LECTURE 10

Extensions Of Mendelian
Genetic Analysis

Micky Vincent

Introduction - Beyond Mendel

Since Mendels work was rediscovered in the early 1900s:
- Researchers have studied the many ways genes influence an individuals
phenotype.
- These investigations are called neo-Mendelian genetics (neo is Greek for new).
- Types of inheritance observed by researchers that did not conform to the
expected Mendelian ratios:
1. How alleles affect phenotype.
- Not always simple dominant/recessive issue.
2. Gene interaction.
- Phenotype controlled by more than one gene.
3. Sex-linked genes (X-linkage in X/Y organisms).
4. Phenotype can depend on more than genotype.
- Environmental effects.

Modifications of Dominance Relationships

Complete dominance and complete recessiveness are two extremes in the range
of dominance possible between pairs of alleles.
Many allelic pairs are less extreme in their expression, showing incomplete
dominance or codominance.

a. In incomplete dominance, a heterozygotes phenotype will be intermediate

between the two possible homozygous phenotypes.
b. In codominance, the heterozygote shows the phenotypes of both
homozygotes.
c. At the molecular level, these relationships between pairs of alleles depend
upon patterns of gene expression.

Alleles
Alleles are alternate forms of the same gene.
- i.e. eye colours and blood groups.
The allele occurring most frequently in a population (the normal allele) is called
the wild-type (wt) allele.
Wt allele is usually dominant and is expressed as the wild-type phenotype.
Wt allele used as standard for comparison of all mutations (alternative alleles)
of the gene/locus.

Mutation is the ultimate source of new alleles.

New phenotypes result from changes in functional activity of gene product:
- Eliminating enzyme function.
- Changing relative enzyme efficiency.
- Changing overall enzyme function.

Alleles
To write allele symbols, for simple Mendelian traits:
- 1st letter of recessive form.
- Lowercase = recessive allele.
- Uppercase = dominant allele.
Example: ABO blood groups are written as IA, IB and i.

Multiple Alleles Human Blood Group

Individuals can have up to two alleles for a single gene (diploid, homologous
chromosomes).
Multiple alleles applies when there are three or more alleles of the same gene in
a population.
Many genes have multiple alleles:
a. Two or more different alleles (i.e. eye colour).
b. May display a hierarchy of dominance (i.e. fur colour).
c. May display codominance (i.e. blood type).
Classic example is human ABO blood groups.
ABO blood groups result from a series of three alleles (IA, IB and i) that combine to
produce four phenotypes (A, B, AB and O).
Both IA and IB are dominant to i, while IA and IB are
codominant to each other. The resulting
phenotypes are shown in the table on the right:

Biochemical Genetics of the Human ABO Blood Group

Karl Landsteiner discovered human ABO blood groups in the early 1900s, and
received the 1930 Nobel Prize in Physiology or Medicine for this work.

There are three alleles at the ABO locus, IA, IB, and i. From these three alleles, four
phenotypes are produced:
a. Type A individuals have the A antigen on their red
blood cells (RBCs). Their genotype is IA/IA or IA/i.
b. Type B individuals have the B antigen on their
RBCs. Their genotype is IB/IB or IB/i.
c. Type AB individuals have both the A and the B
antigen on their RBCs. Their genotype is IA/IB.
d. Type O individuals have neither the A nor the B
antigen on their RBCs. Their genotype is i/i.

Biochemical Genetics of the Human ABO Blood Group

Modifications of Dominance Relationship -

Incomplete Dominance

Incomplete dominance is an allelic relationship where dominance is only partial.

The dominant allele is unable to produce the full phenotype seen in a
homozygous dominant individual (partial expression).
In a heterozygote, the recessive allele is not expressed.
The result is a new, intermediate phenotype.
Some examples of incomplete dominance
a. Flower color in snapdragons involving two alleles, CR
and CW. Red-flowered plants (CR/CR) crossed with whiteflowered ones (Cw/Cw) produce all pink progeny (CR/Cw ).
b. Palomino horses (golden-yellow body with nearly white mane and tail) are
another example.

Modifications of Dominance Relationship -

Incomplete Dominance

In this case, 50% of

the CR protein is not
sufficient to produce
the red phenotype

1:2:1 phenotypic ratio

NOT the 3:1 ratio
observed in simple
Mendelian inheritance

Fig. 13.7 Incomplete dominance in chickens

At the molecular level, two copies of CB produce

black, while 1 copy is sufficient to produce only
the gray Andalusian blue phenotype.

Modifications of Dominance Relationship -

Codominance

In codominance, the heterozygotes phenotype includes the phenotypes of both

homozygotes.
No dominance or recessiveness.
No blended phenotype (not incomplete dominance).
Some examples of codominance
- The human M-N blood group involves red blood cell antigens that are less
important in transfusions. There are three types:
i. Type M, with genotype LM/LM.
ii. Type MN, with genotype LM/LN.
iii. Type N, with genotype LN/LN.

Molecular Explanations of Incomplete Dominance and Codominance

Current explanations involve levels of gene expression for each allele in the pair.
a. In incomplete dominance, the recessive allele is not expressed, and the
dominant allele produces only enough product for an intermediate phenotype.
b. In codominance, both alleles make a product, producing a combined phenotype.
c. By contrast, a completely dominant allele creates the full phenotype by one of
two methods:
i. It produces half the amount of protein found in a homozygous dominant
individual, but that is sufficient to produce the full phenotype. These genes
are haplosufficient.
ii. Expression of the one active allele may be upregulated, generating protein
levels adequate to produce the full phenotype.

Gene Interactions and Modified Mendelian Ratios

Phenotypic traits are result from complex interactions of molecules under genetic
control.
Genetic analysis can often detect the patterns of these reactions. For example:
a. In the dihybrid cross AaBb X AaBb, nine genotypes will result.
b. If each allelic pair controls a distinct trait and exhibits complete dominance, a
9:3:3:1 phenotypic ratio results.
c. Deviation from this ratio indicates that interaction of two or more genes is
involved in producing the phenotype.
Two types of interactions occur:
a. Different genes control the same trait, collectively producing a phenotype.
b. One gene masks the expression of others (epistasis) and alters the phenotype.
In the real world larger numbers of genes and complex gene interactions are
often involved in forming traits (i.e. formation of the eyes).

Gene Interactions That Produce New Phenotypes

Nonallelic genes that affect the same characteristic may interact to give novel
phenotypes, and often modified phenotypic ratios. Examples include:
a. Comb shape in chickens.
- Comb shape in chickens, influenced
by two gene loci to produce four
different comb types.

Gene Interactions That Produce New Phenotypes

Gene Interactions That Produce New Phenotypes

Nonallelic genes that affect the same characteristic may interact to give novel
phenotypes, and often modified phenotypic ratios. Examples include:
a. Comb shape in chickens.
- Comb shape in chickens, influenced
by two gene loci to produce four
different comb types.
b. Fruit shape in summer squash shows
a 9:6:1 ratio.
- Two genes are involved, each
completely dominant.
- Interaction between the two loci
produces a new phenotype

Epistasis
In epistasis, one gene masks the expression or effects of another gene.
a. A gene that masks another is epistatic.
b. A gene that gets masked is hypostatic.
Several possibilities for interaction exist, all producing modifications in the 9:3:3:1
dihybrid ratio:
a. Epistasis may be caused by recessive alleles, so that a/a masks the effect of B
(recessive epistasis).
b. Epistasis may be caused by a dominant allele, so that A masks the effect of B
(dominant epistatis).
c. Epistasis may occur in both directions between genes, requiring both A and B
to produce a particular phenotype (duplicate recessive epistasis).

Epistasis Recessive Epistasis

In recessive epistasis, the F2 ratio is 9:3:4. Examples include:
a. Coat color determination in Labrador retriever dogs .
- Gene B/- makes black pigment, while b/b makes brown.
- Another gene, E/- allows expression of the B gene,
while e/e does not.
- Genotypes and their corresponding phenotypes:
i. B/- E/- is black.
ii. b/b E/- is brown (chocolate).
iii. -/- e/e is yellow with nose and lips either dark (B/- e/e) or pale (b/be/e)

b/b E/-

B/- E/-

Dark pigment present in fur

-/- e/e

B/- e/e

No dark pigment present in fur

Epistasis Recessive Epistasis

In recessive epistasis, the F2 ratio is 9:3:4. Examples include:
b. Coat color determination in rodents .

Epistasis Recessive Epistasis

Human example of recessive epistasis is albinism (albino).
Albinism- four genes control pigmentation in humans.
- One of the four genes in recessive form effects the other three even though they
are at different loci.
- Resulting in the absence of the skin pigment melanin in hair and eyes.
Albinism causes the following traits:
- White hair.
- Very pale skin.
- Pink pupils.

Essential Genes and Lethal Alleles

Some genes are required for life (essential genes), and mutations in them (lethal
alleles) may result in death.
Dominant lethal alleles result in death of
both homozygotes and heterozygotes,
while recessive lethal alleles cause death
only when homozygous.
Dominant lethals are rare, since death before
reproduction would eliminate the gene from
the population.
In human, a dominant lethal gene causes
Huntington disease, characterized by progressing
central nervous system degeneration.
- The phenotype is not expressed until
individuals are in their 30s.
Another example is the yellow body color
gene in mice.

Essential Genes and Lethal Alleles

Human examples of recessive lethal alleles include:
a. Tay-Sachs disease, due to an inactive gene for the enzyme hexosaminidase.
- Homozygous individuals develop neurological symptoms before 1 year of age,
and usually die within the first 34 years of life.
b. Hemophilia results from an X-linked recessive allele, and is lethal if untreated.

recessive lethal

dominant lethal

Gene Expression and the Environment

Development of an organism from a zygote is a series of generally irreversible
phenotypic changes resulting from interaction of the genome and the environment.
Four major processes are involved:
a. Replication of genetic material.
b. Growth.
c. Differentiation of cells into types.
d. Arrangement of cell types into defined tissues and organs.
Internal and external environments interact with the genes by controlling their
expression and interacting with their products.

Effects of the Environment

Age of onset is an effect of the individuals internal environment.
- Different genes are expressed at different times during the life cycle, and
programmed activation and inactivation of genes influences many traits.
- Human examples include:
i. Pattern baldness, appearing in males aged 2030 years.
ii. Duchenne muscular dystrophy, appearing in children aged 25 years.
Temperature may alter the activity of enzymes so that they function normally at
one temperature but are nonfunctional at another.
- An example is fur color in Himalayan rabbits
i. These white rabbits develop darker fur on the cooler parts of their bodies
(ears, nose and paws).

Effects of the Environment

Chemicals can have significant effects. Two examples:
i. Phenylketonuria (PKU):
- an autosomal recessive defect in metabolism of the amino acid phenylalanine.
- If not treated by restricting phenylalanine in the diet, severe mental
retardation and other symptoms result.
ii. Phenocopy:
- a modification of the phenotype caused by environmental conditions (e.g.
chemicals), mimicking a known gene mutation.
- Phenocopies are not hereditary, and the individual does not carry the
allele(s) being mimicked.
- Examples of phenocopies include:
i. Rubella, which produces cataracts, deafness and heart defects in a fetus
whose mother is infected during the first 12 weeks of pregnancy, mimics
rare recessive alleles.
ii. The drug thalidomide, mimics the effects of the genetic disorder
phocomelia, suppressing development of long bones in the limbs.

Nature versus Nurture

Phenotypes seen for many traits are influenced by both genes and environment.
Some human examples:
i. Human height has both genetic and environmental components.
- Genetically, children tend to have about the same stature as their parents.
- Environmentally, diet and health care are probably responsible for the increase
in human height of about 1 inch per generation over the last century.
ii. Alcoholism is an example of a behavioral trait influenced by both genes and
environment.
- Individuals with alcoholic biological fathers are significantly more likely to
become alcoholics than those with non-alcoholic biological fathers.
- Environment plays a key role also, since alcoholism can only develop if
alcohol is available.
- Genes make individuals more or less susceptible to alcohol abuse, perhaps
by affecting metabolism of alcohol or development of personality traits
involved in drinking.

Nature versus Nurture

Some human examples:
iii. Human intelligence is an example of a very complex relationship
between genes and environment.
- Genes also influence IQ among people, with adopted children scoring closer to
their biological parents than to their adoptive parents.
- Environmental influences are seen in studies of identical twins, who frequently
differ in IQ scores.
- Interactions between many genes and all aspects of the environment are
involved in forming human intelligence.
- Genes cant be changed, but the environment can be altered to affect this
very complex phenotype.

Penetrance and Expressivity

Penetrance and Expressivity

Penetrance describes how completely the presence of an allele corresponds with
the presence of a trait.
It depends on both the genotype and the environment of the individual:
- If all those carrying a dominant mutant allele develop the mutant phenotype,
the allele is completely (100%) penetrant.
- If some individuals with the allele do not show the phenotype, penetrance is
incomplete. If 80% of individuals with the gene show the trait, the gene has
80% penetrance.
- Human examples include:
i. Brachydactyly involves abnormalities
of the fingers, and shows 5080%
penetrance.
ii. Many cancer genes are thought to
have low penetrance, making them
harder to identify and characterize.

Penetrance and Expressivity

Expressivity describes variation in expression of a gene or genotype in individuals.
Two individuals with the same mutation may develop different phenotypes, due to
variable expressivity of that allele.
Like penetrance, expressivity depends on both genotype and environment, and
may be constant or variable.
A human example is osteogenesis imperfecta, inherited as an autosomal dominant
with nearly 100% penetrance.

- Three traits are associated with the allele:

i. Blueness of the sclerae (whites of eyes).
ii. Very fragile bones.
iii. Deafness.
- Osteogenesis imperfecta shows variable expressivity, because an individual with
the allele may have one, two, or all three of its symptoms, in any combination.
Bone fragility is also highly variable.

Penetrance and Expressivity

Penetrance and Expressivity

Some genes involved in human genetic disease have both incomplete penetrance
and variable expressivity. An example is neurofibromatosis.
- The allele is an autosomal dominant that shows 5080% penetrance and
variable expressivity ranging from mild skin discolouration to neurofibroma
tumors of various sizes, tumors of eye, brain or spinal cord and curvature of the
spine.

Incomplete penetrance and variable expressivity complicate medical genetics and

genetic counseling.