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Gene interaction I:
# Types of mutation & departure
# from Mendelian ratios
# 4BBY1070
# Genetics and Molecular Biology
Dr. Barry Panaretou
>
[email protected] 1
How mutations affect gene function & how this in turn
leads to an understanding of the molecular basis of
dominance.
o There are types of dominance other than full
dominance.
o A unique inheritance pattern results from genes
present on the X chromosome.
o Some traits are sex-limited and some are sex-
influenced.
Learning outcomes:
To understand that departure from Mendelian ratios
arises because:
o Mitochondrial and chloroplast DNA is only inherited
maternally. 2 All traits had clear dominant recessive patterns.
Mendel picked characteristics that he could score
easily.
Seeds were either green or yellow; wrinkled or round;
flowers were either white or purple.
The molecular basis of dominant and recessive
alleles drove genetic research in the early 20th and
mid-20th century.
This lead to understanding why certain mutations are
dominant and why others are recessive ( via
characterizing the effects on function of the encoded
proteins).
From this functional perspective, we recognise the
following types of mutation: 3(i) Amorphic (null)
I. Loss of function
Produces no protein at all, or protein product completely
lacks function.
Usually recessive (as one wild-type copy will suffice)
e.g. CFTR
D508 allele
Cystic fibrosis transmembrane conductance regulator
> 4
CFTR, pumps Cl - out of cells, leads to water exiting the cell by
osmosis (maintains a free flowing mucus layer).
CFTR
Cl -
> Cell
> membrane Cell
> membrane
(cystic fibrosis: lifespan reduced, ca. 50% reach 40 th birthday)
loss of Cl - gradient, mucus becomes thicker, leads to lung
infections, blockage of ducts in pancreas and intestines
Mutant CFTR D508 does not exit the endoplasmic reticulum Wild-type CFTR is Dominant phenotype can mask
the recessive allele because one wild-type copy is able
to maintain the Cl - gradient.
CFTR D508 is Recessive cystic fibrosis only appears
if an individual is homozygous for this allele (no CFTR
at the cell membrane, so no Cl - gradient) (ii) Hypomorphic ( leaky)
I. Loss of function
Protein function is reduced either due to less protein
made, or product itself displays less activity.
e.g. alleles of the gene encoding Tyrosinase - in the
pathway that produces melanin from tyrosine.
C - wild type allele
maximum activity of
tyrosinase, dark
pigmentation
cch - chinchilla allele,
activity is reduced, less
pigment made
Usually recessive (as the wild-type copy will provide
sufficient activity).
cch / c ch
C / C or C/ c ch (i) Hypermorphic
II. Gain of function
An increase in activity; either more protein is made, or
the protein itself has greater activity.
Usually dominant (as presence of a wild-type protein
of normal function is of no consequence if a
hyperactive protein is also present)
e.g. Hereditary pancreatitis (HP)
Trypsin-1 made by the pancreas. If it becomes active
prematurely, it will start to digest the pancreas - but it splits
itself by cutting at Arginine117 (inactivates trypsin)
In HP, Arg117 is mutated to H117 - trypsin-1 can t be
inactivated, and acute pancreatitis is the result. (ii) Antimorphic (dominant negative)
II. Gain of function
Disturbance in function that interferes with protein
encoded by a normal allele (usually applies to
situations when a protein operates as a hetero- or
homo-multimer).
FBN1 encodes fibrillin-1; assembles into long chains to
form fibres of connective tissue.
Mutations in FBN1 (lead to
truncation of FBN1 protein and
causes Marfan syndrome)
Unusually tall, long limbs,
arachnodactyly (spider fingers) (iii) Dominant lethal
II. Gain of function
In human populations we only see this class of mutant later
on in life, since onset of a disease is caused by accumulation
of the mutant product.
e.g. Huntington s disease; onset typically at 40 years of age.
Dominant lethal alleles are very rare. For them to exist in
a population, the affected individual must reproduce
before dying.
Huntington s disease is caused by a triplet expansion in
the HD locus (>36 CAG), giving a polyglutamine tract in
the protein. Leads to aggregation of protein into
neurotoxic fibrils. (iii) Dominant lethal
II. Gain of function
Heterozygous individual develops HD, because
mutant polypeptide will aggregate regardless of
presence of wild-type protein .
Disease doesn t appear until adult life (accumulation
of HD aggregates is slow). (iv) Neomorphic
II. Gain of function
Alters the function of the protein ( new form) so usually
dominant.
e.g. antennapedia in Drosophila - gene mutated so
that protein now causes development of legs where
eyes should be.
antennapedia W+ Mendel followed traits controlled by dominant and
recessive alleles.
However, this is rare in nature.
Dominance of one allele over another is rarely
complete, and we recognize:
Incomplete (or partial) dominance
Co-dominance
Such traits display non-Mendelian ratios at the level of
the phenotype.
# Departure from Mendelian ratios -results in a blend of characteristics
Four oclock plants
Wild type (red) x white
CC
c
c c c
ccC C
C C
All pink
cC
F2
C
c
CC
cc
Cc
Cc
1:2:1
red:pink:white
Not 3:1
Incomplete (partial) dominance: e.g. ABO blood group
Three different alleles at locus I: IA, I B or i
Any person can have 2 of the three alleles
IA IA or IA i blood type A
> A
> AA
> A
IB IB or IB i blood type B B
> BB
> B
i i blood type O
IA IB AB blood type B
> AA
> B
> CODOMINANCE
Co-dominance - where the presence of both
alleles is detected equally. Significance of ABO blood groups is apparent for blood
transfusion:
Individual of blood type: Makes antibodies of type:
A B
> A
> AA
> A
B A
> B
> BB
> B
AB Neither
> B
> AA
> B
O A & B Recipient - B Donor - B
Antibody to A
Donor - A
Agglutination Normal wild type mice have dark coats.
A mutation, yellow , gives a lighter coat.
Lethal alleles also distort Mendelian segregation ratios If a yellow mouse is mated to a homozygous wild type,
A 1:1 ratio of yellow to wild type mice is always seen:
Ay
AyAA
A
A
AyA
AA
AA
> 1 : 1
AyA : AA
Suggests:
A single gene with two alleles is responsible
Yellow mouse was heterozygous
Allele for yellow is dominant. 3 : 1
yellow : wild type
Expected:
Obtained:
2 : 1
yellow : wild type
no cross of yellow x yellow has ever produced all
yellow offspring
AyA
AAy
A
Ay
AA
AyAAyAy
Heterozygous cross:
Suggests that a homozygous (A yAy) yellow mouse
is impossible to obtain. 3 : 1
yellow : wild type
Expected:
Obtained:
2 : 1
yellow : wild type
AyA
AAy
A
Ay
AA
AyA
Heterozygous cross: The allele for yellow is a recessive lethal with
respect to viability.
A homozygous (A yAy) mouse dies before birth
(lethal in utero )
The allele for yellow is dominant to the wild type
allele with respect to effect on colour.
But... All Manx cats are heterozygous for a dominant allele
that causes no tail to form.
Homozygous Manx cats do not exist.
This allele interferes with normal spinal development.
Never born because the spinal deformity is so severe. Lethal alleles in humans: the fate of a million human zygotes
> 85% live
> births
15% miscarried
7.5%
Miscarried owing to chromosom
abnormalities
The collection of lethal alleles in the population
is referred to as the genetic load.
# *
Remaining 7.5%:
Homozygous for lethal genes
Lethal in utero
# *Genes present on the X chromosome exhibit unique
patterns of inheritance in comparison with autosomal
genes (because males inherit their X from the mother)
Inheritance of genes on the X chromosome (X-linkage)
# Departure from Mendelian ratios e.g. haemophilia A (mutation in gene for blood
clotting factor VIII on X chromosome).
Will occur most frequently in males.
XH
XH
Xh
Y
XH Xh XH Xh
XH Y XH Y
All daughters of affected fathers are carriers.
Cannot be passed from father to son. X-linkage
XHXh
XHY
XhY XHXH
By probability, half the sons of a carrier will be
affected , and half her daughters will be
carriers .
XHY
XHYXhY XhXH XHXHOther X-linked recessive traits (ca. 400 known
in humans):
Red-green colour blindness
Duchenne muscular dystrophy
X-linked ichthyosis
> frequency per 10,000
> males
800
3
2Traits affected by sex, but relevant genes found
on autosomes
Influence of sex:
(i) Sex-limited
The phenotype is absolutely limited to one sex
e.g. milk yield in dairy cattle, no. of eggs laid by poultry Traits affected by sex, but relevant genes found
on autosomes
Influence of sex:
(ii) Sex-influenced (usually dependant on
hormone constitution)
e.g. Male pattern baldness
e.g. B is dominant in presence of high levels of testosterone
Dominant in , recessive in
> Though much less
> pronounced and
> expressed later in life
Bald
Not bald
Not bald
Bb Bald
bb Not bald
BB Bald
Genotype Phenotype High 2D:4D Equal 2D:4D Low 2D:4D The 2D:4D ratio: in males, the 2nd digit is shorter
than the 4th . Other way round in females.
Children with Asperger s syndrome (a form of autism)
show a sex ratio of 9:1 male:female, so likely to be
sex-influenced. Mitochondria and chloroplasts contain their own circular
genome (e.g. mtDNA encodes 13 polypeptides plus
rRNA and tRNA)
These organelles are
inherited exclusively from
the maternal side of a cross
i.e. mitochondria from
sperm or pollen are
excluded from the zygote
Maternal inheritance. A number of human diseases are caused by mutations
in mtDNA (mitochondrial cytopathies). The organs most
affected are those that use high amounts of energy
(ATP) e.g. muscle and nerve e.g.
MELAS myopathy, encephalopathy, lactic
acidosis, stroke-like episodes.
LHON Leber s hereditary optic neuropathy so affects both sexes
can only be passed on by the mother
matrilineal does not follow any of the autosomal or
sex-linked inheritance patterns
An affected mother would transmit the disorder to
all offspring.
but offspring of affected fathers are normal
mitochondrial cytopathy
Non-Mendelian, cytoplasmic, extranuclear
inheritance. Mendelian ratios appear when mutations are fully
penetrant and show consistent expressivity
But.few genes display these properties
This is another cause of a discrepancy between
genotype and phenotype (giving rise to non-
Mendelian ratios).
Penetrance and expressivity Discrepancy between genotype and phenotype
can arise due to:
A. Incomplete penetrance
When the phenotype associated with a genotype fails
to appear in some cases
e.g. polydactyly - a dominant mutation, yet only 25-
30% of individuals who carry the mutant allele
develop extra digits
> http://withfriendship.com/user/servex/polydactyly.php
When phenotype varies in the degree of magnitude.
Penetrance and expressivity are controlled by i) genotype at
other loci and/or ii) environmental factors.
e.g. Individuals with Wardenburg syndrome (autosomal
dominant)
Such an allele is also pleiotropic i.e. affects more than
one character.
Discrepancy between genotype and phenotype
can arise due to:
B. Variable expressivity
Hearing loss
Differently coloured eyes
White forelock of hair
Premature graying of hair
Can display any or all four of the principal features of the
syndrome. The effect of mutation on protein function explains why
an allele is dominant or recessive.
Complete dominance is rare. Lack of dominance, co-
dominance and lethal alleles lead to appearance of
Non-Mendelian ratios
X-linked, sex-limited, and sex-influenced traits also
result in distortion of Mendelian ratios.
Summary:
Mitochondrial and plastid DNA is inherited in matrilineal
fashion only.
Penetrance and expressivity describe the appearance
and magnitude of a phenotype, respectively.