Mendelian Genetics 2

Question 1

Why do recessive traits typically skip generations?

Answer 1

If the trait is rare, (a rare disease)the allele will be rare, and inheritance of 2 recessive alleles will not likely to appear in different generations of the same family

-instead, autosomal recessive traits, we expect sporadic occurrence in single generation(sib-ship)

Question 2

Recessive autosomal traits appear ________ in both sexes

Answer 2

Equally

Question 3

How often do Dominant traits appear?

Answer 3

• Dominant traits almost always appear in each generation

- Affected individuals all have an affected parent. Dominant autosomal traits appear equally in both sexes

Question 4

What causes recessive traits?

Answer 4

Typically loss of function of the gene

• A loss of function allele must be inherited from each parent
• If there is complete loss of function, the term “null” is often used
• If both parents are heterozygous (Aa), each conception has a 25% chance of being homozygous for the recessive allele

Question 5

What is Albanism?

Answer 5

An autosomal recessive condition in humans

Question 6

What causes albinism?

Answer 6

The enzyme tyrosinase performs San essential step in the conversion of tyrosine (an amino acid) into melanin(skin pigmentation)

Question 7

Describe the inheritance of albanism

Answer 7

-Most people are homozygous for functional alleles

• But, a person only needs one functional copy to have skin pigmentation
  - So people who are Aa for the gene encoding tyrosinase have normal pigmentation
  - People who are AA are indistinguishable to Aa

-If both parents are Aa (carriers) they would have a 25 chance upon each conception of having a child with albinism

Question 8

Albinism is an example of a ….

Answer 8

A condition where there are multiple different genes are involved

Question 9

Why is albinism an example of a condition where there are multiple genes involved?

Answer 9

• There are many components in the pathways to produce melanin pigments
• there are many steps in the synthesis of melanin, each step involves a different enzyme
• each enzyme typically encoded for by a different gene
• So there are many different mutations that might cause loss of function of the pathway (only need to have complete loss of the activity of one enzyme that controls one step; and the entire pathway is comprised)

Question 10

Give an example of complement action analysis to study albinism

Answer 10

Imagine we mix cell lysate from a culture of cells derived from two different people, both of whom were albino

If the combined cell lysates were able to make the pigment, then we would say that the two lysates, “complemented “ each other,

Because on their own they were deficient, combining the lysates enable the function to be carried out

Question 11

Describe hereditary deafness

Answer 11

• An example of a heterogenous trait
• The ear is complex
• More than 50 genes are directly responsible in the development of the ability to discern sound
• It should be surprising then that there are plenty of examples where a deaf man and deaf woman have children who have normal hearing children

Question 12

Describe Tay-Sach’s disease

Answer 12

• Autosomal recessive
• Deficiency of hexosaminidase A, HEXA
• Progressive, inexorable decline of central nervous system
• Unaffected at birth, but at around6 months of age decline occurs. Inexorable deterioration
• A specific ganglioside( a type of lipid sugar molecule) accumulates in lysosomes

Question 13

How does HEXA play a role in Tau Sach’s?

Answer 13

HEXA (hexosaminidase A) is a biological catalyst/enzyme

• So loss of one copy (or null allele) is ok, as long as the other may function
• Loss of both HEXA allele causes Tay-Sach’s

Question 14

Describe the effect of A HEXA deficiency on Tay Sach’s

Answer 14

Tay-Sach’s disease (due to hexosaminidase A HEXA deficiency)

HEXA/HEXA = 100% activity

HEXA/hexa= 50% activity(carrier- no disease)

hexa/hexa= close to 0% activity= Tay-Sach’s disease

Question 15

How are mutant alleles depicted in some texts?

Answer 15

Some texts will use an asterisk (*) or an “m” to designate that it is the mutant allele that causes the trait

Question 16

What causes dominant traits- dominant disorder?

Answer 16

1. Haploinsufficiency
   - one functional copy of a gene is not enough to avoid the disorder
   - inheritance of one loss of function allele, and one normal allele causes disease
2. Gain of function(or attainment of novel function- note the subtle difference)- the gene does something new (causes the disorder) or is unregulated
3. Dominant negative- when multiple proteins associate together, if the mutation causes the higher order structure to assemble incorrectly, it can cause a disorder

Typically dominant negative mutations are worse than haploinsufficiency

4. Cancer genetics

Question 17

Define haploinsufficiency

Answer 17

Haploinsufficiency

• one functional copy of a gene is not enough to avoid the disorder
• inheritance of one loss of function allele, and one normal allele causes disease

Question 18

Define dominant negative

Answer 18

Dominant negative- when multiple proteins associate together, if the mutation causes the higher order structure to assemble incorrectly, it can cause a disorder

Typically dominant negative mutations are worse than haploinsufficiency

Question 19

Give a real world manifestation of haploinsufficiency

Answer 19

• autosomal dominant
• Familial hypercholesterolemia
• Many types- we focus on only one: LDLR deficiency
• The LDL receptor functions to clear LDL-cholesterol from the blood (uptake into the liver)
• If one copy of LDLR is nonfunctional, not enough receptors exist on liver cell(hepatocyte), and too much cholesterol stays in the blood

Question 20

Describe a manifestation of gain of function

Answer 20

• Autosomal dominant
• Achondroplasia
• The FGFR3 gene encodes a receptor that responds to a hormone( FGF; fibroblast growth factor)
  - its job to pass on a signal inside the cell
• In response to this signal, cells in the growth plates of the long bones ossify and stop growing
• In achondroplasia, the FGFR3 protein is persistently active (it is not regulated), it is just “on”
• So premature ossification occurs, bones are not as long as they should be, and person has dwarfism
• gain of function of the protein product of the gene

Question 21

Describe huntings disease as a gain of function disease

Answer 21

Autosomal dominant- gain of function(attainment of a novel function)

-Huntington disease(HD)

• Caused by an expansion of three nucleotides in the exon of a gene
  
  • Normally there is 10-33 repeats of CAG
  • CAG codon codes for glutamic amino acid
• This area of the genome is sometimes unstable
  - As repeat becomes longer, it becomes more unstable
• If repeats expand too far, it becomes pathogenic
  - Causes onset neurodegradation
• An example of attainment of a novel function(gain of function)
• The new function is not understood, but it leads to neuronal death

Question 22

Give a manifestation of dominant negative

Answer 22

• Marfan syndrome
• Mutation in the gene -> different protein produced

-Both alleles are expressed(autosomal)
The protein formed from the mutant gene doesn’t assemble properly with other proteins
Causes higher order structures to not form properly (an interference)

-Marfan syndrome: leads to connective tissue problems (all related to connective tissue):

• Chest wall deformity
• tall stature
• Risk of heart defect
• Eye lens subluxation

-Only need one copy for this effect to occur, so autosomal dominant, in this case(dominant negative)

Question 23

Describe where dominant negative effect is seen

Answer 23

• Usually observed for multi,Eric proteins(proteins with more than one submit) or proteins that interact with other proteins
• The protein product of the mutant gene interferes with the association of the multimeric
• this creates an unstable multimeric protein/abnormal non-functional multimer

Question 24

What is incomplete (partial) dominance?

Answer 24

Final appearance of the trait (phenotype) is mid-way between the two alleles

Flower color: red - pink -white

Hair: curly ~ wavy straight

Question 25

Depending on the __________ of an allele, a recessive trait may be seen in multiple generations of a family

Answer 25

Frequency

Question 26

What pseudo dominance?

Answer 26

Pseudo dominance of an autosomal recessive disorder

• This is when an autosomal recessive disorder is seen successive generations
• Gives the appearance that the disorder is dominant, but in fact it is just recessive

Question 27

Give an example of a disease that is autosomal recessive

Answer 27

Sickle cell disease is an example of autosomal recessive and psuedodominance

Question 28

What is sickle cell disease?

Answer 28

• is autosomal recessive
• Most people have AA alleles, and do not have sickle cell disease
• A person with one “S” allele and one of the normal “A” alleles is genotype “AS” is a carrier and is said to have “sickle cell trait”
• Upon stress: deoxygenation of the hemoglobin, high temperature, the hemoglobin that has the proteins formed from the “SS” alleles tends to polymerize
• Distorts shape of the RBC

Question 29

Describe the genetics behind malaria and blood disorders

Answer 29

• Over many generations, populations exposed to malaria accumulate mutations in genes that lead to blood disorders
• When in heterozygous state, the person has a slightly increased probability to survive a malaria infection

H

Question 30

What are the 3 reasons we might see pseudo dominance?

Answer 30

1. High frequency of the recessive allele (high carrier frequency in population )
2. Consanguinity
3. By chance (sometimes it happens; if you look at enough events)

Question 31

What is codominance ?

Answer 31

• Both the maternal and the paternal alleles are expressed
• Both can be equally detected
• Examples: ABO blood type
• another example:

roan fur in cattle:
-Red (RR = all red hairs), white (WW= all white hairs) or roan (RW= red and white hairs together)

Question 32

What is blood type ABO controlled by?

Answer 32

Is controlled by the terminal sugar on a specific protein (that is a glycoprotein) on the cell surface

Question 33

What determines A, B and O blood type?

Answer 33

• A, B or O blood type is determined by a sugar structure attached to a protein on the surface of the RBC
• Type O does not have a terminal sugar

Question 34

What blood type is the universal donor and why?

Answer 34

• Type O is the universal donor (it has A or B antigens on its surface)
• Type AB is universal acceptor (both A and B are recognized as “self”

Question 35

Explain the relationship between blood type and the immune system

Answer 35

• Some proteins on the red blood cell(RBC) have sugar groups attached to them , and they face to the outside of the cell
• These sugar groups can act as antigens (an antigen is something that can be recognized by the immune system)
• The developing immune system must recognize antigens present naturally in each of us during development as “self” to avoid autoimmune reactions
• If incompatible blood types are given an immune reaction can occur

Question 36

A person has AB blood group, what alleles May their parents have?

Answer 36

A person with AB blood group has received allele A and B, each from one parents

So the parents may be AA and BB or AO and BO

Question 37

A person has blood group A, what alleles May their parents have/had?

Answer 37

May have received A allele from both parents or A and O between both their parents

Question 38

A person has B blood group, what alleles did they possibly receive from their parents?

Answer 38

May have received A alleles from both parents or B allele from one parent and O allele from the other parent

Question 39

A person has a blood group O, what alleles did their parents have?

Answer 39

Has received O alleles from both parents