Functional Genetics 1 Flashcards
(20 cards)
What is alkaptonuria? and how is it inherited?
High levels of alkaptone in urine, presenting with other symptoms like rheumatism and blue colouration of ears/hands.
= A pleitropic disease.
Alkaptone increases in urine when diet enriched with phenylalanine.
Autosomal recessive transmission
= Loss of function
Where is metabolic defect causing alkaptonuria?
ALkaptone is an intermediate in the phenylalanine degradation pathway on way to Krebs cycle.
Alkaptone accumulates due to loss of function mutation in HGO enzyme.
What other diseases are implicated in changes to enzymes involved in Phenylalanine degradation pathway?
Phenylketonuria = Phenylalanine hydroxylase = Instead of catabolism of phenylalanine, it is converted to phenylpyruvic acid which is toxic to developing brain.
Tyrosinemia = Tyrosine transaminase = Null mutation leads to tyrosine accumulation.
Albinism = Tyrosinase (Epistatic to downstream mutations).
What is phenylketonuria?
Null mutation in phenylalanine hydroxylase.
Instead of being catabolised, phenylalanine is converted to phenylpyruvic acid.
This is highly toxic to developing brain.
= gestating mother and newborn need low phenylalanine diet.
How is Sickle cell anaemia inherited?
How does mutation change Hb and RBC behaviour?
Autosomal, recessive trait.
Single point mutation in gene encoding beta subunits of Hb.
Glutamine ( hydrophilic) is substituted for Valine ( hydrophobic side chain).
Exposing hydrophobic region and conf. change to Hb beta subunits.
Sickle-cell haemoglobin accumulates and crystallises into fibres = reduced O2 capacity. = stiff and sickle shaped.
What is Sickle cell anaemia phenotype?
Long inflexible polymers of Sickle-cell Hb leads to stiff and Sickle shaped RBCs.
= blocking blood flow to hands and feet = pain + swelling.
Spleen damage renders more susceptible to infections.
What was responsible for Mendel’s wrinkled peas?
Lossing of function Mutation in gene coding for SBE / Starch branching enzyme.
Amylose not converted to branch amylopectin.
Reduced starch content lead to abnormal shaping of amyloplasts and wrinkled phenotype.
What is a pleiotropic mutation?
Examples?
Mutation influencing more than oen phenotypic trait - although seemingly unrelated, they are linked by a common molecular mechanism.
Sickle cell anaemia - spleen damage, pain + infections
Alkaptonuria - blue ears/hands, dark smelly urine.
Albinism - vision, red eyes, white hair.
What is auxotrophy?
Inable to synthesise a particular organic compound required for normal growth.
What is Ade2 mutant?
Adenine auxotrophy in yeast.
On adenine supplemented medium, colonies are red.
Loss of function mutation in Ade2 is pleitropic.
Accumulation of AIR - pigmented in red.
How can deafness and pigmentation defects be linked?
Single mutations in genes involved in differentation of melanocytes and migration from neural crests to terminal locations in inner ear.
These melanocytes can migrate from neural crests and play a structural role in inner ear, contribute to signal transmission pathway.
= Loss of function mutation may lead to pigment defect AND loss of role in signal transmission of audition.
What is a loss of function mutation?
A null mutation:
Protein is completely absent or completely inactive (equivelant to phenotype in absence of protein).
What phenotypes can you observe with null mutations in Mice albinism?
Tyr mutation = Albino.
Slaty/Grey = TRP2
Brown = TRP1
Black = accumulate black pigment Cysteinyl-DOPA
Phaeomelanin is light.
Eumelanin is dark…
What is a partial loss of function mutation?
The proteins “dose” is less than 50% compared to wild type (In diploids)..
What is a conditional mutation?
Example?
Results in specific phenotype under certain conditions - either restrictive or permissive.
Under permissive conditions, mutation has no effect.
Under restrictive conditions, mutation has effect on phenotype.
Thermosensitive = hot is restr.
Crysosensitive = cold is restr.
E.G
Thermosensitive Tyrosinase in himalaya mice phenotype.
In paws/nose = cooler than 30C so permsisive conditions.
Core body = hotter than 30C = restrictive conditions.
Cell cycle division mutants (CDC):
Under restrictive temperatures, m1 mutants arrest at G1/S checkpoint (G1/S checkpoint protein, CDK4 e.g) mutated to halt cell cycle.
What is yeast life cycle?
Two mating types: a and alpha.
2 haploid cells of opposite types undergo morphogenesis to form schmoos.
Cell fusion, nuclear fusion, producing a diploid zygote.
The diploid zygote will produce 2 alpha and 2 a meiospores.
1 meiotic event produces 4 functional spores.
What is the genome of yeast like?
16 chromosomes in haploids.
Different mating types a or alpha.
Sex determined by C11 locus.
6000 genes, in 12 million bp.
Chromosomes segregate at end of metaphase.
Cohesin complex destroyed when sister chromatids attach to MT.
What is haplosufficiency?
Haploinsufficiency?
A single allele is sufficient to produce enough functional protein to give WT phenotype in diploids.
= No doss limiting effect from loss of 1 allele.
A single allele is not sufficient to produce enough functional protein for WT phenotype.
= Heterozygote carriers can be mildly affected too then!! = Incomplete dominance!
What is INCOMPLETE dominance?
Gene products from two codominant alleles in a heterozygote BLEND to form a phentoype that is intermediate to those of homozygotes!!
In the case of haploinsufficient genes, heterozyzgotes which are mildyl affected phenotype are showing incomplete dominance!
What does NF1/ Neurofibromatosis show?
(Special case of what?
Autosomal dominance, caused by a loss of function mutation (unusual)
Dominant inheritance, but caused by a LOSS of function mutation.
2 mutant alleles are required for triggering tumour formation in NF1.
BUT
because Single NF1 mutants will ACQUIRE a second mutation, this will lead to diseased phenotype.
