Extensions of Mendelian Genetics

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Extensions of Mendelian Genetics
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Extensions to Mendelian

• Multiple alleles
• Modifications of dominance relationships
• Gene interactions
• Essential genes, lethal genes
• Gene expression and environment

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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.

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Fig. 12.3, In complete dominance in chickens
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• Different types (modifications) of dominance
  relationships
• 3. Codominance
• Alleles are codominant to one another.
• Phenotype of the heterozygote includes the
  phenotype of both homozygotes.
• e.g., ABO blood groups sickle-cell anemia

Fig. 4.7
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Multiple alleles

• Genes have multiple alleles.
• WHY?
• Do different alleles produce different
  phenotypes?

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ABO blood groups

• ABO blood groups A, B, AB, and O
• IA and IB are dominant to i, while IA and IB are
  codominant.

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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
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• ABO inheritance is Mendelian
• Possible parental genotypes for type O offspring
• i/i x i/i
• IA/i x i/i
• IA/i x IA/i
• IB/i x i/i
• IB/i x IB/i
• IA/i x IB/i

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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.

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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.

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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.

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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.

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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.

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Eosin x White
P Cross w (X) Y
we (X) we/w XX we/Y XY
we (X) we/w XX we/Y XY
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F1 x Wild type
w(X) Y
we (X) we/w XX we/Y XY
w (X) w/w XX w/Y XY
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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(N1)/2 genotypes N homozygotes, and N(N-1)/2
heterozygotes
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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
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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.

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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 (-/-).
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Different types of dominance

• Incomplete dominance
• Codominance
• Complete dominance

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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.

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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.

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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).

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• 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/9331 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.

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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.

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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

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Fig. 12.6
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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.

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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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All are modifications of 9331

• 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).

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Recessive Epistasis (934)

• 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.

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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.

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Fig. 12.9, Recessive epistasis F2 934
(all mice have B)
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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.

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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.

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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.

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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.

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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.

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Fig. 12.11, Lethal alleles in mice, Yellow body
color
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Gene Expression and Environment

• Replication of genetic material
• Growth
• Differentiation of cells into types
• Arrangement of cell types into defined tissues
  and organs

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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 dont show
  phenotype, penetrance is incomplete (e.g. 80
  penetrant).
• Brachydactyly (50-80 penetrant).
• Many cancer genes have low penetrance.

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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.

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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.

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Fig. 12.12, Penetrance and expressivity
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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.

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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)

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• Male Pattern Baldness
• (Fig. 12.14)
• OMIM 109200
• Autosomal
• Dominant in males
• Recessive in females
• Also influenced by testosterone

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• Male Pattern Baldness
• (Fig. 12.14)
• OMIM 109200
• Autosomal
• Dominant in males
• Recessive in females
• Also influenced by testosterone

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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.