lecture 10 - extension mendelian genetics 2013

8/19/2019 Lecture 10 - Extension Mendelian Genetics 2013

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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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• 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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b. Coat color determination in rodents .

• In recessive epistasis, the F2 ratio is 9:3:4. Examples include:


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• 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 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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• 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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• 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.

lecture 10 - extension mendelian genetics 2013

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