Beyond Mendel…

• Since Mendel’s work was rediscovered in

the early 1900’s:
• Researchers have studied the many ways genes
influence an individual’s phenotype
• These investigations are called neo-Mendelian
genetics (neo from Greek for “new”)
• Chapter 4 examines types of inheritance
observed by researchers that did not conform to
the expected Mendelian ratios
 Extensions of Mendelian
Genetics
• How alleles affect phenotype
– Not always simple dominant/recessive issue
• Gene interaction
– Phenotype controlled by more than one gene
• Sex-linked genes (X-linkage in X/Y
organisms)
• Phenotype can depend on more than
genotype
– Environmental effects
 Alleles
• Alleles are alternate forms of the same gene
– 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
– Wt allele used as “standard” for comparison of
all mutations (alternative alleles) of the
gene/locus
 Mutations
• Mutation
– Ultimate source of new alleles
– Genetic information is modified
• often (not always) produces altered gene product
– New phenotypes result from changes in functional
activity of gene product
• Eliminating enzyme function
• Changing relative enzyme efficiency
• Changing overall enzyme function
– E.g. enzyme specificity
 Allele Symbols
• For simple Mendelian traits:
• 1st letter of recessive form
• Lowercase = recessive allele
• Uppercase = dominant allele
• Other systems: Drosophila
• Use 1st letter of mutant allele (or combination of 2 or 3
letters) to name all alleles at this locus
• If trait is recessive, use lowercase; uppercase if
dominant
• Wild-type is indicated by the same letter (s), but with a
superscript “+” (e.g. Wr and Wr + for wrinkled and wt
wing alleles), or when using /, Wr/+ for heterozygote
 Drosophila Conventions (cont.)
• Example: body color
• Ebony mutant phenotype is indicated by e
• Normal gray (wild-type) is indicated by e+
• Three possible genotypes:
• e+/e+ : gray homozygote (wild type)
• e+/e : gray heterozygote (wild type)
• e /e : ebony homozygote (mutant)
• Or the above could be simple +/+; +/e and e/e
 More Conventions…
• The Drosophila system can be applied to other
organisms as well:
• When no allelic dominance, uppercase letters and
superscripts designate alternate alleles
• R1 and R2, LM and LN
• There are other systems of genetic nomenclature:
• leu - for bacteria with mutation blocking leucine
biosynthesis
• BRCA1 for a human gene associated with inheritied
risk of breast cancer
 Incomplete Dominance
• Cross between two parents with contrasting
traits
• Offspring with an intermediate phenotype
• incomplete or partial dominance
• Example: red snapdragon crossed with white
snapdragon
• F1 offspring have pink flowers
• F2 generation (Fig. 4.1), ¼ are red, ½ are pink, and
¼ are white
• Note: phenotypic and genotypic ratios are the same
• Each genotype has its own phenotype
 Incomplete
Dominance
• red x white P1 generation
– pink F1
– 0.25/0.50/0.25 ratio of
red/pink/white in the F2
generation
 Incomplete Dominance
• Clear-cut [visual] examples of incomplete
dominance are relatively rare
• However, heterozygotes exhibiting wild-type
phenotype may have intermediate level of
gene expression
• Example: Tay-Sachs disease
• Homozygous recessives die from fatal lipid-
storage disorder, hexosaminidase activity absent
• Heterozygotes appear normal, but have ½ wt
enzyme activity when compared to homozygous
normal non-carriers
• Threshold effect…
 Codominance
• Codominance
• two alleles at a locus produce different and
detectable gene products in heterozygote
• No dominance or recessiveness
• No “blended” phenotype (not incomplete
dominance)
• Example: MN blood group in humans
• Red blood cell glycoprotein surface antigen
has two forms (M and N)
• An individual may exhibit either or both
 Multiple Alleles
• 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
• Any gene can be modified in multiple places/ways,
• each unique change produce a different allele (but not
necessarily different phenotype)
• NOTE: multiple alleles studied in populations, not
individuals
• Classic example is human ABO blood groups
 ABO Blood Groups

• Human ABO blood groups provide example of a

multiple allele situation
• A and B antigens present on surface of blood cells
(similar to MN blood group antigens)
• A and B antigens controlled by gene on chromosome 9
• By 1924, studies of blood types of many families
suggested that 3 alleles of a single gene were
responsible for ABO phenotypes
 Review of ABO blood groups
• Phenotype of individual determined by mixing blood
sample with antiserum containing type A or type B
antibodies
• Four possible phenotypes:
• Person has A antigen only (A phenotype)
• Person has B antigen only (B phenotype)
• Person has both antigens (AB phenotype)
• Person has neither antigen (O phenotype)
• Sample crosses in Table 4.1
• Note that a cross of a type A person with a type B
person can give offspring of all 4 possibilities
 ABO Antigens

• H substance is
possessed by all and is
the precursor for both
the A and B antigens
– A antigen has an added
N-acetylgalactosamine
– B antigen has an added
galactose
 The Bombay Phenotype

• Woman typed as type O, but

– One parent has type AB blood and
– She is an obvious IB allele donor to two children…
• Woman subsequently found to be homozygous
FUT1 at the fucosyl transferase locus
– No fucose on H substance, no substrate to make A or
B antigens
– Example of epistasis (more later)
 Bombay Pedigree

• Family pedigree
showing inheritance of
Bombay allele
 Multiple Alleles
• Although ABO blood types in humans is
considered a classic example of multiple
alleles, most all loci exhibit this
phenomenon
– Eye color locus for Drosophila (Morgan’s
famous white-eyed mutant) has over 100
known alleles
 Lethal Alleles
• Many gene products are essential to survival
of an organism
– Lethal alleles represent “essential genes”, lethal in
homozygous state
• Time of death is dependent upon when the gene
product is essential to development
– Loss of function alleles can be recessive lethal (often
are)
• Heterozygotes may tolerate a non-functional mutant
allele if wt allele produces sufficient product for
organism survival
• Sometimes recessive lethal are still dominant with
respect to phenotype
 Lethal Alleles
• Example: agouti (coat color) in mice
agouti x agouti  all agouti
yellow x yellow  2/3 yellow, 1/3 agouti
agouti x yellow  ½ yellow, ½ agouti
– Explanation: mutant yellow dominant over wt agouti
and homozygous agouti lethal. Mutant allele always
on (gain of function), deletion actually affects
neighboring essential gene
Agouti
Allele
 Lethal Dominant Mutations
• Both homozygous and heterozygous states are
lethal
• Generally very rare
• Example: Huntington disease (humans)
– Nervous and motor system degeneration
– Commonly begins to be exhibited after age forty (but
can be much earlier)
• Children already born
• Afflicted persons are heterozygous (Hh)
 Crosses of Two Gene Pairs with
Different Modes of Inheritance

• E.g. autosomal recessive locus with a

codominance locus
• Remember: although the 9:3:3:1 ratio will be
altered, all unlinked loci will still follow
Mendel’s principle of independent assortment…
• Regular Punnett square and determine
phenotypes individually or forked method
 Dihybrid
cross with
two loci
having
different
patterns of
inheritance
 Epigenesis
• Many phenotypes affected/controlled by more
than one gene
– “gene interaction” (occurs at many levels for many
reasons)
• Epigenesis
– Development is a cascade of events
– Each ensuing step of development increases the
complexity of the organ and is under the
control/influence of many genes
 Epistasis
• Epistasis
– The effect of one gene pair (locus) masks or modifies
the effect of another gene pair
• Examples
– Recessive alleles at one locus override expression of
alleles at another locus. Alleles at 1st locus are said to
be epistatic to the masked hypostatic alleles at the 2nd
locus
– Allele(s) at one locus may require specific allele at
another locus, these pairs are said to complement each
other
• The FUTI allele and ABO phenotype is an
example of epistasis
FUTI and
ABO
Phenotype
 Analyzing Other “Unique”
Inheritance Patterns
• Assumptions/conventions
– In each case distinct phenotypes are produced
(discontinuous variation)
– Genes are not linked
– Complete dominance at any locus, unknown
genotypes of dominant phenotypes recorded as A-
or B- (AA or Aa, BB or Bb)
– All P1 crosses involve homozygous individuals
– F2 phenotypes are 9/16 A-B-, 3/16 A-bb, 3/16aaB-
and 1/16 aabb (dominance makes genotypes in
group phenotypically equivalent)
 Coat Color in Mice

• Agouti (A) is wt and caused by alternating

bands of pigment on each hair
• Black (a) is recessive to agouti
• B locus mutation (recessive, b) can eliminate all
color
– Albino (bb) and A locus “doesn’t count”
 Coat Color in Mice

• Cross agouti (AABB) and albino (aabb) mice

• F1 are all agouti (AaBb)
• F2 progeny have 9:3:3:1 ratio but…
– 9/16 have genotype of A-B- and are agouti
– 3/16 are A-bb and are albino (make pigment, no “B”)
– 3/16 are aaB- and are black
– 1/16 are aabb and are albino (no pigment, no “B”)
• Final phenotypic ratio is 9:4:3
• Explanation….
 One Explanation for Epistasis
• Colorless precursor converted to back
pigment by wt B gene product
• Black pigment deposited to hair in agouti
pattern by gene A product
• Since a recessive allele at one locus (b)
masks/supresses the expression of the
dominant allele at another locus this is
called recessive epistasis
 Dominant Epistasis

• Dominant allele at one locus suppresses/masks

expression of alleles at another locus
• Example: fruit color in summer squash
– Allele A is dominant and gives white fruit
– If aa, Bb/BB gives yellow, bb gives green
– Cross AABB with aabb, F2 is AaBb, cross F2
– Final phenotypic ration is 12 white, 3 yellow and 1
green (see figure 4-7 and analyze to see why)
 White-flowered Sweet Peas

• Complementary gene interaction

– Must have at least one dominant allele at each locus (A-B-)
to have the phenotype
• Cross two white-flowered peas
– all F1 are purple
– F2 was 9/16 purple, 7/16 white
• Explanation: multiple enzyme pathway
– Precursor converted to intermediate by Gene A product
– Intermediate converted to purple pigment by Gene B product
 Fruit Shape in Summer Squash
• Disk-shaped fruit (AABB) crossed with long
fruit (aabb)
• F1 is all disc-shaped fruit
• F2 includes both parental phenotypes plus
spherical variants in 9:6:1 ratio
– 9/16 A-B- disc
– 3/16 A-bb sphere, 3/16 aaB- sphere
– 1/16 aabb long
– Disc requires dominant alleles at both loci, sphere
requires a dominant allele at one/either locus and no
dominant alleles at either locus give long
 Eye Color in Drosophila
• Wt color is brick red
• Cross two autosomal recessive mutants (brown and
scarlet)
– F1 is wt color
– F2 has wild scarlet brown and white in a 9:3:3:1 ratio
• Mendelian ratio… but only one character involved (eye color)
• Explanation
– Wt is two pigments deposited into compound eye
– Brown mutant and scarlet mutant are blocked in respective
pigment pathways
– Both pathways blocked yields white eyes
 Epistasis and
Drosophila Eye
Color
Modified Dihybrid F2 Ratios
 Modified Ratios
• Note that although many ratios are possible
for the dihybrid crosses, in all cases
segregation and independent assortment
rules are not violated
• Genotypic ratios remain the same and
therefore phenotypic ratios expressed in
1/16ths as before
• What changes is how you convert
genotypes to phenotypes
 Pleiotrophy
• One gene has effect(s) on multiple phenotypes
• Many examples
– Cystic fibrosis
– Marfan syndrome
– Porphyria variegata
• Cannot metabolize porphyrin, deep red urine
• Becomes toxic to brain (also abdominal pain muscular
weakness fever insomnia headaches vision problems,
delerium, etc.)
• King George III of England (U.S. Revolution) may have
suffered from condition
 Chromosome-based Sex
Determination
• X,Y system used for sex determination by many
animal and plant species
– X is a large chromosome and encodes many genes
– Y is a small chromosome with few genes (not
homologous to X in the traditional sense but has
pairing region for synapsis)
– Males therefore have a single copy of genes encoded
by the X chromosome, hemizygous
• These genes have unique inheritance/expression
properties resulting from their “X-linkage”
 X-linkage in Drosophila

• First documented by Thomas Morgan, 1910

– White-eyed mutant
– Inheritance pattern clearly related to sex of
parent carrying allele and offspring
– See figure 4-11
 Inheritance of
White-eyed Trait
• Results depend of sex of
red and white-eyed
members of P generation
• In each case ½ of F1 is
red and ½ is white (but
all red are female and
white are male)
• F2 results also sex-
dependent
X-linkage and Chromosomes
 X-linkage and Humans

• Many traits controlled by X chromosome-linked

traits
– Red/green color blindness is classic example
– Numerous significant genetic-based diseases
– Only females are carriers of recessive alleles
• Males are hemizygous
 Pedigree

Likely Genotypes
Sex-based Influences On Phenotype

• Sex-limited inheritance
– Specific phenotype limited to one sex
• Sex-influenced inheritance
– Sex influences expression of phenotype but not
limited to one sex or another
– Known examples are autosomally-encoded by
expression is dependent upon hormone
constitution of individual (sex)
 Fowl Feathering
• Cock feathering is longer, more curved and pointed
• Hen feathering is shorter and more rounded
• Inheritance of this phenotype is controlled by a pair of alleles (H
and h) at a single autosomal locus
– But actual expression can be modified by the individual’s sex hormones
HH male – hen feathered HH female – hen feathered
Hh male – hen feathered Hh female – hen feathered
hh male – cock feathered hh female – hen feathered
• H is dominant over h, h only expressed in males, some populations
fixed for one or the other allele,
 Other Sex-limited and Sex-
influenced Inheritance
• Autosomal genes responsible for milk yield
in dairy cattle are sex limited
– Independent of genotype, bulls give no milk
• Pattern baldness in humans and horn
formation in Dorsett Horn sheep is sex-
influenced
– E.g. in BB women hair loss is reduced and
occurs later than in BB men, Bb women
generally not affected
 Phenotype Is Not Always a Direct
Reflection of Genotype

• Penetrance – the percentage of individuals that

show at least some degree of expression of the
mutant genotype
– Partial penetrance
• Expressivity – the range of expression of the
mutant phenotype (see Fig. 4-16)
– Can be the result of either or both genetic
background differences or environmental effects
 Expressivity

• “Eyeless” mutation in
Drosophila
– Reduces eye size from a partial
reduction to complete elimination
(average 0.25 to 0.50)
 Genetic Background Effects

• Genetic suppression – mutant allele at a locus

partially or completely restores the wt
phenotype of another locus homozygous (or
hemizygous) for a mutant allele
• Position effect – the physical location of a gene
influences its expression (relative position to
other genetic material
– Translocations or inversions
– Heterochromatin effects…
 Position Effect

• (a) female heterozygote for

white eye genotype
showing normal dominant
phenotype
• (b) chromosomal
rearrangement leading to
variegated effect (also
female heterozygote for
white eye)
 Environmental Effects
• Temperature effects
– Evening primrose produces red flowers at 23C and
white flowers at 18C
– Siamese cats and Himalayan rabbits have darker fur on
cooler areas of body (tail, feet, ears)
• Enzymes lose catalytic function at higher temperature
• Temperature sensitive mutations
– Mutant allele only expressed (phenotype) at
[generally] lower temperature
– ts phage mutants, restrictive and permissive
temperatures
• Heat-shock genes
 Nutritional Effects
• Nutritional mutations
– Prevent synthesis of nutrient molecules
– Auxotrophs
– Phenotype expressed or not depending upon the diet
• Phenylketonuria
– Loss of enzyme to metabolize phenylalanine
– Severe problems unless low Phe diet
• Galactosemia (very bad again) and lactose
intolerance (unpleasant)…
 Delayed Onset of Phenotypic
Expression
• Tay-Sachs disease
– Autosomal recessive
– Hexosaminidase A, lipid metabolism, baby normal for
a few months, dies by age 3
• Lesch-Nyhan syndrome
– X-linked recessive
– Purine salvage enzyme defect (HGPRTase)
– Normal for about 6 months, then…
• Duchene muscular dystrophy
– X-linked recessive
– Diagnosed 3-5 years old
 Delayed Onset - Dominant
• Huntington disease
– Autosomal dominant
– Progressive cell death in brain, generally over
10 year period, ultimately lethal
– Onset commonly between age 30-50 (mean age
of 38)
 Genetic Anticipation
• Genetic anticipation
– Phenotype exhibits a progressively earlier age of
onset and increased severity with each successive
generation
• Myotonic dystrophy
– Autosomal Dominant
– Most common type of adult muscular dystrophy
– Trinucleotide expansion, 5-35 copies normal, 35-
150 somewhat affected, 1500 severely affected
• Number of repeats increases with each generation
• Fragile X and Huntington disease also show correlation
between number of repeats and severity
 Genetic Imprinting
• Genomic or parental imprinting - phenotypic
expression depends upon the parental origin of
the chromosome carrying the particular allele
– Certain chromosomal regions imprinted during
gametogenesis
• Methylation of CpG or CpG islands (5meC produced)
• Prader-Willi and Angelman syndromes
– Different/unique phenotypes
– Both loci in 15q1 region
– One maternally-imprinted, other paternally-imprinted
• Uniparental disomy