Dominance Relationships

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One final topic with regard to chromosome
segregation during the process of cell division
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DNA in chromosomes replicates prior to cell
division...
This event is coordinated to internal signals
within the cell and external signals provided by
the cells environment...
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Fig. 4.7
Which is bracketed by two phases of varying
length.
DNA synthesis occurs during S phase of
interphase.
A number of checkpoints exist within the cell
cycle to coordinate the division process...
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There are checkpoints in the cell cycle to
monitor for correct DNA replication and
appropriate chromosomal orientation... fig. 4-11
in text
A breakdown in control mechanisms can lead to
uncontrolled growth
Mutations in genes involved in mediating these
processes can lead to oncogenesis
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Dominance Relationships

• In Mendels experiments, his traits showed
  complete dominance heterozygotes had phenotypes
  similar to homozygotes with two copies of the
  dominant allele
• In 1903, A. Garrod demonstrated that human traits
  were transmitted according to Mendels laws...

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Phenotype for alcaptonuria individuals with the
disease show urine which blackens upon exposure
to air
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Alcaptonuria inherited as Mendelian Trait

• inheritance pattern of 31 in affected families
  (autosomal recessive)
• Garrod noted that affected individuals built up
  homogentisic acid in their urine
• Garrod postulated that the disease was due to a
  defect in an enzymatic pathway
• inborn error in metabolism first suggestion
  that genes can code for enzymes

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Oxidized to black pigment (abnormal urine)
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Dominance Relationships Incomplete Dominance

• Not all traits show an inheritance pattern of
  complete dominance
• In some instances, the phenotype of the
  heterozygote (A_) can be distinguished from that
  of the homozygote (AA)
• e.g. inheritance of flower color in snapdragons.

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white
Phenotype distinguished from either parent
121 ratio
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alcaptonuria
haplosufficient
Flower color in snap dragons
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Multiple Alleles at a Single Chromosomal Locus

• Diploid individuals carry two copies of each
  gene heterozygotes carry two different alleles
• Within the population at large, however, there
  may be many different alleles for any given gene
  locus
• e.g. A, a, A1, A2, A3, etc.

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Example the beta globin gene

• Beta (?) globin is a component of the adult
  hemoglobin molecule (HbA)
• hemoglobin A 2 ?-globin subunits
• 2 ?-globin subunits
• alpha and beta globin are different genes
  (?-globin gene is on chromosome 16 ?-globin gene
  on chromosome 11)

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Example the beta globin gene

• Multiple alleles of the beta globin gene exist in
  human populations
• Mutations result in allelic variation and the
  production of hemoglobins with different physical
  properties

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Hemoglobin C
146 aa
146 aa
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• Sickle cell anemia
• inherited as recessive disorder
• Under conditions of low oxygen tension,
  hemoglobin S will precipitate, causing cells to
  sickle

• cells will both aggregate and be susceptible to
  destruction, leading to circulation problems and
  anemia

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Electrophoresis can be used to identify allelic
variation
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-

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• Hb S/C
• Hb A/ C
• Hb A/S
• Hb S
• Hb S
• Hb A/S
• HbA

-
migration
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DNA-DNA hybrids can also be used as a means of
detecting alleles...
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AA
AS
SS
Denatured DNA spotted on paper and reacted with
A (top) or S (bottom) probe...
See text, pp. 32-33.
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The Alpha-1-antitrypsin Gene has Multiple Alleles
in Human Populations

• Alpha-1-antitrypsin (A-1-A) protease inhibitor
  produced in liver, released into bloodstream
• A-1-A required to prevent tissue damage from
  released cellular proteases
• neutrophil elastase released from white blood
  cells during infections must be inactivated by
  A-1-A

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Alpha-1-Antitrypsin Deficiency

• Some alleles of A-1-A are not efficient protease
  inhbitors
• Individuals homozygous for certain alleles are at
  risk for emphysema later in life
• Some alleles produce proteins that are not
  properly released from the liver, leading to
  liver damage

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A large number of A-1-A variants are observed in
human populations
A-1-A is a glycoprotein sugar residues are
attached as a post-translational modification,
changing its mobility.(reason for multiple bands
on gel, even for homozygotes)
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ZZ 1/700 in Caucasian populations 70 risk of
developing emphysema
MZ 2-3 of Caucasian populations
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Interactions between environment and genotype
PiZZ homozygotes and smoking
Genetic Screening Is the test accurate and
useful? Who should be screened? Who should
receive the information?
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Dominance Relationships Codominance

• In this situation, the heterozygote exhibits the
  phenotypes of both alleles at a given gene locus
• Suppose that mutations at a given gene locus
  produce enzymes that have different enzymatic
  propertiesdifferent alleles could produce
  different metabolic products

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Example ABO blood Groups
Cell membrane
(Precursor)
Different sugar molecules are added two distinct
phenotypes
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• A and B are dominant to O phenotype
• AB is codominant phenotype both alleles expressed

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Y
Y
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Y
Agglutination!
Y
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N.B.situation is complicated by many other blood
group antigens (e.g. Rh, MN, etc.)
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Deviations from Mendelian Ratios due to Single
Gene, Polygenic or Environmental Interactions

• Lethal Alleles two copies of a particular
  allele will lead to death of homozygous class
  during embryogenesis
• e.g. yellow locus of mice

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X
All yellow mice are heterozygous for AY allele
AY dominant for coat color
Homozygotes for AY are lethal
Lethality inherited as recessive trait
21 ratio of yellownormal
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Aabb (albino)
aaBB (albino)
This situation leads to a functional test for
allelismsince these two mutations show
complementation, the mutations carried by the
parents are found in different genes.
AaBb (normal)
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Deviations from Mendelian Ratios due to Single
Gene, Polygenic or Environmental Interactions

• Phenocopy an environmental exposure or insult
  leads to a mimicry of a genetic disorder
• exposure of multiple family members may suggest a
  genetic origin, although cause is environmental,
  NOT genetic

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Kwashiorchor protein deficiency leads to
phenocopy of albinism
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Deviations from Mendelian Ratios due to Single
Gene, Polygenic or Environmental Interactions

• The degree of phenotypic expession of an allele
  can be influenced by its interactions with other
  genes and with the environment
• Variable expressivity the degree or severity
  that a given genotype exhibits in its phenotype

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Variable Expression Anonychia
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Variable Expression Neurofibromatosis
Café au lait spots
tumors
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