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LECTURE 10
Extensions Of MendelianGenetic Analysis
Micky Vincent
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Introduction - Beyond Mendel…
1. How alleles affect phenotype.
2. Gene interaction.
4. Phenotype can depend on more than genotype.3. Sex-linked genes (X-linkage in X/Y organisms).
• Since Mendel’s work was rediscovered in the early 1900’s:
- Types of inheritance observed by researchers that did not conform to the
expected Mendelian ratios:
- Researchers have studied the many ways genes influence an individual’sphenotype.
- These investigations are called neo-Mendelian genetics (neo is Greek for “new”).
- Environmental effects.
- Not always simple dominant/recessive issue.
- Phenotype controlled by more than one gene.
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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 heterozygote’s phenotype will be intermediate
between the two possible homozygous phenotypes.
b. In codominance, the heterozygote shows the phenotypes of bothhomozygotes.
c. At the molecular level, these relationships between pairs of alleles depend
upon patterns of gene expression.
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Alleles
• Alleles are alternate forms of the same gene.
• Wt allele used as “standard” for comparison of all mutations (alternative alleles)
of the gene/locus.
• 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.
- i.e. eye colours and blood groups.
• New phenotypes result from changes in functional activity of gene product:
• Mutation is the ultimate source of new alleles.
- Changing overall enzyme function.
- Eliminating enzyme function.
- Changing relative enzyme efficiency.
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Alleles
• Example: ABO blood groups are written as IA, IB and i.
• To write allele symbols, for simple Mendelian traits:
- 1st
letter of recessive form.- Lowercase = recessive allele.
- Uppercase = dominant allele.
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Multiple Alleles – Human Blood Group
• 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:
• 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.
• Classic example is human ABO blood groups.
• Many genes have multiple alleles:
b. May display a hierarchy of dominance (i.e. fur colour).
a. Two or more different alleles (i.e. eye colour).
c. May display codominance (i.e. blood type).
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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:
b. Type B individuals have the B antigen on theirRBCs. Their genotype is IB/IB or IB/i.
a. Type A individuals have the A antigen on their red
blood cells (RBCs). Their genotype is IA/IA or IA/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.
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Biochemical Genetics of the Human ABO Blood Group
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Modifications of Dominance Relationship - Incomplete Dominance
• Incomplete dominance is an allelic relationship where dominance is only partial.
• In a heterozygote, the recessive allele is not expressed.
•
The dominant allele is unable to produce the full phenotype seen in ahomozygous dominant individual (partial expression).
• The result is a new, intermediate phenotype.
• Some examples of incomplete dominance
a. Flower color in snapdragons involving two alleles, CRand CW. Red-flowered plants (CR/CR) crossed with white-
flowered ones (Cw/Cw) produce all pink progeny (CR/Cw ).
b. Palomino horses (golden-yellow body with nearly white mane and tail) are
another example.
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Modifications of Dominance Relationship - Incomplete Dominance
1:2:1 phenotypic ratio
NOT the 3:1 ratioobserved in simple
Mendelian inheritance
In this case, 50% of
the CR protein is not
sufficient to produce
the red phenotype
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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.
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Modifications of Dominance Relationship - Codominance
• In codominance, the heterozygote’s phenotype includes the phenotypes of both
homozygotes.
• 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.
• No dominance or recessiveness.
• No “blended” phenotype (not incomplete dominance).
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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 thedominant 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 dominantindividual, 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.
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Gene Interactions and Modified Mendelian Ratios
• Phenotypic traits are result from complex interactions of molecules under genetic
control.
• Two types of interactions occur:
a. Different genes control the same trait, collectively producing a phenotype.
• 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 isinvolved in producing the 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 areoften involved in forming traits (i.e. formation of the eyes).
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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.
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Gene Interactions That Produce New Phenotypes
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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 showsa 9:6:1 ratio.
- Two genes are involved, each
completely dominant.
- Interaction between the two loci
produces a new phenotype
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Epistasis
• In epistasis, one gene masks the expression or effects of another gene.
• 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).
a. A gene that masks another is epistatic.
b. A gene that gets masked is hypostatic.
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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).
No dark pigment present in fur
-/- e/e B/- e/e
Dark pigment present in fur
b/b E/- B/- E/-
iii. -/- e/e is yellow with nose and lips either dark (B/- e/e) or pale (b/be/e)
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Epistasis – Recessive Epistasis
b. Coat color determination in rodents .
• In recessive epistasis, the F2 ratio is 9:3:4. Examples include:
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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.
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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.
• Another example is the yellow body color
gene in mice.
• 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.
•
Dominant lethals are rare, since death beforereproduction would eliminate the gene from
the population.
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Essential Genes and Lethal Alleles
• Human examples of recessive lethal alleles include:
b. Hemophilia results from an X-linked recessive allele, and is lethal if untreated.
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 3 –4 years of life.
recessive lethal dominant lethal
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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:
• Internal and external environments interact with the genes by controlling their
expression and interacting with their products.
a. Replication of genetic material.
b. Growth.
c. Differentiation of cells into types.
d. Arrangement of cell types into defined tissues and organs.
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Effects of the Environment
• Age of onset is an effect of the individual’s internal environment.
- Different genes are expressed at different times during the life cycle, andprogrammed activation and inactivation of genes influences many traits.
- Human examples include:
i. Pattern baldness, appearing in males aged 20 –30 years.
ii. Duchenne muscular dystrophy, appearing in children aged 2 –5 years.
• Temperature may alter the activity of enzymes so that they function normally atone 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).
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Effects of the Environment
• Chemicals can have significant effects. Two examples:
- 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.
i. Phenylketonuria (PKU):
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 fetuswhose 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.
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Nature versus Nurture
• Phenotypes seen for many traits are influenced by both genes and environment.
•
Some human examples:
- 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.
i. Human height has both genetic and environmental components.
ii. Alcoholism is an example of a behavioral trait influenced by both genes andenvironment.
- 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.
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Nature versus Nurture
• Some human examples:
- 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.
iii. Human intelligence is an example of a very complex relationshipbetween genes and environment.
- Interactions between many genes and all aspects of the environment are
involved in forming human intelligence.
- Genes can’t be changed, but the environment can be altered to affect this
very complex phenotype.
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Penetrance and Expressivity
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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 has80% penetrance.
- Human examples include:
i. Brachydactyly involves abnormalities
of the fingers, and shows 50 –80%
penetrance.ii. Many cancer genes are thought to
have low penetrance, making them
harder to identify and characterize.
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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 tovariable expressivity of that allele.
- 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.
i. Blueness of the sclerae (whites of eyes).
ii. Very fragile bones.
• 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:
iii. Deafness.
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Penetrance and Expressivity
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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 50 –80% 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 andgenetic counseling.
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