Chapter 4: Extensions of Mendelian Analysis

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Chapter 4 Extensions of Mendelian Analysis

• Inheritance of a trait usually does not follow
  simple Mendelian ratios
• Genetic and biochemical complexities of gene
  products
• Affects of environment on development of
  phenotype
• But segregation and assortment of chromosomes and
  gene loci in eukaryotes are still UNIVERSAL

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Multiple Alleles

• More than 2 alleles can exist for a single locus
• A diploid individual will have only two alleles,
  
• one on each homologous chromosome
• Multiple alleles can have a hierarchy of
• dominance relationships
• Example ABO alleles

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ABO Blood Groups in humans

• Donor and recipient types must be matched because
  blood group alleles specify molecular groups,
  called antigens, that are attached to outside of
  RBC
• Antigen
• Molecule recognized as foreign
• Stimulates the production of antibodies
• Antibody
• Specific protein molecule that recognizes and
  binds to antigens

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ABO Blood Types and Alleles

• Four blood phenotypes O, A, B, AB
• Three possible alleles at ABO locus
• IA, IB, i 
• Blood groups differ by alteration of cell surface
  oligosaccharide, which can be an antigen when
  introduced into other organisms

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ABO Alleles and Antigens Presented

• Type A displays A antigen on cell surface
• Type B displays B antigen on cell surface
• Type AB displays A and B antigens on cell surface
• Type O displays H antigen on cell surface

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Effects of ABO Genotypes on Blood Group Phenotypes

• 6 genotypes give rise to 4 phenotypes A, B, AB,
  O blood
• IA / IA Type A
• IB / IB Type B
• IA / IB Type AB
• i / i Type O
• IA / i Type A
• IB / i Type B
• Alleles IA and IB are completely dominant to i
• Alleles IA and IB are codominant

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Effects of ABO Genotypes on Blood Group Phenotypes

• Alleles IA and IB are codominant
• Both phenotypes fully expressed
• Both present on surface of red blood cells (RBC)
• Alleles IA and IB are completely dominant over i
• H antigen is a precursor that is converted into A
  and B antigens by IA and IB alleles
• Antibodies to the H antigen dont exist in
  individuals with A and B type blood because the H
  antigen is transiently present in their cells

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Phenotypic Responses to Blood Transfusions
Blood Type of Compatable Donor

• Blood Type Recipient
• A A or O
• B B or O
• AB A, B, AB, or O
• O O
• H antigens converted into A or B by IA and IB
  alleles

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Drosophila Eye Color

• Drosophila has over 100 mutant alleles at the
  eye-color locus on the X chromosome.
• The white-eyed variant allele is designated w
• The wild-type (brick red) allele is w
• A recessive allele, we, produces eosin
  (reddish-orange) eyes.

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• Complete Dominance
• One allele completely masks the effect of another
  allele
• Heterozygous dominant phenotype indistinguishable
  from homozygous dominant phenotype
• Complete Recessiveness
• Recessive allele only expressed when organism
  homozygous

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Heterozygous Dominant vs Homozygous Dominant
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Two explanations for Complete Dominance

• Enzyme may not be needed in large quantities, not
  a limiting factor in pathway
• These genes are haplosufficient
• Transcription of the one active allele may be
  upregulated, generating protein levels adequate
  to produce the full phenotype.

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Incomplete Dominance

• Incomplete (partial) Dominance
• One allele not completely dominant to another
• Heterozygous phenotype intermediate between
  homozygous parents
• Recessive allele not expressed and in
  heterozygote dominant allele produces only enough
  gene product to produce intermediate phenotype
• Two doses of gene product needed for full
  phenotypic expression found in homozygous
  dominant individuals
• In homozygous recessive condition, phenotype of
  no gene expression results (ex. white flowers)

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Inheritance of Flower Color in Snapdragons

•  Pure breeding parents red R1R1 and white R2R2
• F1 hybrid all pink (R1R2) flowers
• F2 (R1R2 x R1R2)
• 25 red (R1R1),
• 50 pink(R1R2),
• 25 white (R2R2)

See also fig 4.3
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Underlying Cause of Incomplete Dominance in
Snapdragons

• R1 codes for functional enzyme
• R2 allele non-functional
• In heterozygote, the functional allele does not
  fully compensate for the nonfunctional allele
• Only half of normal amount of enzyme produced,
  pink pigment produced
• Enzyme is a limiting factor

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Codominance

• Codominance
• Heterozygote exhibits the phenotypes of BOTH
  homozygotes (not a phenotype intermediate to both
  parents)
• Functional products result from both alleles in
  a het.
• Ex. ABO, IA and IB alleles
• Both A and B antigen produced and displayed on
  RBCs

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Codominance

• The human M-N blood group involves red blood cell
  antigens that are less important in transfusions.
  There are three types
• Type M, with genotype LM/LM
• Type MN, with genotype LM/LN
• Type N, with genotype LN/LN

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Dominant and recessive alleles, and functionality

• Functional genes are typically dominant
• (a single allele sufficient to cause phenotype)
• Nonfunctional genes are typically recessive

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Wild Type and Mutant Alleles

• Wild Type alleles Most commonly found alleles in
  nature
• Typically code for functional product
• Typically dominant 
• Mutant alleles
• Typically result in loss of function of gene
  product
• Typically recessive

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Gene Interactions and Modified Mendelian Ratios

• In the dihybrid cross, if each allelic pair
  controls a distinct trait and exhibits complete
  dominance, a 9331 phenotypic ratio results
• Deviation from this ratio indicates that
  interaction of two or more genes is involved in
  producing the phenotype

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Two types of interactions occur

• Gene interactions that produce new phenotypes
• Epistasis One gene masks the expression of
  others and alters the phenotype
• Examples here are dihybrid, but in the real
  world larger numbers of genes are often involved
  in forming traits

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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
• Ex. Comb shape in chickens, fruit shape in summer
  squash

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Comb type in chickens

• Two loci each with dominant/recessive alleles
  interact to produce 4 phenotypes in 9331 ratio
  in F2 dihybrid cross
• ratio genotype phenotype
• 9/16 R_P_ walnut comb
• 3/16 R_pp rose comb
• 3/16 rrP_ pea comb
• 1/16 rrpp single comb

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Chicken Comb

• Interaction of alleles at 2 loci produces new
  comb shapes
• These interactions fit the expected ratios for a
  Mendelian dihybrid cross
• The molecular basis for each phenotype is
  unknown, but it appears that the dominant alleles
  R and P each produce a factor that modifies comb
  shape from single to a more complex form

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Generation of an F2 961 ratio in dihybrid cross
for fruit shape in summer squash
A cross between true-breeding spherical strains
(AAbb X aaBB) produces a disk-shaped F1
(AaBb) F2 9/16 disk-shaped (AB) 6/16
spherical (Abb or aaB) 1/16 long
(aabb) A dominant allele of either gene and
homozygous recessive genotype at other gene
yields sphere
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Epistasis

• In epistasis, one gene masks the expression of
  another, but no new phenotype is produced
• A gene that masks another is epistatic
• A gene that gets masked is hypostatic

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Several possibilities for interaction exist, all
producing modifications in the 9331 dihybrid
ratio

• Epistasis may be caused by recessive alleles, so
  that aa masks the effect of B (recessive
  epistasis)
• Epistasis may be caused by a dominant allele, so
  that A masks the effect of B (dominant epistasis)
• Epistasis may occur in both directions between
  genes, requiring both A and B to produce a
  particular phenotype (duplicate recessive
  epistasis)
• Aka. Complimentary gene action

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Recessive epistasis

• Occurs in coat color determination in rodents,
  which show
• Wild mice have individual hairs with an agouti
  pattern, bands of black (or brown) and yellow
  pigment.
• Agouti hairs are produced by a dominant allele,
  A.
• Mice with genotype aa do not produce the yellow
  bands, and have solid black hairs

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Hair Shaft from Animal with Agouti Phenotype
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Recessive epistasis

• C allele Responsible for development of any
  color at all
• Is epistatic over the agouti (A) locus.
• Mice with genotype cc (1/4 overall) will be
  albino, regardless of genotype at A locus
• In the cross AaCc X AaCc, the offspring will be
• i. 9/16 agouti (AC)
• ii. 3/16 solid (aaC)
• 4/16 albino
• (3/16 Acc, 1/16 aacc)

Recessive epistasis Generation of an F2 934
ratio for coat color in rodents
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Duplicate recessive epistasis (complementary gene
action)
For complementary gene action A homozygous
recessive genotype at either or both of two loci
is sufficient to mask dominant phenotype Need
at least one dominant allele at each locus for
dominant phenotype to be produced Both enzymes
in a pathway must be functional to produce product
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Duplicate recessive epistasis Generation of an
F2 97 ratio for flower color in sweet peas
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Review of Biochemical Pathways
When several genes form an enzyme pathway for
final product, each gene of pathway may influence
expression of other pathway genes Gene A Gene
B Gene C Gene D Substrate -gt -gt -gt
-gt Product
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Flower Color in Sweet Peas
Independent loci C and P Each codes for a
different enzyme for anthocyanin synthesis
pathway 
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Flower Color in Sweet Peas
Plants homozygous for a recessive allele at
either locus have white flowers because
pigment synthesis is blocked
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Flower Color in Sweet Peas
A double heterozygote has one functional allele
at each locus Both enzymes are made, the
pigment is made Plants have purple flowers
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Complementary Gene Action
Alternative explanation for complementary gene
action C and P each produce part of an
enzyme Must have one C and one P to have
functional enzyme
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Complementary Gene ActionF2 progeny of dihybrid
cross

• 9/16 A_B_ purple flowers (has both A and B
  enzymes functional)
• 3/16 aaB_ white flowers (defective A enzyme)
• 3/16 A_bb white flowers (defective B enzyme)
• 1/16 aabb white flower (defective A and B
  enzymes)
• F2 ratio 9 purple7 white

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Gene interactions

• Interactions between genes can produce many types
  of phenotypes. They are detected by deviations
  from expected phenotypic ratios. Table 4.3 shows
  examples
• The complex relationships of epistasis play a
  role in many human genetic disorders, further
  complicating their analysis

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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
• Recessive lethal alleles cause death
• An example is the yellow body color gene in mice

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Affects of Lethal Mutations on Mendelian Ratios

• Segregation of recessive lethal alleles
• Ex. coat color in mice
• A allele confers wild-type color (agouti)
• Ay allele
• Dominant with respect to producing yellow coat
  color
• Recessive with respect to determining life or
  death
• AA
• AAy
• AyAy

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Affect of Lethal Mutations on Mendelian Ratios

• If parents are heterozygous AAy
• Living progeny segregate
• 1/3 AA,
• 2/3 AAy,
• Absent class of progeny
• ¼ AyAy,
• When two heterozygotes are crossed and produce a
  21 ratio of progeny, a recessive lethal allele
  is suspected
• Q. The yellow variety never breeds true. T/F

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Molecular Structure of the Ay Recessive Lethal
Allele

• Agouti gene adjacent to Merc gene essential in
  embryonic development
•  Ay Allele 120,000 bp deletion, connects agouti
  gene with Merc promoter
• Deletes Merc gene loss of function
• Constitutively expresses agouti gene
• ? causing yellow gain of function

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Lethal Alleles

• Persistence of lethal alleles
• Recessive lethal alleles
• Dominant lethal alleles usually
• Delayed-action dominant lethal alleles may persist

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Human recessive lethal alleles

• Tay-Sachs disease, autosomal recessive, resulting
  from 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
• Enzyme deficiency prevents proper nerve function
• Hemophilia results from an X-linked recessive
  allele, and is lethal if untreated

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Human dominant lethal alleles

• Dominant lethals are rare, since death before
  reproduction would eliminate the gene from the
  pool
• Huntington disease
• Progressing central nervous system degeneration
• Phenotype is not expressed until individuals are
  in their 30s, death in 40s or 50s

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Gene Expression and the Environment

• Development of a multicellular 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
• Replication of genetic material
• Growth
• Differentiation of cells into types
• 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

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Penetrance

• Penetrance The frequency with which a dominant
  or homozygous recessive gene manifests itself in
  the phenotype of an individual
• Depends on both the genotype (e.g., epistatic
  genes) and the environment of the individual
• If all those carrying a dominant mutant allele
  develop the mutant phenotype, the allele is
• 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

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Non-Penetrance

• Phenotype not expressed even though gene for
  trait is present
• Ex. Recessive epistasis in mice
• Inhibitor C locus prevents agouti or black
  phenotype from developing from the A locus

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Illustrations of the concepts of penetrance and
expressivity in the phenotypic expression of a
genotype
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Human examples of Penetrance

• Brachydactyly involves abnormalities of the
  fingers, and shows 5080 penetrance
• Many cancer genes are thought to have low
  penetrance, making them harder to identify and
  characterize

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Expressivity

• Expressivity The degree to which a penetrant
  gene or genotype is phenotypically expressed in
  an individual
• Two individuals with the same mutation may
  develop different phenotypes, due to
• Like penetrance, expressivity depends on both
  genotype and environment

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Illustrations of the concepts of penetrance and
expressivity in the phenotypic expression of a
genotype
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Expressivity

• A human example is osteogenesis imperfecta,
  inherited as an autosomal dominant with nearly
  100 penetrance.
• Three traits are associated with the allele
• Blueness of the sclerae (whites of eyes).
• Fragile bones (to varying degree)
• Deafness
• Osteogenesis imperfecta shows variable
  expressivity, because an individual with the
  allele may have 1, 2 or all 3 of the above
  symptoms, in any combination

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Penetrance and Expressivity

• Some genes have both incomplete penetrance and
  variable expressivity. Ex. neurofibromatosis
• The allele is an autosomal dominant that shows
  5080 penetrance and variable expressivity
• Individuals with a penetrant allele show a wide
  range of phenotypes, from just spots on the skin
  to Neurofibroma tumors of various sizes and
  tumors of eye, brain or spinal cord
• Incomplete penetrance and variable expressivity
  complicate medical genetics and genetic
  counseling

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Illustrations of the concepts of penetrance and
expressivity in the phenotypic expression of a
genotype