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Text authored by Dr. Peter J. Russell
Slides authored by Dr. James R. Jabbur
CHAPTER 13
Extensions of & Deviations from
Mendelian Genetic Principles
Extensions of Mendelian Principles
can alter expected Mendelian ratios
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Sex Linkage (last chapter; we covered)
Multiple alleles
Codominance
Incomplete dominance
Polygenics
Genetic Interactions
 Between
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non-allelic genes on different loci
Environmental effects
Lethal alleles
Linkage
Multiple Alleles
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Although a gene only
exists in two forms in an
individual (alleles), many
forms exist in a population
(polymorphisms)
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The number of possible
genotypes in a multiple
allelic series depends on
how many alleles are
involved [n(n-1)/2]
ABO Blood Groups
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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
ABO inheritance follows Mendelian principles
Biochemistry of ABO Red Blood Cell grouping
 The ABO locus produces RBC antigens by encoding
glycosyltransferases, which add sugars to polysaccharides
on membrane glycolipid molecules (the H antigen)
Activity of the IA gene product, a-N-acetylgalactosamyl
transferase, converts the H antigen to the A antigen
 Activity of the IB gene product, a-D-galactosyltransferase,
converts the H antigen to the B antigen
Neither enzyme is present in an i/i individual, and so the
H antigen remains unmodified
Role of blood antigens and antibodies in blood transfusions
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Type AB blood is a
universal recipient,
but can only donate
blood to an AB
typed individual
Type O blood is a
universal donor,
but can only
receive blood from
type O, due to the
presence of anti-A
and B antibodies in
the serum
The H antigen and the Bombay blood type
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Production of the H antigen is controlled by a different
genetic locus from the ABO enzymes
Rarely, an individual lacks the dominant allele H needed
for H antigen production (h/h genotype)
This genotype results in the Bombay blood type, which is
similar to type O except that Bombay blood type individuals
produce anti-O antibodies that are not seen in true type O
individuals
Drosophila Eye Color
Drosophila has over 100
mutant alleles at the eye-color
locus on the X chromosome,
affecting the spectrum
between white and red eye
color in the fly
Alfred Sturtevant concluded
that eosin (pink) and white eye
color results from mutation in
a single gene encoding red
eye color (dominant)
In the cross to the right, the
eosin female and white male
produce eosin females. Thus,
the eosin allele is dominant to
the white allele
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In the cross to the right,
eosin-eyed F1 females
(we/w) were crossed with
wild-type, red-eyed males
(w+/Y)
All female progeny are redeyed (w+/w or w+/we)
Male progeny are either
eosin-eyed (we/Y) or whiteeyed (w/Y)
Thus, red-eye color is
dominant over eosin-eye color
or white-eye color
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Modifications of Dominance Relationships
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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
incomplete dominance, a heterozygote’s
phenotype will be intermediate between the two
possible homozygous phenotypes
 In codominance, the heterozygote shows the
phenotypes of both homozygotes
 At the molecular level, these relationships between
pairs of alleles depend upon patterns of gene
expression
 In
Incomplete Dominance
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Incomplete dominance is an allelic
relationship where dominance is only partial
In a heterozygote, the recessive allele is
not expressed. The one dominant allele is
unable to produce the full phenotype seen
in a homozygous dominant individual. The
result is a new, intermediate phenotype.
Examples include palamino color in horses,
flower color in snapdragons, coat color in
fowl and sickle-cell anemia in humans
Animation: Incomplete Dominance & Codominance
Palomino horses
When palominos are
interbred, their progeny are:
1⁄4 cremello (cream colored)
with the genotype Ccr/Ccr
1⁄2 palomino with genotype
C/Ccr
1⁄4 chestnut (full coat color)
with genotype C/C
The C allele allows for the
full expression of coat color
genes, while the Ccr allele
dilutes the expression of
coat color genes
Snapdragon flower color
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A cross between a
white-flowered plant
and a red-flowered
plant will produce all
pink F1 offspring.
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Self-pollination of the
F1 offspring produces
25% red, 50% pink and
25% white offspring.
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Note: the phenotype
ratio is 1:2:1
Andalusion Fowl
Codominance
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In codominance, the heterozygote’s phenotype includes
the phenotypes of both homozygotes
Examples of codominance include:
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The ABO blood series, in which a heterozygous IA/IB individual
will express both antigens, resulting in blood type AB
The human MN blood group, which involves red blood cell
antigens that are less important in transfusion. There are three
types:
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Type M, with genotype LM/LM
Type MN, with genotype LM/LN
Type N, with genotype LN/LN
Molecular Explanations of Incomplete
Dominance and Codominance
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Current explanations involve levels of gene expression for
each allele in the pair
In codominance, both alleles make a product, producing a
combined phenotype
In incomplete dominance, the recessive allele is not
expressed and the dominant allele produces only enough
product for an intermediate phenotype
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Dominant genetic disorders also exhibit incomplete dominance when
involving a gain-of-function phenotype (i.e. heterozygous oncogene)***
By contrast, a completely dominant allele creates the full
phenotype by one of two methods:
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It produces half the amount of protein found in a homozygous dominant
individual, but that is sufficient to produce the full phenotype. These
genes are haplosufficient
 Expression of the one active allele may be upregulated, generating
protein levels adequate to produce the full phenotype
Essential Genes and Lethal Alleles
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Some genes are required for life (essential
genes) and mutations in them may result in
death (lethal alleles)
 Roughly
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one-third of all genes are essential
Dominant lethal alleles result in the death of
both homozygotes and heterozygotes
Recessive lethal alleles cause death only
when homozygous
An example of lethality is the yellow body color
gene in mice (yup, body color?!?)
Example of a Lethal Gene: Yellow body color gene in mice
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Yellow crossed with non-yellow results in a ratio of 1
yellow:1 non-yellow. This suggests yellow is
heterozygous…
Yellow mice never breed true, another indication of
heterozygosity. But when yellow is bred with yellow,
the result is about 2 yellow:1 non-yellow (instead of
the predicted 3:1 ratio)
Castle and Little (1910) proposed that yellow
homozygotes die in utero and are therefore missing
from the progeny. The yellow allele has a dominant
effect on coat color but also acts as a recessive lethal
allele
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Yellow is an allele of the
agouti locus, designated AY.
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When heterozygotes are crossed
(AY/A+ X AY/A+), death of the
homozygous agouti (AY/AY)
results in a 2:1 ratio of progeny
(instead of a predicted 3:1 ratio)
 Thus, when two agouti
heterozygotes are crossed, a
recessive embryonic lethal allele
is suspected
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Agouti embryonic lethality is
caused by a lack of Raly activity
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The Ay allele results from the
deletion of an upstream sequence,
removing the normal promoter of
the aguoti gene. Thus, the gene is
transcribed from the upstream
promoter of Raly, producing an
abnormal and non-functional
transcript for Agouti and Raly
examples we have already discussed…
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Human examples of recessive lethal alleles are:
Tay-Sachs disease: 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.
 Hemophilia: results from an X-linked recessive allele, and
is lethal if untreated.
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A dominant lethal gene causes Huntington disease,
characterized by progressive central nervous system
degeneration. The phenotype is not expressed until
individuals are in their 30’s. Dominant lethals are
rare, since death before reproduction would eliminate
the gene from the pool
Gene Expression and the Environment
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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:
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Replication of genetic material
Growth
Differentiation of cells into types
Arrangement of cell types into defined tissues and organs
Internal and external environmental factors interact with
the genes by controlling their expression and interacting
with their products
Penetrance and Expressivity
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Penetrance describes how completely the
presence of an allele corresponds with the
presence of a trait (yes or no)
It 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
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 has 80%
penetrance
 Human examples include:
 Brachydactyly involves abnormalities of
the fingers, and shows 50–80%
penetrance
 Many cancer genes are thought to have
low penetrance, making them harder to
identify and characterize
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Expressivity describes variation in the expression
of a gene or genotype in individuals (how much?)
 Two individuals with the same mutation may
develop different phenotypes, due to variable
expressivity of that allele.
 Like penetrance, expressivity depends on both
genotype and environment, and may be
constant or variable
 Human example: Osteogenesis imperfecta is
inherited as an autosomal dominant with nearly
100% penetrance. However, it has variable
expressivity
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Some genes have both incomplete penetrance and variable expressivity
 Neurofibromatosis is an autosomal dominant disorder with 50-80% penetrance and
variable expressivity
 Individuals with the disease show a wide range of phenotypes
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Incomplete penetrance and variable expressivity complicate medical genetics and
counseling
Effects of the Environment
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Age of onset is an effect of the individual’s
internal environment. Different genes are
expressed at different times during the life
cycle, and programmed activation and
inactivation of genes influences many traits
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Human examples include:
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Pattern baldness, appearing in males aged 20–30 years
Duchenne muscular dystrophy, appearing in children aged
2 to 5 years
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Sex of the individual affects the expression of some
autosomal genes
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Sex-limited traits can appear in one sex but not the other
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Examples include:
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Milk production in dairy cattle, where both sexes have milk genes,
but only females express them
Facial hair distribution in humans
Sex-influenced traits appear in both sexes, but the sexes
show either a difference in frequency of occurrence or an
altered relationship between genotype and phenotype
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Examples include:
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Pattern baldness, controlled by an autosomal gene that is
dominant in males and recessive in females
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The genotype b/b produces pattern baldness in both men and women
The genotype b+/b+ gives a non-bald phenotype in both sexes
The genotype b+/b will lead to the bald phenotype in men, and the
non-bald phenotype in women.
Cleft lip and palate (2:1 ratio of males to females)
Gout, rheumatoid arthritis, osteoporosis, lupus (ratios vary)
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Temperature may alter the
activity of enzymes so that they
function normally at one
temperature but are nonfunctional
at another
The Siamese phenotype occurs in
cats homozygous for the
recessive allele (cS) of the albino
(C) locus, which encodes a
tyrosinase
Tyrosinase is required in the
melanin synthesis pathway.
Activity of the tyrosinase encoded
by cS is temperature sensitive
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Kittens are uniformly warm, and so stay
light colored
 As cats grow, extremities become
cooler, and tyrosinase becomes active,
allowing melanin to be made and fur on
the points to become darker
Anybody see
a mouse?
Obviously, chemicals can have significant
effects on physiology
 Phenylketonuria (PKU) is an autosomal
recessive defect in the metabolism of the
amino acid phenylalanine
 If the defect is not treated by restricting
phenylalanine in the diet, severe mental
retardation and other symptoms result
 Cells respond differently to folic acid and
retinoic acid*** (next slide)
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Sidney Farber, M.D.
Nature versus Nurture
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Phenotypes seen for many traits are influenced
by both genes and the environment
Some human examples include:
 Human
height (diet, health, physical fitness)
 Alcoholism (adopted children and foster parent rates)
 Intelligence (good schools and nutrition)
Maternal Effect
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Some maternally derived phenotypes are produced
by the maternal nuclear genome rather than
inherited as extranuclear genes (maternal effect v.
maternal inheritance)
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Proteins/mRNA deposited in the oocyte direct early
embryo development by turning on/off nuclear genes
An example is shell coiling in the snail, where the
maternal dominant D allele produces a right handed
coil (maternal recessive d produces left)
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At the molecular level, shell coiling is directed by the
orientation of the mitotic spindle in the first mitotic division
following fertilization
Animation: Maternal Effect
Determining the Number of Genes Involved in
a Set of Mutations with the Same Phenotype
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The relationship between a phenotype and a gene can
be studied through mutants identified by a unique
phenotype relative to wild-type
The complementation test (cis-trans test) determines
whether independently isolated mutations for the same
phenotype are in the same or different genes by crossing
two mutants
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If mutations are in different genes, the phenotype will be wildtype (complementation)
If mutations are in the same gene, the phenotype will be mutant
(no complementation)
Drosophila provides an example…
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The genes encoding body
color are ebony and black.
Wild-type body color is
grayish yellow. If two truebreeding mutant, blackbodied strains are crossed,
all F1 are wild type due to
complementation
Gene Interactions & Modified Mendelian Ratios
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Phenotypes result from complex
interactions of molecules under genetic
control
Deviation from expected Mendelian ratios
indicates that interaction of two or more
genes is involved in producing the
phenotype
Two types of interactions occur:
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Different genes control the same general trait,
collectively producing a phenotype
One gene masks the expression of other(s) and alters
the phenotype (epistasis)
Gene Interactions That Produce New Phenotypes
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Non-allelic genes that affect the same
characteristic may interact to give novel
phenotypes, and often modified phenotypic
ratios (from the usual dihybrid 9:3:3:1 ratio)
 An example is eye color in Drosophila, in
which 2 loci (bw and st) are involved
At least one wild-type allele for each locus must be
present to produce wild-type red eyes
 The bw locus encodes a red pigment
 The st locus encodes a brown pigment
 Flies mutant for both bw and st have white eyes

Epistasis
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In epistasis, one gene masks the expression of
another, but no new phenotype is produced
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A gene that masks another is epistatic
A gene that gets masked is hypostatic
Several possibilities for interaction exist, all producing
modifications in the 9:3:3:1 dihybrid ratio:
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Epistasis may be caused by recessive alleles, so that a/a
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 genetic loci to produce a particular phenotype
(duplicate epistasis; dominant or recessive types)
…summary of epistatic ratios from heterozygote cross
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An example of recessive
epistasis is exhibited in coat
color determination in
rodents
Wild-type mice have
individual hairs with an
agouti pattern (bands of
black/brown and yellow
pigment). Agouti hair is
produced by a dominant
allele (A)
The B allele encodes a
tyrosinase-related protein,
which produces black
(dominant) or brown
(recessive) pigment
The C allele encodes a
tyrosinase and is responsible
for the development of any
color at all, so it is epistatic
over A and B
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Another example of
recessive epistasis is
exhibited in coat color
determination in labrador
retrievers
The B gene produces
black (dominant) or brown
(recessive) pigment
E facilitates expression of
the aforementioned gene;
e does not
An example of dominant epistasis is provided by summer
squash fruit…
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The theoretical
biochemical pathway
below postulates
genetic dominance
Yellow is recessive to
White but is dominant
to Green
An example of duplicate recessive epistasis, or complementary
gene action, is flower color determination in sweet peas
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The theoretical
biochemical pathway
above postulates
genetic dominance
The c/c alleles
determine whether the
flower will have color;
the P allele
determines whether
purple is produced
Extranuclear Inheritance
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Extranuclear DNA is found in mitochondria and chloroplasts
Their genes encode rRNA for ribosomes of the organelles, tRNAs
and a few organelle proteins whose functions are related to energy
generation and photosynthesis
Extranuclear genes exhibit non-Mendelian inheritance (this genetic
material is contributed by the female in the oocyte)
Mutations in mtDNA can produce human genetic disorders. Examples
include:
 Leber’s hereditary optic neuropathy (LHON). Optic nerve
degeneration results in complete or partial blindness in midlife
adults.
 Kearns-Sayre syndrome produces three types of neuromuscular
defects, for example heart disease
In most mtDNA disorders, cells of the affected individuals have a mix
of normal and mutant mitochondria (heteroplasmy)