fundamental molecular lecture 2 mutations 2 Flashcards
what are the 4 types of the recessive mutation ablinism?
Conversion of Tyrosine to Melanin: Four genes in humans:
OCA1: tyrosinase enzyme
mutants have severe albinism
OCA2: P Protein (tyrosinase ‘helper’)
mutants have mild albinism
OCA3: tyrosine-related gene (very rare)
mutants have weak albinism
OCA4: SLC45A2 Protein (tyrosinase helper)
mutants have mild albinism
what effect does albinism cause to the substrate tyrosine and the product melanin?
-there is too much substrate of tyrosine
-there is too little product of melanin produced
what does less melanin cause?
more prone to skin cancer
what is phenylketonuria?
High Phenylpyruvic acid
Progressive brain dysfunction
Mutation
Phenylalanine hydroxylase gene
Recessive condition
what is the treatment for phenylketonuria?
Phenylpyruvic acid birth test
Low phenylalanine diet
if mutant version e has no or less activity, what causes the phenotype?
too much substrate (phenylalanine) and too little product (tyrosine)
How does each mutation affect the
FUNCTION of THAT gene or gene product (protein)?
In ALL cases: LESS or NO activity of enzyme (the gene product)
How does each mutation affect PHENOTYPE?
TOO MUCH substrate or
TOO LITTLE product
what mutations cause too much substrate being produced?
alkaptonuria and PKU
what mutation causes less/ none products being produced?
albinism and cretinism
what is rule of thumb 1?
to avoid confusion ALWAYS think from the mutant
allele’s point of view
The mutant allele x- is recessive to the wild-type allele X+
(= X+ is of course dominant to x-: but this can get very confusing: AVOID)
The WILD TYPE (WT) organism is the reference state.
what are the wild types in model organisms and natural populations?
In model organisms (yeast, fly, worm..): have reference Wild-Type specimens
In natural populations (human, animal, plant…): the Wild-Type allele
for EACH gene is the most common allele in the population.
what is the rule of thumb 2?
Remember that genes make gene products
It is the gene products (usually proteins) that affect phenotype
– they have FUNCTION.
Dominance/Recessivity is determined
by how the pool of product (usually
protein) encoded by the two alleles
functions in a heterozygote
what is rule of thumb 3?
Most Recessive mutations are LOSS-of-FUNCTION- Extreme case= Complete Loss of Function “NULL”
what is rule of thumb 4?
Most Dominant mutations are GAIN-of-FUNCTION
(can be complete or incomplete dominance)
more of a “normal” function (whatever that is) e.g.,
i) More active enzyme (e.g., RAS oncogene: stuck in “on” state)
ii) Produce more protein (hence more overall activity in the pool of gene product)
new function (unrelated to what the normal gene does)
Presence or not of WT allele makes no difference
The former is more common
what is incomplete dominance?
Dominant mutations are rarely fully (= “completely”) dominant aka Mendel.
INCOMPLETE DOMINANCE
Having ONE mutant allele is enough not to be normal (in a heterozygote)
Having TWO mutant alleles is worse or different again (in a homozygote)
Geneticists rarely worry about COMPLETE vs
INCOMPLETE dominance:
ONE mutant allele is enough to change phenotype
what is achondroplasia?
Most common form of dwarfism: Autosomal dominant (but see next slide)
99% of cases: ONE of TWO missense point mutations in FGFR3
Fibroblast
Growth Factor
Receptor 3
FGFR3 normally acts to inhibit/slow limb growth, turned on by FGF binding
Mutant receptor is locked in a more active state, whether FGF bound or not… hence more of ”normal activity:” which is to INHIBIT bone growth.
what are facts about achondroplasia?
Only 20% have a parent with achondroplasia
80% of the mutations are generated in a parent’s germ line (so called “de novo” [from new] mutations: one of those 200……) Sorry: it’s the guys
Most de novo mutations are an identical point mutation= the most mutable single site known in the human genome
Two heterozygous (affected) parents sire:Normal and Achondroplasia children in 1:2 ratio
what is Huntingtons disease (gain of new function)?
Progressive neurodegeneration
Autosomal dominant mutation
Rare: 1/10,000 people
Gene: HTT
Protein: Huntingtin – unknown function (cytoskeleton?)
Symptoms:
Onset 30s-50s
First symptom: Loss of limb control
Mortality: 10-15 years after first symptoms
how does Huntingtons occur?
CAG triplet encodes “glutamine”
Wild-type allele has a CAG repeat near start of Open Reading Frame
(<35 units: = polyglutamine repeat near N-terminus of protein)
Mutant allele: CAG repeat gets LONGER
hence, Longer polyglutamine repeat in the protein = TOXIC
why are most mutations that affect a gene recessive?
This is true even before any natural selection …
i.e., MOST random mutations coming into a population are RECESSIVE
Random change (mutation of a gene or application of a sledgehammer to your car in a blind rage… ):
It is much more likely to cause damage (car, protein…) and thus make it work less well than normal (Loss-of-function: recessive)
than it is to
make it work better or differently to normal (Gain of function: dominant)
