EXTENSIONS OF MENDELIAN INHERITANCE

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EXTENSIONSOFMENDELIAN INHERITANCE

• Chapter 4

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MENDELIAN INHERITANCE

• Simple Mendelian inheritance
• Traits affected by a single gene
• Two alleles exist for this gene
• 31 phenotypic ratio in the F2 generation

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MENDELIAN INHERITANCE

• Mendelian inheritance
• Describes patterns that obey two laws
• Law of segregation
• Law of independent assortment
• Includes simple Mendelian inheritance
• Can be more complex than simple Mendelian
  inheritance
• Some transmission patterns do not display a
  simple dominant/recessive relationship

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MENDELIAN INHERITANCE

• Wild-type alleles are the most prevalent alleles
  in a population
• Encoded protein is generally
• Functional
• Made in the proper amount
• Confer various phenotypes
• e.g., Purple flowers, round seeds, etc.

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MENDELIAN INHERITANCE

• Mutant alleles have been altered by mutation
• Tend to be rare in natural populations
• Commonly defective in ability to express
  functional protein
• Encoded protein is often
• Produced in reduced amount (decreased synthesis)
• Less functional (decreased function)
• Often inherited in a recessive fashion
• Confer various phenotypes
• e.g., White flowers, wrinkled seeds, etc.

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MENDELIAN INHERITANCE

• Genetic diseases are caused by mutant alleles
• Fail to produce a specific cellular protein in
  its active form
• Loss-of-function mutants

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MENDELIAN INHERITANCE

• Diploid individuals possess two copies of most
  genes
• Sex-linked traits are an exception

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MENDELIAN INHERITANCE

• Simple dominant/recessive relationship
• Fairly common among many genes
• One copy of the dominant allele is sufficient to
  produce the dominant phenotype
• Recessive allele does not affect the phenotype of
  heterozygotes
• Production of functional protein is reduced by
  50
• 50 is adequate to provide a normal phenotype
• Homozygotes produce more wild-type protein than
  necessary

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MENDELIAN INHERITANCE

• Simple dominant/recessive relationship
• Production of functional protein may be reduced
• Heterozygote may produce more than 50 of the
  normal amount
• Expression of the normal gene may be increased in
  the heterozygote
• Up regulation

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ESSENTIAL GENES

• Absence of a specific protein may result in a
  lethal phenotype
• Gene is an essential gene for survival
• An estimated 1/3 of all genes are essential for
  survival
• Mutant allele is a lethal allele
• Has potential to cause death
• Generally inherited in a recessive manner

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ESSENTIAL GENES

• Nonessential genes are not absolutely required
  for survival
• Likely to be beneficial to the organism
• Some rare mutations in nonessential genes can be
  lethal

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LETHAL ALLELES

• Most lethal mutations are in essential genes
• A minority are in nonessential genes

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LETHAL ALLELES

• Many lethal alleles prevent cell division
• Death at a very early stage
• Some lethal alleles exert their effect later in
  life
• e.g. Huntington disease causes a progressive
  degeneration of the nervous system
• Age of onset is generally 30 50

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LETHAL ALLELES

• Some lethal alleles exert their effect only under
  certain environmental conditions
• Conditional lethal alleles
• Extensively studied in experimental organisms
• Why do you think this is the case?
• e.g., Temperature-sensitive (ts) lethals
• May kill developing Drosophila larva at 30oC
• Larva will survive if grown at 22oC
• Protein structure is altered such that it doesnt
  function correctly at the nonpermissive
  temperature
• Nonfunctional or rapidly degraded

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LETHAL ALLELES

• Some lethal alleles act only in some individuals
• Semilethal alleles
• Some individuals die, while others do not
• The difference is likely the result of
  environmental conditions and the actions of other
  genes

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LETHAL ALLELES

• Lethal alleles may produce ratios that seemingly
  deviate from Mendelian ratios
• e.g., Creeper phenotype in chickens
• Shortened wings and legs
• Creeps rather than walking normally

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LETHAL ALLELES

• All creeper birds are heterozygous
• Creeper x wild-type ? 11 phenotypic ratio
• Creeper phenotype is dominant

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LETHAL ALLELES

• All creeper birds are heterozygous
• Creeper x creeper ? 21 creepernormal ratio
• Creeper allele is a recessive lethal
• Creeper homozygotes are dead
• Effects of this allele
• Dominant for the creeper phenotype
• Recessive for death

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INCOMPLETE DOMINANCE

• Heterozygotes sometimes display a phenotype
  intermediate between the homozygotes
• Incomplete dominance
• e.g., Flower color in the four-oclock,
  snapdragons, carnations, etc.
• Homozygous red (CRCR) x homozygous white (CWCW)
• F1 offspring (CRCW) are heterozygous and pink
• F2 offspring display 121 phenotypic and
  genotypic ratios

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INCOMPLETE DOMINANCE

• Incomplete dominance in flower color
• The white allele results in a lack of production
  of functional protein required for pigmentation
• Heterozygotes produce half the normal amount of
  protein
• Less pigment is produced
• Pink color is the result
• Gene dosage effect

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INCOMPLETE DOMINANCE

• Many traits appear to be dominant
• Closer examination shows that some are actually
  incompletely dominant
• e.g., Seed shape in Mendels peas
• RR and Rr produce round seeds
• rr produces wrinkled seeds
• Decreased starch deposition

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INCOMPLETE DOMINANCE

• Rr heterozygotes actually display intermediate
  starch deposition
• R is dominant to r at the level of visual
  examination
• R is incompletely dominant at the level of
  starch biosynthesis

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MULTIPLE ALLELES

• Individuals possess two copies of each gene
• At most, they possess two different alleles
• More than two different alleles for a given gene
  can exist in a population
• Multiple alleles

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MULTIPLE ALLELES

• Coat color in rabbits is determined by alleles of
  the C gene
• Four different alleles exist
• C full coat color
• cch chinchilla
• ch himalayan
• c albino
• Any particular rabbit possesses only two alleles

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MULTIPLE ALLELES

• Dominant/recessive relationships between coat
  color alleles
• C is dominant to cch, ch, and c
• cch is recessive to C, but dominant to ch, and c
• ch is recessive to C and cch, but dominant c
• c is recessive to C, cch, ch
• C cch ch c

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MULTIPLE ALLELES

• Dominant/recessive relationships between coat
  color alleles
• C provides full coat color
• cch produces a partial defect in coloration
• ch results in pigmentation only in certain parts
• Temperature-sensitive conditional allele
• c is a defective allele producing no protein
  necessary for pigment production
• Given this information, can you explain the
  various dominant/recessive relationships between
  the alleles?

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CONDITIONAL ALLELES

• ch is a temperature-sensitive conditional allele
• Results in pigmentation only in certain parts of
  the body
• Encoded enzyme functions only in cooler areas of
  the body
• Ends of extremities, tail, paws, nose, ears
• Similar temperature-sensitive alleles are found
  in other animals
• e.g., Siamese cat

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CONDITIONAL ALLELES

• xxx

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ABO BLOOD TYPES

• Red blood cells contain carbohydrate chains on
  their plasma membranes
• Antigens
• Recognized by immune systems antibodies
• A, B, and O antigens determine human blood type
• Synthesized by three alleles of a single gene
• IA, IB, and i

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ABO BLOOD TYPES

• The i gene produces an enzyme
• Glycosyl transferase
• Attaches sugar branches to carbohydrate trees
  present on the surface of red blood cells
• i allele encodes a defective enzyme
• No sugar branches are attached
• IA and IB alleles encode enzymes with different
  substrate specificities
• Different sugar branches are attached

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ABO BLOOD TYPES

• i is recessive to both IA and IB
• ii ? type O blood
• IA and IB are codominant
• IAIB ? AB blood
• Possesses both A and B antigens

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ABO BLOOD TYPES

• Different antigens are recognized by different
  antibodies
• People make antibodies only to antigens they do
  not possess themselves
• e.g., Type A makes antibodies to the B antigen

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ABO BLOOD TYPES

• Blood typing is essential for safe blood
  transfusions
• Transfused blood must not contain antigens
  recognized by recipients antibodies
• Transfusion reaction can be fatal
• What types of blood can you receive? How about
  me?

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ABO BLOOD TYPES

• Transfusion reaction
• Antibodies simultaneously bind to multiple red
  blood cells
• Blood cells are clumped together
• Small blood vessels are clogged
• Hinders blood flow to tissues beyond
• Hemolysis of RBCs
• Reduced O2-carrying ability
• Released hemoglobin precipitates in kidneys
• Kidney shutdown

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OVERDOMINANCE

• Heterozygotes sometimes display characteristics
  superior to those of either homozygote
• e.g., Larger, disease resistant, drought
  resistant, etc.
• Overdominance or Heterozygote advantage

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OVERDOMINANCE

• Sickle-cell disease
• Autosomal recessive disorder
• Caused by an aberrant b-globin allele (HbS)
• Glutamic acid (HbA) ? valine (HbS)
• Cells sickle under low oxygen concentrations
• Multiple deleterious effects

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OVERDOMINANCE

• Sickle-cell disease
• Reduced RBC lifespan
• Last a few weeks instead of four months
• Anemia
• Sickled cells clog capillaries
• Localized areas of oxygen depletion and tissue
  damage
• Painful crises
• Shortened lifespan

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OVERDOMINANCE

• Sickle-cell disease
• The HbS allele has been found at a fairly high
  frequency in human populations exposed to malaria
• Why would something bad be found at such high
  levels?
• Shouldnt natural selection reduce its frequency
  to a much lower level?

Malaria
Sickle cell disease
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OVERDOMINANCE

• Malaria
• Caused by protozoans in the genus Plasmodium
• Spends part of its life cycle within the
  Anopheles mosquito
• Spends part of its life cycle within red blood
  cells
• HbS protein interferes with their propagation
• HbAHbS heterozygotes have an increased
  resistance to malaria

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OVERDOMINANCE

• HbSHbS is detrimental
• Sickle cell disease
• HbAHbA is detrimental
• No resistance to malaria
• HbAHbS is the most fit genotype
• Only very mild anemia
• Resistance to malaria

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OVERDOMINANCE

• Natural selection affects the frequency of the
  HbS allele in populations
• Increased survival of HbAHbS heterozygotes
  increases the frequency of the HbS allele
• Increased mortality of HbSHbS homozygotes
  decreases the frequency of the HbS allele

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OVERDOMINANCE

• Relationships between HbA and HbS
• Sickle cell disease
• HbA is incompletely dominant to HbS
• Heterozygotes are mildly anemic
• Types of proteins produced
• HbA is codominant to HbS
• Heterozygotes produce both proteins
• Malaria resistance
• HbA is recessive to HbS

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OVERDOMINANCE

• Many of the Africans transported to the New World
  as slaves came from regions where malaria and
  sickle-cell disease were prevalent
• As a result, 0.25 of African-Americans have
  sickle cell disease
• 10 are carriers of the HbS allele

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OVERDOMINANCE

• Proteins sometimes function as a complex with
  multiple subunits
• Each subunit is a separate polypeptide
• e.g., A dimer consists of two subunits
• A1A2 dimers may function optimally over a wider
  set of conditions than A1A1 or A2A2
• Greater activity confers advantage to
  heterozygotes

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OVERDOMINANCE

• Proteins encoded by different alleles may
  function optimally under different conditions
• e.g., One protein may function best at slightly
  elevated temperatures
• Organisms possesses activity over a wider range
  of temperatures
• Activity over greater range of conditions
  confers advantage to heterozygotes

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OVERDOMINANCE

• Plant and animal breeders often cross two highly
  inbred strains to produce hybrids
• Hybrids often display traits superior to both
  parental strains
• Heterosis or hybrid vigor
• Valuable in improving quantitative traits
• e.g., Size, weight, growth rate, etc.
• Different from overdominance
• Hybrids are heterozygous for many genes, not just
  one

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INCOMPLETE PENETRANCE

• Dominant alleles generally influence a trait
  when present in heterozygotes
• Occasionally, this does not occur
• Some individuals possessing the dominant allele
  lack the dominant phenotype
• Incomplete penetrance
• e.g., Polydactyly
• Measure is at the population level
• If 60 of heterozygotes exhibit the trait, it is
  60 penetrant

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EXPRESSIVITY

• Polydactyly is an autosomal dominant condition
• Not all individuals with the allele are
  polydactyl
• Incomplete penetrance
• The number of extra digits can vary
• e.g., One person may have one additional toe,
  while another may have extra digits on both hands
  and feet
• This variation is known as the expressivity of
  the trait
• Low expressivity vs. high expressivity in the
  previous example

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EXPRESSIVITY AND PENETRANCE

• The molecular basis for incomplete penetrance and
  expressivity may not always be understood
• Range of phenotypes is thought to be due to
  environmental influences and/or due to
  interactions with other genes

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ENVIRONMENTAL INFLUENCE

• Environmental conditions may have a great impact
  on an individuals phenotype
• e.g., Temperature and amount of light can affect
  snapdragon flower color
• Phenotype of F1 heterozygotes depends on these
  conditions
• Cool, bright light ? red
• Warm, shady ? ivory

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ENVIRONMENTAL INFLUENCE

• The outcome of phenylketonurea (PKU) is
  influenced by diet
• Autosomal recessive disorder
• 1/8,000 1/15,000 births among Caucasians in the
  United States
• Deficient in an enzyme (phenylalanine
  hydroxylase) required for the catabolism of the
  amino acid phenylalanine
• Breakdown products reach toxic levels in the
  blood
• Various detrimental effects
• Mental retardation, underdeveloped teeth,
  foul-smelling urine, etc.

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ENVIRONMENTAL INFLUENCE

• The outcome of phenylketonurea (PKU) is
  influenced by diet
• Identification of phenylketonurics at birth is
  critical
• Newborns are routinely screened in the United
  States
• Modified (low-phe) diet avoids the damaging
  effects of this disorder
• Of these three phenylketonuric children, only
  the middle one was raised on a low-phe diet

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SEX-INFLUENCED TRAITS

• An allele may be dominant in one sex but
  recessive in the opposite sex
• Sex-influenced inheritance
• Phenomenon of heterozygotes
• e.g., Pattern baldness in humans
• BB ? bald
• bb ? bald males, nonbald females
• bb ? nonbald
• Pattern baldness is related to levels of male sex
  hormones

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SEX-INFLUENCED TRAITS

• Pattern baldness can be passed from father to son
• Sex-linked traits cannot

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SEX-LIMITED TRAITS

• Sex-limited traits occur only in one sex
• e.g., Breast growth and beard growth in humans
• e.g., Ornate plumage in male birds
• hh ? hen-feathered females, cock-feathered males
• Hh ? hen-feathered
• HH ? hen-feathered

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SEX-LIMITED TRAITS

• Sex-limited traits occur only in one sex
• Cock-feathered and hen-feathered phenotypes are
  related to sex hormones
• hh female with ovary removed will develop
  cock-feathered phenotype

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• Sex-linked traits are determined by genes on the
  X-chromosome
• Sex-influenced and sex-limited traits are
  determined by genes on autosomes

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GENE INTERACTIONS

• Most traits are affected by two or more genes
• Gene interactions
• Two or more different genes influence the outcome
  of a single trait
• e.g., Height, weight, growth rate, and
  pigmentation are determined by many genes in
  combination with environmental factors

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GENE INTERACTIONS

• Comb morphology in chickens is influenced by two
  different genes
• Four different phenotypes exist
• Rose comb
• Pea comb
• Walnut comb
• Single comb

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GENE INTERACTIONS

• Rose comb x pea comb
• F1 generation consisted entirely of walnut combed
  individuals
• 4 different phenotypes appeared in the F2
  generation
• 9/16 Walnut comb
• 3/16 Rose comb
• 3/16 Pea comb
• 1/16 Single comb

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GENE INTERACTIONS

• Four separate phenotypes of a single trait exist
• A single trait is determined by two different
  genes
• R (rose) is dominant to r
• P (pea) is dominant to p
• R and P are codominant (walnut)
• rrpp produces a single comb

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GENE INTERACTIONS

• The wild sweet pea (Lathyrus odoratus) normally
  has purple flowers
• Several true-breeding white-flowered varieties
  exist

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GENE INTERACTIONS

• The wild sweet pea (Lathyrus odoratus)
• Purple-flowered x white-flowered cross
• F1 generation is entirely purple-flowered
• F2 generation displays a 31 purplewhite ratio
• The purple allele is dominant to the white allele

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GENE INTERACTIONS

• The wild sweet pea (Lathyrus odoratus)
• Purple-flowered x white-flowered cross
• F1 generation is entirely purple-flowered
• F2 generation displays a 31 purplewhite ratio
• The purple allele is dominant to the white allele

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GENE INTERACTIONS

• The wild sweet pea (Lathyrus odoratus)
• When two different white-flowered lines were
  crossed, the resulting F1 generation was entirely
  purple-flowered!
• Self-fertilization of this F1 generation
  produced an F2 generation with both
  white-flowered and purple-flowered individuals
• 9/16 purple-flowered
• 7/16 white-flowered
• 97 ratio is a modified 9331

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GENE INTERACTIONS

• The wild sweet pea (Lathyrus odoratus)
• Two different genes are involved in determining
  flower color
• Epistasis
• One gene can mask the phenotypic effects of a
  second gene
• C is dominant to c
• P is dominant to p
• Individuals homozygous recessive for either (or
  both) of these two genes are white-flowered

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GENE INTERACTIONS

• The wild sweet pea (Lathyrus odoratus)
• Two different proteins participate in a common
  function
• Precursor ? intermediate
• Requires enzyme C
• Intermediate ? purple pigment
• Requires enzyme P
• Both enzymes are required for production of
  purple pigment

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EOSIN EYES IN Drosophila

• Wild-type Drosophila are red-eyed
• White eyes are the result of a recessive X-linked
  allele
• Xw is the red allele
• Xw is the white allele
• Eosin eyes are the result of a different mutation
  in the white allele
• Xw-e is the eosin allele

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EOSIN EYES IN Drosophila

• Eosin-eyed females
• Xw-eXw-e
• Eosin eyes
• Eosin-eyed males
• Xw-eY
• Light eosin eyes
• Result of gene dosage effect
• Only one copy of the eosin allele is present in
  males
• Less of the eosin pigment is made than in females

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EOSIN EYES IN Drosophila

• What results would you expect from each of the
  following crosses between different true-breeding
  lines?
• White-eyed ? x red-eyed ?
• Red-eyed ? x eosin-eyed ?
• Eosin-eyed ? x white-eyed ?

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EOSIN EYES IN Drosophila

• Wild-type Drosophila are red-eyed
• White eyes are the result of a recessive X-linked
  allele
• Xw is the red allele
• Xw is the white allele
• Eosin eyes are the result of a different mutation
  in the white allele
• Xw-e is the eosin allele

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EOSIN EYES IN Drosophila

• Eosin-eyed females
• Xw-eXw-e
• Eosin eyes
• Eosin-eyed males
• Xw-eY
• Light eosin eyes
• Result of gene dosage effect
• Only one copy of the eosin allele is present in
  males
• Less of the eosin pigment is made than in females

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EOSIN EYES IN Drosophila

• What results would you expect from each of the
  following crosses between different true-breeding
  lines?
• White-eyed ? x red-eyed ?
• Red-eyed ? x eosin-eyed ?
• Eosin-eyed ? x white-eyed ?