Genetics 1 Flashcards
Mutations effect all kinds of proteins - name them
1 Enzymes
2 Proteins involved in transport and storage
3 Structural proteins
4 Proteins involved in growth, differentiation and development
5 Receptor and signaling proteins
Which proteins present with a recessive mode of inheritance
Enzymes
Transport and storage proteins
Which proteins present with a dominant mode of inheritance
Structural proteins
Proteins involved in growth, differentiation and development
Receptor and signaling proteins
Protein defects vary in severity - what three things could happen
Null mutation
Loss of function
Gain in function
Protein defects vary in severity - what three things could happen - null mutation
The underlying mutation might completely destroy a protein
Protein defects vary in severity - what three things could happen - loss of function
The mutation may reduce the protein’s activity
Protein defects vary in severity - what three things could happen - gain in function
The mutation may alter the proteins activity, even convey a new function
Single gene defects show what type of inheritance
Four Mendelian models 1 Autosomal dominant 2 Autosomal recessive 3 X linked dominant 4 X linked recessive OR - Mitochondrial inheritance (that doesn't follow Mendelian rules)
Single gene defects - Recessive disorders cause disease in what state
Homozygous
Dominant disorders cause disease in what state
Heterozygous
Single gene defects - Mendelian rules of inheritance - With one heterozygous and one homozygous parent - expect what for a typical dominant allele
50% of the children will be impacted by the disorder in the heterozygous state (Aa)
Single gene defects - Mendelian rules of inheritance - With both parents heterozygous - expect what for a typical recessive allele
25% will get a recessive allele in the homozygous state (aa)
Mendelian rules - recurrence and occurrence risk
They are the same!
So every child that you have has the same risk
Single Gene - Recessive Inheritance
One normal allele is enough to prevent disease because a loss in gene dosage can be compensated
Single gene - recessive inheritance - why is one normal allele enough to prevent disease
Loss in a gene dosage can be compensated for - enzymes are highly regulated and so they will adjust to the metabolic situation
Single gene - dominant inheritance
Disease will still show in heterozygous state
Many different models to explain dominant inheritance
Single gene - dominant inheritance - why does disease show in heterozygous state for proteins involved in growth, differentiation, and development
Critical in gene dosage because their activity is not regulated
Single gene - dominant inheritance - why does disease show in heterozygous state for receptor and signaling proteins
Esp. those with a gain in function
Because signal is like an alarm so if you have 25, even if just 1 goes off, there is a response
Single gene - dominant inheritance - why does disease show in heterozygous state for structural proteins
(ex cytoskeletal or skeletal proteins)
Subunits need to fit just right to form the macromolecular structure so if just one is off, the entire structure does not come together or assemble well
Single gene - causes for dominant inheritance
Haploinsufficiency
Dominant negative effect
Gain in function mutation
Lack of back up (two hit model)
Single gene - causes for dominant inheritance - Haploinsufficiency
In the haploid state, you are not making enough proteins - ex of hgb where you need a lot and even though you have one healthy in the heterozygous state, it can’t ramp up enough to meet needs so you end up with an insufficiency
Single gene - causes for dominant inheritance - Dominant negative effect
Protein that hangs around and just by being there has a negative effect on the other proteins
Impacts mostly structural proteins
Single gene - causes for dominant inheritance - Gain in function mutation
Receptor that triggers a signal transduction cascade even in the absence of ligand
Impacts mostly signal transduction proteins
Single gene - causes for dominant inheritance - Lack of backup (two hit model)
Explains a lot of CA hereditary syndromes
There are specific alleles that are supposed to stop cell division at certain times but with heterozygous one of your brakes is already defective and puts you at a higher risk
Single gene - X linked inheritance
M - one X
F - two X but one is inactivated
Fathers pass X to daughters, Y to sons
Y initiates M development
Single gene - X linked inheritance - if father has a mutation on X
it will not be passed to son but will always be passed to daughter
Single gene - X linked inheritance - X chromosome inactivation
Every cell has to decide which X to inactivate and say half inactivate one X and half inactivate the other - F are mosaic - if it is a true recessive disorder, F won’t show the disorder (it is in the heterozygous state)
Single gene - X linked inheritance - example of a severe X linked disorder
Muscular dystrophy - M die early in life, F are able to live normally though because half of their cells are still ok and able to regenerate
Single gene - Mitochondrial Inheritance
Does not follow Mendelian rules
Mitochondria come from ovum and are inherited only from mother
Cells have many mitochondria with many copies of the chromosome - Variable expression of mutant phenotype
Single gene - mitochondrial inheritance - what cells are impacted the most
Those that consume the most energy
Like optic nerve
Can lead to muscle deterioration and blindness
Single Gene - example of autosomal recessive diseases
PKU (an enzyme defect)
CF (defective transporter)
Single Gene - example of autosomal dominant diseases
Neurofibromatosis
Huntingon Disease
Achondroplasia
Collagen disorders
Single gene - autosomal recessive diseases - characteristics of an autosomal recessive pedigree
Affected children usually have normal parents
Both sexes are equally affected
Consanguinity increases risk
Both parents hetero so risk for child to get disease in homozygous state is 25%
Single gene - autosomal recessive diseases - characteristics of an autosomal recessive pedigree - Consanguineous matings
If you see a child from a consanquineous marriage - it is likely a recessive disorder
Their chances of having the mutant allele is higher than what you would expect from random mating
Single Gene - example of autosomal recessive diseases - PKU - what is it
Cause by a defect in phenylalaning hydroxylase (PAH)
Phenylalanine accumulates and damages the developing CNS
Early dietary intervention is key
Single Gene - example of autosomal recessive diseases - PKU - how common and tx
One of many inborn errors of metabolism
Rare, but more common of the rare ones
Tx is effective in preventing mental retardation
Heel prick soon after birth for blood analysis
Single gene - characteristics of autosomal dominant pedigree
An affected child has at least one affected parent
Both sexes are equally affected
Disease can be transmitted from father to son
Often homozygotes are more severely affected than heterozygotes
Single Gene - example of autosomal dominant diseases - Neurofibromatosis Type 1 (NF1) - what is it
Rare neuro disorder
Caused by defect in neurofibromin gene (large gene - big target)
Single Gene - example of autosomal dominant diseases - Neurofibromatosis Type 1 (NF1) - What are they symptoms
Multiple benign tumors in skin
Benign tumors in iris of they eye (hamartomas or Lisch nordules)
Pigmented skin (cafe au lait)
Tumors of CNS, mental retardation
Single Gene - example of autosomal dominant diseases - Neurofibromatosis Type 1 (NF1) - Expressivity
Variable expressivity
Same mutation but a wide spectrum of what it can cause and no telling how it will present in following generations
Single Gene - example of autosomal dominant diseases - Neurofibromatosis Type 1 (NF1) - Penetrance
All or nothing concept
The % of people with the disease gene who develop symptoms
NF1 has 100% complete penetrance - every carrier will express symptoms
Single Gene - example of autosomal dominant diseases - Huntington Disease - what is it
Neurodegenerative disorder with late onset
Very rare
Caused by gain in function mutation in the huntington gene
Triplet expansion in gene causes protein instability
Single Gene - example of autosomal dominant diseases - Huntington Disease - how does it happen
Repeat of CAG sequence and around 40 repeats it is pretty much a given that the person will develop HD
People hang out on bubble though and when they have kids, the repeat number increases
Once the gene has been switched from pre mutation to full mutation (around 40) the gene will be passed on in a dominant manner
Single Gene - example of autosomal dominant diseases - Huntington Disease - anticipation
The severity of the disease increases when transmitted through a pedigree - this is frequently observed in triplet expansion mutations and is referred to as anticipation
Single Gene - example of autosomal dominant diseases - Achondroplasia - what is it
Most frequent form of dwarfism
Cause by a defect in a fibroblast growth factor receptor (FGFR3)
Single Gene - example of autosomal dominant diseases - Achondroplasia - what type of mutation
Gain in function mutation - receptor is constitutively active - dominant negative effect
Inhibition of bone growth leads to short stature
Illustrates importance of new mutations in autosomal dominant diseases
Single gene - reduced fitness and new mutations
Often an allele carrier has a reduced chance of reproduction (reduced fitness)
Reduced fitness makes the mutant allele disappear from population BUT allele frequencies stay constant because new mutations appear and compensate for the loss of mutant alleles
Single gene - Genetic heterogeneity of collagen disorders - what are the two types of heterogeneity
Allele heterogeneity
Locus heterogeneity
Single gene - Genetic heterogeneity of collagen disorders - what are the two types of heterogeneity - Allele heterogeneity
Different mutations in the same gene have different phenotypes
Single gene - Genetic heterogeneity of collagen disorders - what are the two types of heterogeneity - Locus heterogeneity
Mutations in different genes have the same phenotype
Single gene - Allele heterogeneity example
Some types can be explained by haploid insufficiency and other by dominant negative effect
So same gene but different mutations and different phenotypes
Single gene - X linked recessive main features
No father-son transmission
Affected boys usually have unaffected parents
M affected more than F (because they don’t have back up)
Seems to skip generations by transmission through carrier females
Single gene - X linked recessive examples
Duchenne and Beck MM dystrophies
Single gene - X linked recessive - mm dystrophy - how common - what is it
Rare
Defect in dystrophin leads to mm damage
Dystrophin is large target
Low fitness of affected M - disease if often due to new mutations
Single gene - X linked recessive - mm dystrophy - Recurrence risk
Low because disease is often due to new mutations and chance that second child also gets random new mutation is low
Single gene - X linked recessive - mm dystrophy - Dystrophin staining
Carrier females are mosaics - even though they are just a carrier, it does not look 100% normal, you can see that some cells activated the defective cell so they look abnormal but the half that activated the healthy one look normal
Single gene - X linked dominant
Very rare No father son transmission All daughters of affected father are affected Females more frequently affected Often lethal in males
Single gene - Mitochondrial inheritance - how passed
Passed from mothers to all children
Fathers to nobody
Most are caused by a nuclear mutation but then are passed in a Mandelian mode
Mitochondrial DNA is present in multiple copies
Single Gene - Mitochondrial inheritance - a patient with a mitochondrial disorder has cells with
varying fractions of defective mitochondrial DNA molecules (heteroplasmy)
Single Gene - Mitochondrial Inheritance - example
Leber’s Hereditary Optic Neuropathy (LHON)
Single Gene - Mitochondrial inheritance - LHON
Most prevalent of the mitochondrial disorders
Caused mostly by a mutation in the ND1 gene
Leads to rapid deterioration of the optic nerve
