Lecture 9

New site for REEF connection

Biology 261 02
Lecture 9

Gene interactions
Practice problems from book

Chapter 6: 10,11,13,14,15,16,17,25,27,33
 Details of mid term

The midterm exam will be Fri February 16, 2018.

Exam covers chapters 2-6; lectures 1 through 10.
25 multiple choice questions

Bring a calculator and a pencil to fill in the

answer sheet
Language translation dictionaries are allowed.

There will be two different exams, A and B. Make

sure you note on your answer sheet which exam you
have written – if you get the code wrong all your
answers will be connected to the wrong questions!
 Details of Midterm exam

3 tutorial groups will have their midterm exam outside

of SP S110

Students in Tuesday’s 1:30 tutorial will have their mid-

term in CC111
Students in Tuesday’s 3:30 tutorial with surnames
names from A to H will also be in CC111

Students in Tuesday’s 3:30 tutorial with surnames I to Z

will be in CC115
Students in Wednesday’s 1:30 tutorials will have their
midterm in CC115

Everyone else will have the exam in room SP S110 –

this main lecture room
 Essay question - Jurassic Park (book and movie)
proposed the concept of recreating dinosaurs based on
knowing the sequence of dinosaur genomes. We now
have the sequence of a Neanderthal (ancient hominid
species that went extinct approximately 40,000 years
ago) genome that is essentially as accurate as the
genome of a modern human. Therefore we may have
the potential to recreate a Neanderthal – would you be
interested in trying to recreate extinct species from
genome sequences?
 Up to now we have basically discussed genes as abstract
entities that are manifested by changes in the phenotype of
an organism, and we have talked about them as acting
essentially independently

This approach allows us to get the basic rules of genetics

established, but now we are going to start investigating
why alleles of genes create phenotypes, and how genes can
interact to mess up tidy ratios and simple interpretations

These modifications do not change the fundamental rules,

they just add complexity
 We will add two new points to the concepts that we have
been presenting

Both of these points are themselves considerable

oversimplifications, but they will serve as somewhat useful
generalizations

1. Genes generally encode proteins

2. Proteins are generally enzymes
 The specific DNA sequence of a gene determines the specific
amino acid sequence of a protein - which determines its function.
Citric acid cycle
(TCA or Krebs cycle)

Each modification of
a substrate is
catalyzed by an enzyme.

Each enzyme is
composed of one or
more proteins.

Each protein is
synthesized from one
gene.
 The “one-gene-one-enzyme” hypothesis was developed by
George Beadle and Edward Tatum in the 1940’s based on the
study of mutants of Neurospora.

They selected mutants that required arginine for growth.

They identified three different classes of mutants which could

grow on different biochemical precursors of arginine.

Each class of mutants was due to a mutation in a different gene.

They hypothesized that each mutation caused an inactivation of

an enzyme that acted in the biosynthetic pathway of arginine.
Selection of arginine
requiring mutants of
Neurospora

Mutants grow
when arginine is
added to media.
Some arg- mutants
could grow when
related compounds
were added to the
media instead of
arginine.
The different classes of mutants have different phenotypes
– determined by the compounds which could rescue them.
The mutations were mapped and found to be on different
chromosomes.
precursor ornithine citrulline arginine

Beadle and Tatum proposed this biosynthetic pathway and

hypothesized that the mutations were in genes encoding the three
enzymes of the pathway.
precursor ornithine citrulline arginine

Mutations that cause the loss of active enzymes block the

biosynthetic pathway.
The blocks are circumvented by adding downstream products
to the medium.
Mutations cause the loss of active enzymes and block the pathway.
The blocks are circumvented by adding downstream products.
arg-1+ arg-2+ arg-3+

Enzyme 1 Enzyme 2 Enzyme 3

precursor ornithine citrulline arginine

Genes

arg-1+ arg-2+ arg-3+

Enzymes
A mutation in arg-2 prevents synthesis of citrulline and (arginine),
but if the organism is fed citrulline it can synthesize arginine and
can grow.
arg-1+ arg-2-- arg-3+

Enzymes
Ornithine aminotransferase can make ornithine from proline

Ornithine transcarbamylase turns ornithine to citrulline

Argininosuccinate synthetase, together with

argininosuccinate lyase, can generate arginine from
citrulline
 Question 11
A metabolic pathway has been identified where enzyme 1 turns
precursor A into B, enzyme 2 turns B into C, while enzyme 3
turns B into D. Finally, enzyme 4 condenses C and D together
to generate product F. Which statement about this pathway is
true?

a. A mutation in enzyme 1 can be rescued by supplementation

by either C or D
b. A mutation in step 2 cannot be rescued by supplementation
by compound D
c. Compound F can rescue mutations in step 4, but not step 1
d. Mutations in steps 2 or 3 can be rescued by supplementation
by compound B
 1 2
4
A B C
F
3
D
a. A mutation in enzyme 1 can be rescued by
supplementation by either C or D
b. A mutation in step 2 cannot be rescued by
supplementation by compound D
c. Compound F can rescue mutations in step 4, but
not step 1
d. Mutations in steps 2 or 3 can be rescued by
supplementation by compound B
 Beadle and Tatum’s hypothesis became
“one-gene-one-polypeptide” - and is universally accepted.

It has been demonstrated to be fundamentally true many times over:

Starting in the late 50’s, and through the 60’s and 70’s it was shown
by determining the amino acid sequence of proteins and comparing
active enzymes and inactive mutants. The mutants had altered
amino acid sequences.

Beginning in the 80’s the DNA sequence of genes could be used to

compare wild type genes with mutants. Altered DNA sequences
in mutants could be shown to correspond to altered amino
acid sequences.
Gene interactions – complex inheritance patterns

1. Incomplete and other versions of dominance

2. Co-dominance
3. Recessive lethal alleles
4. Three or more alleles of a single gene
5. Multiple genes that affect the same trait
6. Epistasis
Up to now we have been talking about dominance and
recessiveness as absolute. But the picture of metabolic
pathways and enzymes controlling these pathways can
let us expand the concept of dominance and
recessiveness. Most mutations will be recessive,
because a single functional copy of the gene will
provide the enzyme, and the enzyme will let the
pathway function. However, what happens if the
reduced enzyme amount is not enough to supply the
needed function?
One possibility is that the mutation appears as dominant.
This would be the case if the amount of the missing
protein needs to be at a threshold level, and the
mutation reduces that level below the needed amount.
The cell needs 50 units of enzyme A to function, and
each allele provides 35 units. Thus in the normal
diploid cell, there is more than enough (70 units) of A
for function, but if one allele is non-functional, the
amount drops to 35 units, and the function fails. In the
cell, the mutant phenotype is expressed in the
heterozygote, and thus appears dominant
-Return to this when we talk about recessive lethals
Another way you could have a dominant phenotype for a
mutation is if the mutant gene encodes a protein that is
part of a functional complex. If the protein is able to
join the complex, but not do its job, it could essentially
soak up all the WT proteins into inactive complexes.
Such mutants are called dominant negatives; they are
partially functional.
Hemoglobin is made up of 4 subunits. If one allele was
mutated so that it would inactivate any complex it was
part of, and subunits associated randomly, the
probability that a functional complex of 4 WT subunits
would form is 1/24 or only 6.25% - this could reduce
enzyme levels below that needed for function.
Dominant mutations could also form if an activity was
released from its normal constraints. A good example
of this is the Ras oncogene that is associated with
many human cancers. Ras is a little protein that acts as
a switch to trigger cell growth, and normally it gets
switched off when cell growth is not needed.
Mutations can arise that lock the Ras protein in the on
state, and this leads to dominant activation of the
growth pathway. It doesn’t matter if there are WT Ras
proteins that are properly shutting off, the presence of
the activated Ras leads to a dominant proliferation
phenotype.
Another possible consequence of a missing function is
that the pathway only functions partially. 50% of the
normal enzyme function gets you 50% of the normal
phenotype. This is easy to see if the product is a
pigment, and represents the case of incomplete
dominance.
 1.Incomplete dominance

– the heterozygote is intermediate in phenotype

between the two homozygotes

RR Rr rr
The amount of enzyme activity for synthesis of the red
pigment is not sufficient to give full red color in
the heterozygote
Incomplete dominance

X
RR rr

Rr
Incomplete dominance

R r

Rr x Rr R RR Rr

r Rr rr

RR Rr rr
1 : 2 : 1
 Frizzled fowl is an unusual genetic character in chickens which causes
the feathers to curl up. Frizzled chickens do not breed true. A cross between two
frizzled individuals results in offspring 1/4 normal, 1/2 frizzled, 1/4 with strange
woolly feathers that fall out and leave the birds naked. Give the genetic explanation
for this trait.
 Frizzled fowl is an unusual genetic character in chickens which causes
the feathers to curl up. Frizzled chickens do not breed true. A cross between two
frizzled individuals results in offspring 1/4 normal, 1/2 frizzled , 1/4 with strange
woolly feathers that fall out and leave the birds naked. Give the genetic explanation for
this trait.

Answer: The frizzled trait is only seen in heterozygotes, and the frizzled birds do not
breed true, i.e. they cannot produce uniform offspring that look like the parents.

The allele causing the trait is an incompletely dominant allele for feather deformation.
The individuals homozygous for the allele for frizzling are naked. We can use the
symbol Fz for the frizzle allele.

F Fz x F Fz 1/4 FF normal
1/2 FFz frizzled
1/4 FzFz naked
 Question 12

Frizzled chicks have become a big seller at Easter. What cross would you
make to maximize your production of frizzled chicks for this market ?

a. Cross two frizzled chickens together

b. Cross a normal and a naked chicken together
c. Cross a normal chicken and a frizzled chicken
d. Cross a frizzled chicken and a naked chicken
2. Co-dominance – 2 alleles are both fully expressed
in the heterozygote

Example: Blood types A, B

2. Co-dominance – alleles are both fully expressed

Example: Blood types A, B

IA IA– gives blood type A, A antigen appears on the red blood cell
A
A

A
A

IB IB– gives blood type B, B antigen appears on the red blood cell
B B

B
B
2. Co-dominance – IA and IB alleles are both fully expressed

Example: Blood types A, B

IA IB– gives blood type AB,

Both A antigen and B antigen appear on the red blood cell

A
B A
B

B
A
A
B
IA IB x IA IB mating can give three types of offspring :

IA IA IA IB I B IB
A type AB type B type

1 : 2 : 1
A A
B
A B A B
B

B
B
A A B
A
B A
 3. Recessive lethal alleles

A recessive lethal allele causes death in individuals that

lack a functional copy of the gene.

This is very easy to see in the model organism S.

cerevisiae, which can grow as a haploid or a diploid

A diploid S. cerevisiae strain can be transformed (just

like we learned last week with bacteria) with exogenous
DNA: we can arrange for this DNA to both carry a
marker and to disrupt the function of an essential gene
 Heterozygous diploid yeast strain

Functional gene

Inactivated gene
 Living colony
Functional gene

Living colony

Dead spore

Inactivated gene
Dead spore
3. Recessive lethal alleles : 2:1 ratio.
A recessive lethal allele causes death in homozygous
individuals.

Example: ML is a dominant allele that is responsible for the

tailless character in Manx cats. It is a recessive allele for
lethality.

A mating between two Manx cats produce tailless

and tailed offspring in a 2:1 ratio.

This is a modified 1:2:1 ratio, in which the homozygous

M LM L
Individuals are not observed because they die in utero.

Tailless Manx cats are always heterozygous.

They cannot breed true.
 m/m Ml /m
Ml – tailless cats
X

m/m Ml / m

1 : 1
 Ml /m x Ml /m

Ml / Ml Ml /m Ml /m m/m
Lethal

2 : 1

The Ml allele is recessive for lethality.

It is dominant for tailessness.
Indicators of a recessive lethal allele:

1. A 2:1 ratio of progeny from a cross

2. A trait that cannot be made to “breed true”

I.e. It is not possible to find two parents with the

trait that produce offspring who all have the trait.
 Question 13
A Drosophila female with short bristles on thorax is crossed to a
normal long bristle male.

F1 Result : 1/3 short bristled female

1/3 long bristled females
1/3 long bristled males

Cross between F1 long bristle male x long bristle

females gives long bristle offspring.
a. Short bristles is an autosomal dominant trait that is a
recessive lethal
b. Short bristles is recessive and sex linked
c. Short bristles is dominant and sex linked
d. Short bristles is dominant, sex linked, and a recessive lethal