenon called genetic complementation
Complementation occurs when the mutations in the
parents affect different genes
Complementation Testing
Complementation testing is performed to determine
if two mutant strains result from mutations of the
same gene (allelic) or different genes (non-allelic).
involves mating two individuals with similar
recessive mutant phenotypes
If wild-type offspring are obtained, the mutations are

inferred to affect two different genes
If mutant offspring are obtained, the mutations are
known to affect the same gene
Complementation Analysis
In complementation analysis multiple crosses are
performed among numerous pure breeding mutants
to try to determine how many different genes
contribute to a phenotype
Mutations that mutually fail to complement one
another are called a complementation group
A complementation group in this context refers to a
gene

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GENETIC

AN I NTE G RATE D APPR OAC H

Slides adapted from lectures by

Copyright 2012 Pearson Education Inc.

Genetics Analysis: An Integrated Approach

Copyright 2012 Pearson Education Inc.

4.1 Dominance relations describe interactions

There are other forms of dominance, including incomplete

Genetics Analysis: An Integrated Approach

Copyright 2012 Pearson Education Inc.

Incomplete dominance, or partial dominance heterozygous individuals display phenotypes

Genetics Analysis: An Integrated Approach

Copyright 2012 Pearson Education Inc.

Genetics Analysis: An Integrated Approach

Copyright 2012 Pearson Education Inc.

Molecular basis of ABO dominance relations

Genetics Analysis: An Integrated Approach

Copyright 2012 Pearson Education Inc.

Dominance Relationships of ABO Alleles

Genetics Analysis: An Integrated Approach

Copyright 2012 Pearson Education Inc.

Genetics Analysis: An Integrated Approach

Copyright 2012 Pearson Education Inc.

Dominant Negative Mutations

Copyright 2012 Pearson Education Inc.

Genetics Analysis: An Integrated Approach

Copyright 2012 Pearson Education Inc.

The C locus for mammalian coat color

Genetics Analysis: An Integrated Approach

Copyright 2012 Pearson Education Inc.

Allelic Series of the C Gene

Genetics Analysis: An Integrated Approach

Copyright 2012 Pearson Education Inc.

Dominance relationships in the allelic series

The cch allele is incompletely dominant to ch

Genetics Analysis: An Integrated Approach

Copyright 2012 Pearson Education Inc.

Genetics Analysis: An Integrated Approach

Copyright 2012 Pearson Education Inc.

Genetics Analysis: An Integrated Approach

Copyright 2012 Pearson Education Inc.

Molecular basis of the C dominance relations

Copyright 2012 Pearson Education Inc.

Genetics Analysis: An Integrated Approach

Copyright 2012 Pearson Education Inc.

Lethal Alleles: The Agouti Locus

Genetics Analysis: An Integrated Approach

Copyright 2012 Pearson Education Inc.

Genetics Analysis: An Integrated Approach

Copyright 2012 Pearson Education Inc.

Molecular basis of the AY lethality

Genetics Analysis: An Integrated Approach

Copyright 2012 Pearson Education Inc.

The traits involved are called sex-limited traits; both sexes

Genetics Analysis: An Integrated Approach

Copyright 2012 Pearson Education Inc.

Male pattern baldness is an example:

Genetics Analysis: An Integrated Approach

Copyright 2012 Pearson Education Inc.

4.2 Some genes produce variable phenotypes

However in some cases different phenotypes can result from

Genetics Analysis: An Integrated Approach

Copyright 2012 Pearson Education Inc.

Genetics Analysis: An Integrated Approach