Extensions of Mendelian Genetics

Extensions to Mendelian
• Multiple alleles
• Modifications of dominance relationships
• Gene interactions
• Essential genes, lethal genes
• Gene expression and environment
 Incomplete Dominance
• Dominance is only partial, one dominant
allele is unable to produce the full
phenotype seen in homozygous dominant
individual.
• Example: plumage color in chickens.
Fig. 12.3, In complete dominance in chickens
Different types (modifications) of dominance relationships:

3. Codominance

1. Alleles are codominant to one another.

2. Phenotype of the heterozygote includes the phenotype of both

homozygotes.

3. e.g., ABO blood groups & sickle-cell anemia

Fig. 4.7
 Multiple alleles
• Genes have multiple
alleles.
• WHY?
• Do different alleles
produce different
phenotypes?
 ABO blood groups
• ABO blood groups; A, B, AB, and O

• IA and IB are dominant to i, while IA and IB

are codominant.
 ABO types
Phenotype Genotype RBC-antigen antibody present in
blood

O i/i none (H) anti-A & B

A IA/ IA or IA/i A anti-B

B IB /IB or IB /i B anti-A

AB IA/IB A and B none

ABO inheritance is Mendelian:

Possible parental genotypes for type

O offspring:

1. i/i x i/i

2. IA/i x i/i

3. IA/i x IA/i

4. IB/i x i/i

5. IB/i x IB/i

6. IA/i x IB/i
 Biochemical basis of ABO
• ABO locus produces RBC antigens by
encoding glycosyltransferases, which add
sugars to an existing polysaccharide on
membrane glycolipids. These
polysaccharides act as the antigen in ABO
system.
 H Antigens
• Most people have an H antigen, a glycolipid, on
blood cells.
• Activity of the IA gene product converts H antigen
to the A antigen by adding the sugar alpha-N-
acetylgalatosamine to H.
• Activity of the IB gene product converts H antigen
to the B antigen by adding the galactose to H.
– Both enzymes are present in AB individual.
– Neither enzyme is present in O individuals.
 Molecular basis of ABO
• blood group O allele differs from the blood
group A allele by deletion of guanine-258.
The deletion, occurring in the portion of the
gene encoding the part near the N terminus
of the protein, causes a frameshift and
results in translation of an almost entirely
different protein. The latter protein is
incapable of modifying the H antigen.
 Molecular basis of ABO
• Yamamoto et al. (1990) found 7 nucleotide
differences between the alleles that code for the A
and B glycosyltransferase enzymes: 4 of the
nucleotide differences were accompanied by
change in amino acid residue in the transferase.
The A gene had A, C, C, G, C, G, and G as
nucleotides 294, 523, 654, 700, 793, 800, and 927;
the B gene was found to have G, G, T, A, A, C,
and A at these positions.
 Drosophila Eye Color
• Drosophila has over 100 mutant alleles at
the eye-color locus on X chromosome.
– The white eyed variant allele is designated as
w.
– The wild type allele is w+
– A recessive allele, we, produces eosin (reddish-
orange) eyes.
 Eosin x White
P Cross w (X) Y

we (X) we/w we/Y

XX XY

we (X) we/w we/Y

XX XY
 F1 x Wild type
w+(X) Y

we (X) we/w+ we/Y

XX XY

w (X) w/w+ w/Y

XX XY
 Number of alleles, number of
genotypes
# alleles # genotypes Homozygotes Heterozygotes
1 1 1 0

2 3 2 1

3 6 3 3

4 10 4 6

5 15 5 10

N(N+1)/2 genotypes; N homozygotes, and N(N-1)/2 heterozygotes

 Molecular basis of multiple
alleles
Drosophila homozygote Phenotype Relative eye pigment
w+ wild type 1.0000
w white 0.0044
wt tinged 0.0062
wa apricot 0.0197
wbl blood 0.0310
we eosin 0.0324
wch cherry 0.0410
wa3 apricot-3 0.0632
ww wine 0.0650
wco coral 0.0798
wsat satsuma 0.1404
wcol colored 0.1636
 ABC transporters
• The most intensively studied ABCG gene is the
white locus of Drosophila. The white protein,
along with brown and scarlet, transports
precursors of eye pigments (guanine and
tryptophan) in the eye cells of the fly. The
mammalian ABCG1 protein is involved in
cholesterol transport regulation (18). Other ABCG
genes include ABCG2 , a drug-resistance gene;
ABCG5 and ABCG8 , coding for transporters of
sterols in the intestine and liver.
The Drosophila compound eye.
(a) relative positions of cells in an
ommatidium of the adult compound
eye.
(b) Electron micrograph of a cross-
section through an ommatidium. Note
the large pigment granules (PG) in
pigment cells. Small pigment granules
(pg) are located close to the base of
the rhabdomeres (Rh), the
photosensitive stacks of microvilli in
photoreceptor cells.
(c) Light micrograph of a section
through a compound eye that is
mosaic for deep orange. The
approximate boundary between the
deep orange (-/-) and wild-type (+/-)
tissue is indicated. Note the absence of
red pigment granules in the part of the
eye that lacks deep orange function
(-/-).
 Different types of dominance
• Incomplete dominance
• Codominance
• Complete dominance
 Molecular basis of dominance
• 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.
• Completely dominant allele creates full phenotype either
by
– Producing half the amount of protein found in homozygous
dominant individual but that is sufficient to produce the full
phenotype (haplo-sufficient alleles).
– Expression of the one active allele maybe upregulated,
generating protein levels adequate to produce the full phenotype.
 Molecular Basis of Recessive
Mutations
• Recessive mutations usually result from partial or
complete loss of a wild type function.
– Amorphic alleles are those that have completely lost
the function. An example would be a mutation in which
production of pigment is completely lost in the
homozygous state, causing albinism.
– Hypomorphic alleles are those in which function is
reduced, but not completely lost. An example would be
a mutation that causes a partial loss of pigmentation,
giving a lighter color when homozygous.
 Molecular Basis of Dominant
Mutations
• Are also called gain-of-function alleles.
– Hypermorphic alleles are those that cause excess product to
be produced.
– Antimorphic alleles are those that produce an altered gene
product that "poisons" or disrupts the function of the normal
gene product.
– Neomorphic alleles cause the gene product to be expressed
in the wrong types of cells, and can have drastic effects,
such as that of the antennapedia gene that coverts the
antennae of flies into legs.
– Haplo-insufficient alleles. In this case, loss of a gene product
causes a recognizably different phenotype in the
heterozygote (homozygous can be lethal).
Gene interactions and modified Mendelian ratios:

Phenotypes result from complex interactions of genes (molecules).

e.g., dihybrid cross of two independently sorting gene pairs, each
with two alleles (A, a & B, b).
9 genotypes (w/9:3:3:1 phenotypes):

1/16 AA/BB
2/16 AA/Bb
1/16 AA/bb
2/16 Aa/BB
4/16 Aa/Bb
2/16 Aa/bb
1/16 aa/BB
2/16 aa/Bb
1/16 aa/bb
Deviation from this ratio indicates the interaction of two or more
genes producing the phenotype.
 Two types of interactions
• Different genes control the same trait,
collectively producing a phenotype.
• One gene masks the expression of others
(epistasis) and alters the phenotype.
 Gene Interactions that produce
new phenotypes
• None allelic genes affect the same
characteristic may interact.
– Comb shape in chickens, influenced by two
gene loci, produce four different comb types.
• Rose-comb
• Pea-comb
• Single-comb
• Walnut-comb
Fig. 12.6
 Hypothesize a mechanism for
these interactions
• Two dominant alleles, two recessive alleles.
• Two genes affect comb shape but different aspects
of it.
– When either gene is not expressed, single shaped; so
these genes are only necessary for modifying the shape
not for the presence of a comb.
– When one of the genes expressed only, a particular
phenotype occurs.
– When both genes are expressed, a novel modified
phenotype occurs.
 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.
 All are modifications of 9:3:3:1
• 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.
• Epistasis may occur in both directions between
genes, requiring both A and B to produce a
particular phenotype (duplicate recessive
epistasis).
 Recessive Epistasis (9:3:4)
• Banding pattern character (A)
– 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 a/a do
not produce yellow bands, and have solid-
colored hairs.
 Recessive Epistasis
• Hair color character (B, and C)
– The B allele produces black pigment, while b/b mice
produce brown pigment. The allele A is epistatic over
B and b, in that it will insert bands of yellow color
between either black or brown.
– The C allele is responsible for development of any
color at all, and so it is epistatic over both the agouti
(A) and the pigment (B) gene loci. A mouse with
genotype c/c will be albino, regarless of its genotype at
the A and B loci.
Fig. 12.9,
Recessive epistasis
F2: 9:3:4

(all mice have B)

 Essential genes, 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
both homozygotes and heterozygotes.
 Yellow body color in mice
• Wild type agouti mice express the agouti gene
only during hair development in the days after
birth, and when plucked hair is being regenerated.
Gene expression is seen in no other tissues and at
no other time.
• Heterozygous mice (Ay/A+) express Ay allele at
high levels in all tissues during all developmental
stages. Tissue specific regulation appears to be
lost in the Ay allele.
 Agouti Gene
• The agouti gene has been cloned recently
and is thought to encode a signaling
molecule that directs follicular melanocytes
to switch from the synthesis of black
pigment, eumelanin, to yellow pigment,
phaeomelanin.
 Ay allele
• Its transcript RNA is 50% longer than that of the
wild type A+; because:
– The Ay allele results from deletion of an upstream
sequence, removing the normal promoter of the agouti
gene.
– The gene is transcribed from the promoter of an upstream
gene called Raly. The beginning of the sequence
encoding Raly is fused with the agouti gene, producing a
longer transcript.
– Embryonic lethality of Ay/Ay mice probably results from
lack of Raly gene activity, rather than from the defective
agouti gene.
Examples of human lethal alleles
• Tay-Sachs disease, resulting from an inactive gene
for the enzyme hexosaminidase. Homozygous
individuals develop neurological symptoms before
1 year of age.
• Hemophilia results from and X-linked recessive
allele, lethal when untreated.
• Dominant lethal allele causes Huntington disease,
characterized by progressing central nervous
system degenaration.
Fig. 12.11, Lethal alleles in mice,
Yellow body color
 Gene Expression and
Environment
• Replication of genetic material
• Growth
• Differentiation of cells into types
• Arrangement of cell types into defined
tissues and organs
 Penetrance
• How completely the presence of an allele
corresponds with the presence of a trait. 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 (100%) penetrant.
– If some individuals with the allele don’t show
phenotype, penetrance is incomplete (e.g. 80%
penetrant).
– Brachydactyly (50-80% penetrant).
– Many cancer genes have low penetrance.
 Expressivity
• Describes variation in expression of a gene
or genotype in individuals.
– Two individuals with the same mutation may
develop different phenotypes.
– Expressivity depends on genotype and
environment.
 Osteogenesis Imperfecta
– Osteogenesis imperfecta,
inherited as an autosomal
dominant with nearly 100%
penetrance.
• Three traits associated with
disease are blueness of sclera,
very fragile bones, and
deafness.
• Shows variable expressivity, an
individual may show one or
more of the symptoms at a
time.
Fig. 12.12, Penetrance and expressivity
 Neurofibromatosis
• The allele is an autosomal
dominant that shows 50-80 %
penetrance and variable
expressivity.
– Mildest form is a few pigmented
areas on the skin.
– Others include, tumors, high
blood pressure, speech
impediments, heaches, large
head, short stature, tumors of
eye, brain or spinal cord,
curvature of the spine.
 Effects of the environment
• Age of onset (pattern baldness)
• Sex (milk production, horn formation)
• Temperature (fur color in himalayan
rabbits)
• Chemicals (phenocopy of a mutation)
Male Pattern Baldness
(Fig. 12.14)

OMIM 109200

•Autosomal

•Dominant in males

•Recessive in females

•Also influenced by
testosterone
Male Pattern Baldness
(Fig. 12.14)

OMIM 109200

•Autosomal

•Dominant in males

•Recessive in females

•Also influenced by
testosterone
Hair-follicle histology and growth cycle. (a) The hair cycle, in which
phases of growth (anagen) are interspersed with phases of regression
(catagen) and rest (telogen). The phases of the cycle affected by null
alleles of particular genes are identified. (b) The major histological
compartments that make up a pilosebaceous unit, as it would appear in an
ideal cross-section through skin tissue. The dashed line depicts the
position of the club hair sheath (the fully regressed bulb region) in the
telogen stage. Abbreviations: APM, arrector pili muscle; DP, dermal
papilla; IRS, inner root sheath; ORS, outer root sheath; SG, sebaceous
gland.