WEDNESDAY JANUARY 20TH, 2021
SECTION A – 11H30PM
SECTION B – 230PM
BIO2133 Genetics
Exploring the gene, its expression, and transmission Hypotheses
Classical genetics merges the knowledge of DNA, genes, mutations and
inheritance with the scientific method to deduce information about Conclusions Predictions
genes, alleles, and gene function from analyses of genetic crosses,
pedigrees, and patterns of inheritance.
It also helps us understand how the results of molecular studies help us Observations
understand aspects of human genetics and genetic disease.
Today’s session…
1. Announcements
2. Recap….
3. FOXP2 gene Case Study….
Phenotype expression:
1. Transcription and Translation…
2. Mutations, genotypes, and phenotype….
3. Gene interactions?
Session Learning Objective
How is genetic information expressed so it affects an
organism’s structure and function?
How do different types of mutations affect genes and the
corresponding mRNAs and proteins?
Identification of the “speech gene” – FOXP2
The story: In 1990, scientists became interested in the KE family in London, half of
whose family members have speech disorders.
DNA sequence dictates protein structure
Genes encode the
order of amino acids
(1˚ structure)
. . . which sets up amino acid interactions . . .
Cys
Cys
. . . that
dictate Lys
protein His
His
conformation
(3˚ structure)
Changes in the primary structure of proteins can
change folding and alter function of a protein
wild type mutant
shape
change this change
amino acid
active site active site
can’t form enzyme is
defective
Wild type alleles…
- usually code for functional proteins
- usually dominant
Mutant alleles…
- usually code for defective proteins
- often recessive
DOMINANT alleles…indicated by CAPITAL letters
recessive alleles…indicated by lower case letters
Loss of function mutations
LOF: Loss Of Function mutations result in a protein that has little or no
enzymatic activity.
Most mutations associated with a
phenotype are LOF.
Why?
Many changes that affect the normal 3˚ structure would
disrupt the active site (even if the mutation affects an
amino acid that is far away from the active site).
Loss of function mutations
Most LOF mutations are recessive.
Why?
Half the amount of wild type gene product is
usually sufficient to give a wild type
phenotype.
Phenotypes in diploid organisms
Phenotype = physical or observable characteristic
e.g., eye color
hair type
ability/inability to digest lactose
ability to synthesize melanin (pigment)
Alleles of a gene are variant forms of the gene
tyrosinase gene
C gene encodes tyrosinase tyrosinase mRNA
C
tyrosine
* c tyrosinase
melanin
C tyrosinase
C
tyrosinase
C tyrosinase
* c
tyrosinase
Why does Cc look as pigmented as CC?
General rule for LOF mutations…
Half the amount of wild type gene product is sufficient to give a wild type phenotype
Example : Tyrosinase wild type allele = C
mutant = c
[enzyme
threshold wild type phenotype
activity]
albino phenotype
Genotype: CC Cc cc
▪ 1 wild type copy → enzyme activity above threshold needed for normal pigmentation, so
carriers unaffected (mutant allele → recessive)
Temperature-sensitive proteins
Proteins unfold upon heating.
Increasing temperature
Missense mutations can destabilize 2˚ and 3˚ structures so the protein unfolds at lower
than normal temperatures.
Tyrosinase protein (for melanin) can be encoded by alleles so that it folds properly only in
the coolest parts of the skin.
Burmese
Siamese
Mutations in regulatory regions and introns
- in promoter could affect transcription
- in intron could affect splicing
pre-mRNA
- in 5’ or 3’ UTR
could affect
mature mRNA translation or mRNA
stability
ORF
Any of these changes could change when, where, or how
much protein is made
“Half the amount of wt gene product is
sufficient for wt phenotype”
Exceptions?
Rare exception #1—haploinsufficiency
Half the number of t protein
molecules is not sufficient to
tt TT maintain normal tail length
wild type short tail mutant
threshold
amount of normal tail
functional “t”
protein
short tail
genotype: tt Tt TT
Rare exception #2—no threshold
e.g., snapdragon flower color
CR: enzyme that makes red pigment
CI: no enzyme activity
Red x Ivory No
CRCR CICI threshold!
Amount of red
pigment
Pink
CRCI Genotype: CRCR CRCI C IC I
Heterozygote has intermediate phenotype… incomplete dominance
Rare exception #3—“poisonous” subunits
…also called “dominant-negative” mutations
Amount threshold “wt” phenotype
of active
protein
“mutant”
aa Aa AA phenotype
Why does Aa have so little activity?
Example: “Poisonous” subunits
protein assembled
alleles: subunits: enzyme: phenotype:
wild type
mutant
heterozygote is
mutant!
How mutations affect phenotype
GOF: Gain Of Function mutations result in a functional protein that…
…is made at the wrong place
…is made at the wrong time
…has a new activity
GOF mutations need not be beneficial
Very few mutations are GOF.
Why?
Only very specific mutations (e.g., specific amino acid changes) will have this
effect
How mutations affect phenotype
Will GOF mutations be dominant or recessive? Can you predict?
depends on threshold!
Most GOF mutations are dominant
For example, only a small amount of the altered protein is sufficient to produce
the mutant phenotype
But there could be cases in which the altered protein in combination with the
wt protein gives a wt phenotype
GOF example #1–normal protein in the wrong place
Antennapedia in Drosophila
Wild type Antennapedia gene is only expressed in the
thorax; legs are made.
A mutation causes the Antennapedia gene to be
expressed in the thorax and also in the head, where
legs result instead of antennae!
What kind of mutation is this?
What phenotype would you predict for the
heterozygote?
GOF example #2–normal protein at the wrong time
Lactose tolerance in humans
Homozygous wt Homozygous mutant
Gene promoter:
ON OFF ON ON
can digest
lactose
lactase
activity
cannot
3 15 3 15
age age
So which allele is dominant? What would be the phenotype of the heterozygote?
Mutant has gain of function… expect lactose tolerance to be dominant
Today’s session…
1. Announcements
2. Recap….
3. FOXP2 gene Case Study….
Phenotype expression:
1. Transcription and Translation…
2. Mutations, genotypes, and phenotype….
3. Gene interactions?
Session Learning Objective
How is genetic information expressed so it affects an
organism’s structure and function?
How do different types of mutations affect genes and the
corresponding mRNAs and proteins?
Learning objectives
Compare different types of mutations and describe how each can
affect genes and the corresponding mRNAs and proteins.
• Explain how the expression of a phenotype is the relative expression of both alleles of a
given gene in a diploid organism.
• Discuss how various factors might influence the relationship between genotype and
phenotype (e.g. incomplete penetrance, variable expressivity, and sex-limited phenotype).
• Given a diagram or information about a transcription factor, explain how the expression of a
gene can be positively or negatively regulated by the product of another gene (i.e. gene
interaction).
ROLES FOR GENES
• Enzymes (catalyze reactions)
• Signalling (e.g. Hormones, messengers)
• Receptors (e.g. Adrenergic receptors)
• Constituent (e.g. Actin, myosin; keratin)
GENE EXPRESSION AND INTERACTIONS
Regulation
G1 (promoters) Multiple genes
P1 Proteins
Development of the jaw
and speech centers
GENE EXPRESSION AND INTERACTIONS
Example: 1 gene, 1 product
G1
P1 (e.g. enzyme)
S1 S2
GENE EXPRESSION AND INTERACTIONS
Example: Control of an enzyme
G2
G1
P2 (e.i. modulator)
P1 (e.g. enzyme)
S1 S2
GENE EXPRESSION AND INTERACTIONS
Example: Control of an enzyme
G2
G1 P2 (e.i. modulator)
P1 (e.g. enzyme)
S1 S2
GENE EXPRESSION AND INTERACTIONS
Example: 2 genes, 1 final product (S3)
G1 G2
P1 (e.g. enzyme) P2 (e.g. enzyme)
S1 S2 S3
In Drosophila, red and yellow eye pigments are synthesized through the
pterin pathway. A part of the pterin pathway (simplified) is shown below.
GENE EXPRESSION AND INTERACTIONS
Example: 2 genes, 1 final product (S3)
G1 G2
P1 (e.g. enzyme) P2 (e.g. enzyme)
S1 S2 S3
GENE EXPRESSION AND INTERACTIONS
Gene products
controlling the
expression of
other genes
GENE EXPRESSION AND INTERACTIONS
• Pleiotropy
• Epistasis
• Gene suppressors
• Complementary genes
• Duplicate genes
