fundamental molecular lecture 2 mutations 2

Question 1

what are the 4 types of the recessive mutation ablinism?

Answer 1

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

Question 2

what effect does albinism cause to the substrate tyrosine and the product melanin?

Answer 2

-there is too much substrate of tyrosine
-there is too little product of melanin produced

Question 3

what does less melanin cause?

Answer 3

more prone to skin cancer

Question 4

what is phenylketonuria?

Answer 4

High Phenylpyruvic acid
Progressive brain dysfunction

Mutation
Phenylalanine hydroxylase gene
Recessive condition

Question 5

what is the treatment for phenylketonuria?

Answer 5

Phenylpyruvic acid birth test
Low phenylalanine diet

Question 6

if mutant version e has no or less activity, what causes the phenotype?

Answer 6

too much substrate (phenylalanine) and too little product (tyrosine)

Question 7

How does each mutation affect the
FUNCTION of THAT gene or gene product (protein)?

Answer 7

In ALL cases: LESS or NO activity of enzyme (the gene product)

Question 8

How does each mutation affect PHENOTYPE?

Answer 8

TOO MUCH substrate or
TOO LITTLE product

Question 9

what mutations cause too much substrate being produced?

Answer 9

alkaptonuria and PKU

Question 10

what mutation causes less/ none products being produced?

Answer 10

albinism and cretinism

Question 11

what is rule of thumb 1?

Answer 11

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.

Question 12

what are the wild types in model organisms and natural populations?

Answer 12

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.

Question 13

what is the rule of thumb 2?

Answer 13

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

Question 14

what is rule of thumb 3?

Answer 14

Most Recessive mutations are LOSS-of-FUNCTION- Extreme case= Complete Loss of Function “NULL”

Question 15

what is rule of thumb 4?

Answer 15

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

Question 16

what is incomplete dominance?

Answer 16

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

Question 17

what is achondroplasia?

Answer 17

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.

Question 18

what are facts about achondroplasia?

Answer 18

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

Question 19

what is Huntingtons disease (gain of new function)?

Answer 19

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

Question 20

how does Huntingtons occur?

Answer 20

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

Question 21

why are most mutations that affect a gene recessive?

Answer 21

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)