Transcript Document

Chapter 13: Extensions of Mendelian Principles:

Multiple alleles

Modifications of dominance relationships

Gene interactions

Essential genes and lethal alleles

Gene expression and the environment

Epigenetics
Multiple alleles:

Not all genes have two forms (alleles), many have multiple alleles.

Diploid individuals have only two alleles, one on each chromosome.
Examples:
ABO blood groups
Drosophila eye color
Fig. 13.3
Human ABO blood groups:
1.
4 blood phenotypes: O, A, B, & AB
2.
3 alleles: IA, IB, I
1.
IA and IB are dominant to i.
2.
IA and IB are codominant to each other.
Phenotype
Genotype
RBC-antigen
Blood-antibody
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
Drosophila eye color:

> 100 mutant alleles for the eye color locus on the X chromosome.
w+ wild type, red
w mutant, white-eye
we mutant, eosin (reddish-orange)
1912, Thomas H. Morgan

Crossed eosin-eyed female with a white-eyed male:

All F1 had eosin eyes.
P Cross
w (X)
Y
we (X)
we/w
XX
we/Y
XY
we (X)
we/w
XX
we/Y
XY
Drosophila eye color:

Alfred H. Sturtevant (1913) observed:
1.
2.
3.

Red (w+) is dominant to white (w) and eosin (we).
Eosin (we) is recessive to red (w+), but dominant to white (w).
Concluded eosin (we) and white (w) are multiple alleles of the
same gene.
Confirmed by crossing F1 female with wild type red-eyed male:
w+(X)
Y
we (X)
we/w+
XX
we/Y
XY
w (X)
w/w+
XX
w/Y
XY
Molecular basis of multiple alleles and dominance relationships:

Genes encode proteins and regulatory factors, substitutions result in
different alleles.

Different alleles of the same gene reflect activity and expression of
the gene product.
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
Number of alleles (n) and number of genotypes (Table 12.3):
# genotypes = n(n + 1)/2
Homozygotes
Heterozygotes
=n
= n(n - 1)/2
# alleles
# genotypes
Homozygotes
Heterozygotes
1
1
1
0
2
3
2
1
3
6
3
3
4
10
4
6
5
15
5
10
Different types (modifications) of dominance relationships:
(depend upon molecular patterns of gene expression)
1.
Complete dominance
2.
Incomplete dominance
3.
Codominance
Different types (modifications) of dominance relationships:
1. Complete dominance (complete recessiveness)
1.
One allele is completely dominant to another.
2.
Phenotype of the heterozygote is the same as homozygous
dominant.
3.
Recessive phenotype is expressed only when the organism is
homozygous recessive.
4.
e.g., Mendel’s pea traits (Fig. 11.5)
Different types (modifications) of dominance relationships:
2. Incomplete (partial) dominance
1.
One allele is not completely dominant to another.
2.
Phenotype of the heterozygote is intermediate between the
phenotypes of homozygotes for each allele.
3.
e.g., plumage color in chickens and palomino horses
Fig. 13.7, Incomplete 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. 4.9
Molecular explanations for dominance relationships:
Complete dominance
Dominant allele creates full phenotype by one of two methods:
1.
Half the amount of gene product produced by homozygote is
sufficient (haplosufficient), OR…
2.
Expression of dominant allele in heterozygote is up-regulated to
match the homozygote.
Incomplete dominance
Recessive allele is not expressed in heterozygote:
1.
Homozygote:
2 doses of a gene product
2.
Heterozygote:
1 dose of a gene product
Codominance
Both alleles are expressed equally resulting in a combined phenotype.
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
2/16
1/16
2/16
4/16
2/16
1/16
2/16
1/16

AA/BB
AA/Bb
AA/bb
Aa/BB
Aa/Bb
Aa/bb
aa/BB
aa/Bb
aa/bb
Deviation from this ratio indicates the interaction of two or more
genes producing the phenotype.
Two types of gene interactions:
1.
Multiple genes control the same trait and by their interactions
produce a new phenotype.
2.
Epistasis - one or more genes mask the expression of other genes
and alter the phenotype.
1.
Different genes control the same trait and collectively produce a
new phenotype, e.g., comb shape in chickens.
4 phenotypes resulting from dominant and recessive alleles at 2 loci:
Rose-comb
Pea-comb
Walnut-comb
Single-comb
R-/pp
rr/PR-/Prr/pp
•
Cross true-breeding rose-combed (RR/pp) and pea-combed (rr/PP)
chickens.
1.
Interaction of two dominant alleles (R & P), produces a third
phenotype (walnut), all F1 are walnut-combed (Rr/Pp).
2.
Fourth phenotype (single-comb, rr/pp) appears in the F2.
3.
F2 is 9:3:3:1 (walnut:rose:pea:single) and fits Mendelian ratios.
4.
Multiple genes involved, and interaction of two dominant alleles (R
& P) produce factors that modify comb shape from a simple
(rose/pea) to more complex form (walnut).
http://www.bio.miami.edu/dana/250/25008_11.htm
l
Fig. 13.9
2.
Epistasis

No new phenotype is produced, but one gene (epistatic) masks the
phenotypic expression of another gene (hypostatic) .
Recessive epistasis, caused by recessive alleles, aa masks the effect
of B at another locus.
Can occur in both directions, requiring A and B to produce a
phenotype (duplicate recessive epistasis).
Dominant epistasis, A masks the effect of B.
Recessive epistasis, coat color determination in rodents:
Three loci involved (agouti = color banded hairs, ~grey):
1.
2.
3.
C allele determines pigment
A allele determines agouti factor
B allele determines color
4.
A allele is epistatic over B locus, inserts bands of color between
black and brown (appears grey).
5.
C allele is epistatic over A and B loci, as cc is albino regardless
of its genotype at the A and B loci.
----cc
A---C-
aaB-C-
(C- = pigment, cc = albino)
(A- = banded, aa = solid)
(B- = black, bb = brown)
Recessive epistasis, coat color determination in rodents (cont.):
1.
Assume for this cross that all mice have one B allele (B- = black)
and there are no brown mice (bb).
2.
Cross true-breeding black-agouti (AA/CC) with albino (aa/cc).
3.
All F1 are agouti Aa/Cc.
4.
In the F2, A-/cc and aa/cc individuals show the same albino
phenotype.
5.
F2 phenotypic ratio is 9:3:4 instead of 9:3:3:1.
Fig. 13.11,
Recessive epistasis
F2: 9:3:4
Essential genes and lethal alleles:
Essential gene =
may result in a lethal phenotype when mutated.
Lethal allele
mutation that results in death.
(can be dominant or recessive)
=
Dominant lethal allele
Recessive lethal allele
Aa and AA die
aa dies
Yellow body color, an example of a lethal allele in mice:

Yellow mice never breed true.

Cross yellow x non-yellow, F1 is 1:1 yellow and non-yellow (all
yellow mice are heterozygotes, AY/A).

Cross yellow x yellow (AY/A x AY/A), F2 is 2:1 yellow:non-yellow
instead of the predicted 3:1 ratio.

Homozygotes (AY/ AY) are aborted in utero.

Yellow is dominant with respect to coat color, but acts as a
recessive lethal allele.

Studies indicate that the AY allele has a large deletion and is fused
to the promoter of a nearby (Raly) gene (Raly is inactivated).
Fig. 13.17, Lethal alleles in mice,
Yellow body color
Why do lethal alleles persist in the population?
Recessive lethal alleles are not eliminated; rare alleles occur in the
heterozygote (protected polymorphism).
Allele frequency q = 0.01
Expected frequency of double recessive homozygotes, q2 = 0.0001
Expected frequency of heterozygotes, 2pq = 0.0198
For complete recessive allele at equilibrium ( = mutation rate and s =
selection coefficient):
q = √ (/s)
If homozygote is lethal (s = 1) then q = √

Influence of the environment on gene expression:
4 major steps to development:
1.
2.
3.
4.
5.
DNA replication
Chromatin synthesis
Growth
Cell differentiation
Arrangement of cells into tissue and organs

Internal and external environments interact with genes and gene
products to control their expression at each stage of development.
Some basic terminology:

Penetrance describes how completely an allele corresponds with a
trait in the population (0-100%) ~ Frequency (+/-)

Expressivity describes variation in expression of a gene or genotype
(can be constant or variable) ~ Variability
Fig. 13.18, Penetrance and expressivity
Some effects of the environment:

Age of onset (male pattern baldness)

Sex (male pattern baldness)

Temperature (influences enzymes, coloration in Siamese cats,
sex determination in reptiles)

Chemicals (phenocopy, chemicals mimic phenotype produced by
rare recessive alleles)

Measles during the first 12 weeks of pregnancy produces
fetal cataracts, deafness, and heart defects.

Thalidomide (1959-1961), prescribed as a sedative for
expectant mothers suppressed limb-bone development.
Male Pattern Baldness
(Fig. 13.20)
OMIM 109200
•Autosomal
•Dominant in males
•Recessive in females
•Influenced by
testosterone
Male Pattern Baldness
(Fig. 13.20)
OMIM 109200
•Autosomal
•Dominant in males
•Recessive in females
•Influenced by
testosterone
Epigenetics:
Study of heritable changes caused by mechanisms other than changes in
the underlying DNA.
 Examples include changes in gene expression caused by DNA
methylation and chromatin/histone modification.
 Persist through cell divisions and multiple generations.
http://learn.genetics.utah.edu/content/epigenetics/
Examples of epigenetic inheritance:
Waterfleas (Daphnia) grow protective helmets in the
presence of predators, stimulated by chemicals produced
by the predators in the environment. The helmets are
passed to the offspring and the next generation. The
grandkids have smaller helmets.
A common fungicide (vinclozolin) used on grape plants
causes low sperm count, prostate, and kidney disease in
laboratory rats. The great grandsons of the rats also have
lower sperm count after the pesticides is removed from the
environment three generations prior.
The incidence of heart disease and diabetes may be
regulated by epigenetic factors. The amount of food your
grandfather ate when he was 9-12 may influence your
susceptibility to these diseases. Age 9-12 is when the cells
are grown that give rise to sperm.
Epigenetics:

While epigenetic changes by definition must persist through
multiple generations, their effects gradually wash out.

How many generations is a current question of interest.

Provides a buffer to changing environmental conditions.

To demonstrate that the change is epigenetic, the trait must be
stable and persist in the F2 generation (to distinguish from maternal
effect – subject of next lecture).