Allelic variation and pleiotropy of

a single gene
Ch5.1

Pleiotropy of a single gene!!!!

 most wild-type genes are
haplosu cent

Mutations in haplosufficient genes are recessive

meaning at even if you

therefore you need to be
have a nonfunctional copy;
homozygous recessive to
you won't loss function if
be able to see/feel the
you still have a functional
copy (doesn't a ect the
mutation
Fig 5-1
phenotype)

Dominant Mutations
However there are
good way to think about this is that some
mutation that activate the genes; so one
of them is su cient to a ect the
phenotype

Having a single copy of the mutation produces a phenotype

(disease) despite having a wild-type copy of the gene.

Could loss-of-function mutations be dominant?

ØTwo models
I. Dominant for (Haploinsufficiency
Mutations dominance of aand mutation
Dom. Negatives)
need two functional genes
and if you miss one of them
it a ects the phenotype

occur typically in
proteins that dimerize
or protein that interacts
with another protein or
another self
• so if one of the copy
has a mutation it
makes it inactive and
it will a ect the
shape/formation of
the dimer
◦ shape is
important for
the function of
the protein

Fig 5-2
 Example of previous slide

Mutations in genes coding ribosomal subunits in Drosophila

Mutations in genes coding ribosomal subunits in Drosophila
are often dominant, haploinsufficiency
are often dominant, haploinsufficiency
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Fig. 3 p[rp49+ J suppresses the short

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and thin bristle phenotype
of M(3)99D. a, Scanning electron micrograph 37 of the dorsal thorax
of a Dp67A; DfBSJ/+ Minute female showing the characteristic
small and thin9.macrochaetae. Fig. 4 Development
Rees, D. C.,A,Lewis,
PNp = M.
notopleurals, A, PSa
& LiJ>"comb, W.= N. J. "'olec. Biol 168, 367
of progeny resulting f
supraalars, A,10.PDc = dorsocentrals,
Recs, A, PPa = postalars
D. C. & Lipscomb, W. N. Proc.and natn.
A, Sci(Fig.
Acad.flies U.S.A. 7B, 51
PSc = scutellars where A= anterior and P = posterior. b, Micro- 2, Table
thorax of W.
I. Lip,comb,
graph of the Idorsal N. Proc
a Dp67A; natn. Acad.
DfB81/p{rp49+ J female mated to (1980
3875-3878
Sci. U.S.A. 77,were p{rp49
 very important gene for

f
preventing cancer

Many p53 mutant alleles in cancer

function as a dominant negative
P53 is a transcription factor that binds DNA
as a homotetramer but needs to form tetramers

in cancer, we often see one of the two alleles is mutated

where it a ects the DNA binding domain and so it can no
longer bind DNA but it does not a ect the protein binding
domain (for it to be able to form a tetramer)
Mutation in the DNA
biding domain in one
of the two alleles
 may have both

F or Partial Dominance (Dose-determinant)

II. Incomplete
ex:

Snapdragon flower color

c/c c+/c+ c+/c

Amount of pigment produced

c/c c+/c c+/c+

Eg. Enzymes that produce pigments

Fig 5-3
III. Codominance (both alleles are expressed/detected)
Genotype Blood Type
Three alleles determine
the blood type: i, IA & IB IA/IA, IA/i A
The gene responsible for
the blood type encodes a IB/IB, IB/i B
glycosyltransferase AB
IA/IB
i/i O

A type

B type
A and B are dominant over O, but codominant wit
h each other in conventional assay
ØSickled
How anddominance
we classify normal red blood
is often cells by the
determined
phenotype we characterize, (methods of detection/observation)

Hb gene encodes beta-globin, which is a subunit of hemoglobin

Phenotype: anemia
HbA/HbA No anemia
HbS/HbS anemia
HbA/HbS No anemal

HbA is dominant to HbS

Phenotype: Blood cell shape

HbA/HbA a normal shape
HbS/HbS a sickle shape

HbA/HbS a slight sickle shape

Fig 5-4 The sickle-shaped cell is caused by a
single mutation in the gene for hemoglobin HbS is incomplete dominant to HbA
depending on the phenotype you can have di erences in
what is dominant and what is recessive
ØHeterozygotes can have theA
protein
S
of both
Phenotype: presence of Hb and Hb at the
alleles
protein level.

shows codominance

if there was a band in the middle it would be

considered incomplete dominance

Fig 5-5

HbA and HbS are codominant because both allele can be clearly
discerned at the protein level
recessiveness depends on the assay can be
objective
IV Recessive lethal
if there are two copies then it becomes lethal

Often heterozygous for recessive lethal mutations

appear normal (most genes are haplosufficient
genes).

We may carry some recessive lethal mutations!!!

ln diploids, recessive lethal mutations are

maintained as heterozygotes.

In haploids, this is not possible because there is

only one copy of a gene
so it just dies
 IV Recessive lethal
Homozygous mutations causing lethality in the animal,
either recessive or dominant mutations
Normal mice have
dark pigmentation,

“yellow mice” have

lighter coats

Yellow x Normal Yellow x Yellow Fig 5-7

Y/Y is lethal

1:1 Yellow :Normal 2:1 Yellow :Normal

The gene is dominant when it comes to the pigmentation
phenotype (yellow), but recessive for viability of the animal
because two copies of the dominant allele cause lethality
IV Conditional alleles

One condition Different condition

Temperature Lower temperature Higher temperature

sensitive
mutants
Functions like WT Non-functional (lethal)

Auxotrophs Minimal media + arginine Minimal media

Functions like WT Non-functional (lethal)

Auxotrophs: organisms that lost the ability to synthesize certain substances

required for their growth.
 Conditional alleles
temperature controlled phenotype

Tyrosine kinase that is active at a lower temperature

to produce black pigmentations
Penetrance and expressivity contrasted

Fig 5-10

Penetrance: the percentage of individuals with a given allele who

exhibit the phenotype of that allele may be obvious in one individual but not
the other

e.g. BRCA2 mutations predispose to breast, ovarian and pancreatic cancers

Why? there are other factors that in uence it

Environment
Interacting genes
Subtlety of mutant phenotype - difficult to diagnose
(psychiatric disorder)
Incomplete penetrance and pedigrees
dominant disease

it wasn't penetrated in this female

II 1 2

III 1 2 3 4 5

Fig 5-9
Penetrance and expressivity contrasted

Fig 5-10
Expressivity: the degree to which a given allele is expressed at the
phenotypic level, the intensity of the phenotype.
Penetrance and expressivity contrasted

Neurofibromatosis type 1 same mutation but di erent a ects