Genetics 1

Question 1

Mutations effect all kinds of proteins - name them

Answer 1

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

Question 2

Which proteins present with a recessive mode of inheritance

Answer 2

Enzymes

Transport and storage proteins

Question 3

Which proteins present with a dominant mode of inheritance

Answer 3

Structural proteins
Proteins involved in growth, differentiation and development
Receptor and signaling proteins

Question 4

Protein defects vary in severity - what three things could happen

Answer 4

Null mutation
Loss of function
Gain in function

Question 5

Protein defects vary in severity - what three things could happen - null mutation

Answer 5

The underlying mutation might completely destroy a protein

Question 6

Protein defects vary in severity - what three things could happen - loss of function

Answer 6

The mutation may reduce the protein’s activity

Question 7

Protein defects vary in severity - what three things could happen - gain in function

Answer 7

The mutation may alter the proteins activity, even convey a new function

Question 8

Single gene defects show what type of inheritance

Answer 8

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)

Question 9

Single gene defects - Recessive disorders cause disease in what state

Answer 9

Homozygous

Question 10

Dominant disorders cause disease in what state

Answer 10

Heterozygous

Question 11

Single gene defects - Mendelian rules of inheritance - With one heterozygous and one homozygous parent - expect what for a typical dominant allele

Answer 11

50% of the children will be impacted by the disorder in the heterozygous state (Aa)

Question 12

Single gene defects - Mendelian rules of inheritance - With both parents heterozygous - expect what for a typical recessive allele

Answer 12

25% will get a recessive allele in the homozygous state (aa)

Question 13

Mendelian rules - recurrence and occurrence risk

Answer 13

They are the same!

So every child that you have has the same risk

Question 14

Single Gene - Recessive Inheritance

Answer 14

One normal allele is enough to prevent disease because a loss in gene dosage can be compensated

Question 15

Single gene - recessive inheritance - why is one normal allele enough to prevent disease

Answer 15

Loss in a gene dosage can be compensated for - enzymes are highly regulated and so they will adjust to the metabolic situation

Question 16

Single gene - dominant inheritance

Answer 16

Disease will still show in heterozygous state

Many different models to explain dominant inheritance

Question 17

Single gene - dominant inheritance - why does disease show in heterozygous state for proteins involved in growth, differentiation, and development

Answer 17

Critical in gene dosage because their activity is not regulated

Question 18

Single gene - dominant inheritance - why does disease show in heterozygous state for receptor and signaling proteins

Answer 18

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

Question 19

Single gene - dominant inheritance - why does disease show in heterozygous state for structural proteins

Answer 19

(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

Question 20

Single gene - causes for dominant inheritance

Answer 20

Haploinsufficiency
Dominant negative effect
Gain in function mutation
Lack of back up (two hit model)

Question 21

Single gene - causes for dominant inheritance - Haploinsufficiency

Answer 21

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

Question 22

Single gene - causes for dominant inheritance - Dominant negative effect

Answer 22

Protein that hangs around and just by being there has a negative effect on the other proteins
Impacts mostly structural proteins

Question 23

Single gene - causes for dominant inheritance - Gain in function mutation

Answer 23

Receptor that triggers a signal transduction cascade even in the absence of ligand
Impacts mostly signal transduction proteins

Question 24

Single gene - causes for dominant inheritance - Lack of backup (two hit model)

Answer 24

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

Question 25

Single gene - X linked inheritance

Answer 25

M - one X F - two X but one is inactivated Fathers pass X to daughters, Y to sons Y initiates M development

Question 26

Single gene - X linked inheritance - if father has a mutation on X

Answer 26

it will not be passed to son but will always be passed to daughter

Question 27

Single gene - X linked inheritance - X chromosome inactivation

Answer 27

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)

Question 28

Single gene - X linked inheritance - example of a severe X linked disorder

Answer 28

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

Question 29

Single gene - Mitochondrial Inheritance

Answer 29

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

Question 30

Single gene - mitochondrial inheritance - what cells are impacted the most

Answer 30

Those that consume the most energy Like optic nerve Can lead to muscle deterioration and blindness

Question 31

Single Gene - example of autosomal recessive diseases

Answer 31

PKU (an enzyme defect) | CF (defective transporter)

Question 32

Single Gene - example of autosomal dominant diseases

Answer 32

Neurofibromatosis Huntingon Disease Achondroplasia Collagen disorders

Question 33

Single gene - autosomal recessive diseases - characteristics of an autosomal recessive pedigree

Answer 33

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%

Question 34

Single gene - autosomal recessive diseases - characteristics of an autosomal recessive pedigree - Consanguineous matings

Answer 34

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

Question 35

Single Gene - example of autosomal recessive diseases - PKU - what is it

Answer 35

Cause by a defect in phenylalaning hydroxylase (PAH) Phenylalanine accumulates and damages the developing CNS Early dietary intervention is key

Question 36

Single Gene - example of autosomal recessive diseases - PKU - how common and tx

Answer 36

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

Question 37

Single gene - characteristics of autosomal dominant pedigree

Answer 37

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

Question 38

Single Gene - example of autosomal dominant diseases - Neurofibromatosis Type 1 (NF1) - what is it

Answer 38

Rare neuro disorder | Caused by defect in neurofibromin gene (large gene - big target)

Question 39

Single Gene - example of autosomal dominant diseases - Neurofibromatosis Type 1 (NF1) - What are they symptoms

Answer 39

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

Question 40

Single Gene - example of autosomal dominant diseases - Neurofibromatosis Type 1 (NF1) - Expressivity

Answer 40

Variable expressivity | Same mutation but a wide spectrum of what it can cause and no telling how it will present in following generations

Question 41

Single Gene - example of autosomal dominant diseases - Neurofibromatosis Type 1 (NF1) - Penetrance

Answer 41

All or nothing concept The % of people with the disease gene who develop symptoms NF1 has 100% complete penetrance - every carrier will express symptoms

Question 42

Single Gene - example of autosomal dominant diseases - Huntington Disease - what is it

Answer 42

Neurodegenerative disorder with late onset Very rare Caused by gain in function mutation in the huntington gene Triplet expansion in gene causes protein instability

Question 43

Single Gene - example of autosomal dominant diseases - Huntington Disease - how does it happen

Answer 43

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

Question 44

Single Gene - example of autosomal dominant diseases - Huntington Disease - anticipation

Answer 44

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

Question 45

Single Gene - example of autosomal dominant diseases - Achondroplasia - what is it

Answer 45

Most frequent form of dwarfism | Cause by a defect in a fibroblast growth factor receptor (FGFR3)

Question 46

Single Gene - example of autosomal dominant diseases - Achondroplasia - what type of mutation

Answer 46

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

Question 47

Single gene - reduced fitness and new mutations

Answer 47

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

Question 48

Single gene - Genetic heterogeneity of collagen disorders - what are the two types of heterogeneity

Answer 48

Allele heterogeneity | Locus heterogeneity

Question 49

Single gene - Genetic heterogeneity of collagen disorders - what are the two types of heterogeneity - Allele heterogeneity

Answer 49

Different mutations in the same gene have different phenotypes

Question 50

Single gene - Genetic heterogeneity of collagen disorders - what are the two types of heterogeneity - Locus heterogeneity

Answer 50

Mutations in different genes have the same phenotype

Question 51

Single gene - Allele heterogeneity example

Answer 51

Some types can be explained by haploid insufficiency and other by dominant negative effect So same gene but different mutations and different phenotypes

Question 52

Single gene - X linked recessive main features

Answer 52

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

Question 53

Single gene - X linked recessive examples

Answer 53

Duchenne and Beck MM dystrophies

Question 54

Single gene - X linked recessive - mm dystrophy - how common - what is it

Answer 54

Rare Defect in dystrophin leads to mm damage Dystrophin is large target Low fitness of affected M - disease if often due to new mutations

Question 55

Single gene - X linked recessive - mm dystrophy - Recurrence risk

Answer 55

Low because disease is often due to new mutations and chance that second child also gets random new mutation is low

Question 56

Single gene - X linked recessive - mm dystrophy - Dystrophin staining

Answer 56

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

Question 57

Single gene - X linked dominant

Answer 57

``` Very rare No father son transmission All daughters of affected father are affected Females more frequently affected Often lethal in males ```

Question 58

Single gene - Mitochondrial inheritance - how passed

Answer 58

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

Question 59

Single Gene - Mitochondrial inheritance - a patient with a mitochondrial disorder has cells with

Answer 59

varying fractions of defective mitochondrial DNA molecules (heteroplasmy)

Question 60

Single Gene - Mitochondrial Inheritance - example

Answer 60

Leber's Hereditary Optic Neuropathy (LHON)

Question 61

Single Gene - Mitochondrial inheritance - LHON

Answer 61

Most prevalent of the mitochondrial disorders Caused mostly by a mutation in the ND1 gene Leads to rapid deterioration of the optic nerve