Extension Of Mendelian Genetics

Question 1

Describe recessive lethal alleles

Answer 1

-Unlikely to be observed in the population

• consider homozygous null mutations in a pathway such as glycolysis
  
  • Glycolysis is an essential pathway almost all biological life forms on earth
  • therefore complete loss of glycolysis is likely to be lethal

Another example might be genes encoding histone proteins
-DNA in chromosomes need their histones

Question 2

Describe homozygous dominant lethal

Answer 2

-Agouti is wild type (normal) mouse

• One “Y” elbow mutation = yellow mouse
  - yellow is a dominant trait

-two “Y”ellow mutations= lethal

So the end result is 2/3 and 1/3 ratios when two heterozygous (yellow mice) mate (AA^y xAA^x)

Question 3

Give an example of the 1/3 and 2/3 ratio homozygous dominant in humans

Answer 3

-Achondroplasia (autosomal dominant; a form of dwarfism)

• Recall, FGFR3 “gain of function” mutation
  - Let A be the normal allele
  - Let A* be the mutation which causes achondroplasia

So, the surviving children (on average) 1/3 of possibilities are of normal stature, and 2/3 have dwarfism. Inheritance of two FGFR3 mutations causes fetal or perinatal lethality

Question 4

Explain the phenomena of Dominant alleles; delayed age of onset

Answer 4

• Consider Huntington’s disease(HD)-a lethal allele, if the patient lives long enough to succumb to the disorder
• If patient doesn’t die of something else, the HD will inexorably be lethal

Question 5

Give 2 examples of dominant disease alleles in the homozygous state

Answer 5

Typically are not found (the disease alleles are already very rare; so it’s extremely rare that they will come together in two individuals)

Example 1: Familial hypocholesterolemia
-AD (heterozygous) adult onset consequences of high cholesterol

-AD(homozygous) childhood onset consequences of high cholesterol

Example 2: Achondroplasia

• AD(heterozygous) dwarfism
• AD (homozygous) lethal during fetal development, or perinatal period

Question 6

Explain how a phenotype May be influenced by many factors

Answer 6

1. Sometimes a trait is influenced strongly by a specific allele (these are Mendelian traits) allele 8s said to have high penetrance
2. Sometimes traits are influenced by many different genes
3. However, modifier genes may alter the trait
4. Environmental exposures May influence a trait
5. For some traits, many genes and combination of environmental exposures may act together to affect a trait-multifactoral traits

Question 7

What are Mendelian traits?

Answer 7

When a trait is strongly influenced by a specific allele then these traits are Mendelian

The allele is said to have high penetrance

Question 8

What is genetic epistle is?

Answer 8

• One gene may be called epistemic to another if it masks the trait of that other gene
• Allows scientists to attempt to arrange genes into pathways (common function and order of effect)
• Genes that act downstream are called epistemic
• Genes that are masked (downstream) are called hypostatic

Question 9

Explain an example of epistasis

Answer 9

-Consider a cell signaling pathway that controls morphology(blobs and projections)

Gene A arrests blobs which form on the cell

Gene B causes blobs to form projections

A loss of function of gene A would be expected to block formation of both blobs and projections

If a different mutation in gene B( such as gain of function) is found that allows projections to form in the absence of gene A function, then we expect that gene B. Functions after gene A

Question 10

What is the Bombay phenotype?

Answer 10

A woman is found to be type O

Her husband is type A

But her children inherit type B from her (no hanky-pinky is going on)
-Mother passes on type B

• There is no father involved
• And she inherited type B from her mother

Therefore something else is going on

Question 11

Explain the Bombay phenotype

Answer 11

-People with Bombay phenotype (blood type) do not create the precursor carbohydrate, so they can be neither A nor B, even if the alleles that control the addition of the sugars are functional for them

In the Bombay Phenotype, the H substance itself cannot be made, so the carbohydrate cannot be matured. Therefore, the person may be neither A nor B (and functionally appears as they type O)

Genetically, type B (mom in previous example

Of course, this is very rare in human populations

Question 12

What is pleiotropy ?

Answer 12

Marfan syndrome as an example

• Many features of the phenotype May be observed that are all caused by (somehow) the sane mutation (same allele)
• Marfan syndrome(fibrillin) and connective tissue problems
• Single gene disorder affects multiple organ systems
  - Chest wall deformity
  - Tall stature
  - Risk of heart disease
  - Eye lens subluxation

Question 13

Describe X-linkage in humans

Answer 13

Females are XX
-The ovum can Contribute only an X to a zygote

Males are XY
- the sperm can contribute either an X or a Y to a zygote

Question 14

How much chromosomes does a human have?

Answer 14

46 chromosomes (44 autosomal chromosomes, come in pairs

Question 15

What chromosome determines the sex?

Answer 15

Sex is determined by the X chromosome

A gamete from a female (ovum) May only be X(female is XX)

A gamete from a male (sperm) May be X or Y (this is because the male is XY)

Question 16

Why is the X chromosome so big compared to the Y chromosome?

Answer 16

There are more than 1,000 genes on the X chromosome

 - some are required for formation of the female sex
 - Most genes on the X chromosome are for “other” functions

Only a few genes are on the Y chromosomes

• Most control the formation of the male sex and spermatogenesis
• Very little for other functions(some intersting exceptions)

Question 17

What is X-inactivation?

Answer 17

During embryonic development, one of the few X chromosomes is deactivated (called X-inactivation) to ensure that males and females have balanced gene expression (a few genes escape this; genes that control formation of the female phenotype)

Question 18

Describe the pairing of X and Y chromosomes

Answer 18

They pair up during mitosis and meiosis

They must be controlled to ensure appropriate

Psuedoautosomal regions of X and Y allow pairing during mitosis and meiosis

Question 19

Give an X-linkage example

Answer 19

Hemophilia A or B

Bleeding disorder; improper hemostasis
-blood clots fail to form; or form too slowly

Many components are in this pathway

We will focus on Hem A and Hem B which are are both X-linked

Mom of a male is an affected carrier of the mutation

Mostly occurs in males(likely to be more severe in males x*Y)

If seen in females, likely to be seen less severe in females

Question 20

What is the royal bleeding disorder?

Answer 20

Hemophilia

Question 21

What is the recurrence risk for the X-linked recessive disorder, hemophilia with a normal father and carrier mother?

Answer 21

• 50% of daughters may be carriers, 50% of daughters may be normal
• 50% of sons may be affected, 50% of sons may be normal

Each conception event is independent

1/4 risk that a child may be affected

Question 22

What is the recurrence risk for the X-linked recessive disorder, hemophilia with an affected father and normal mother?

Answer 22

All daughters of an affected father must be carriers of the mutant allele

A son may not inherit an X-linked mutation from his father

None of his children affected

Question 23

What is the recurrence risk for the X-linked recessive disorder, hemophilia with an affected father and a carrier mother?

Answer 23

Each conception is independent event, but on average:

50% of daughters may be carriers; 50% of daughters may be affected

50% of sons may be affected; 50% of sons may be normal

Question 24

What does it mean to be hemizygous?

Answer 24

Due to XY sex determination

A typical male may not be homozygous for anything on the X chromosome

Males only have one X chromosome

Males with hemophilia are hemizygous for a mutant gene

Females have two copies of the X chromosome

Question 25

Describe sex influenced inheritance

Answer 25

Some traits are influenced by the sex of the animal(person) who has the allele

• Male pattern baldness
• More extreme in males but can still be observed in females
• the effect is thought to be exerted by testoserone
• Lots of disease examples in humans

Question 26

Describe sex-limited inheritance

Answer 26

Feathers in the do,entice fowl(hen vs cock)
-hens don’t have the characteristic long feathers

Milk production in a dairy cow
-bulls don’t have make milk

Question 27

What are conditional mutations?

Answer 27

Temperature sensitivity as an example

A Himalayan rabbit and a Siamese catBoth show dark fur color on snout, ears, and paws. These patches are due to effect of a temperature-sensitive allele responsible for pigment production

Question 28

What is anticipation?

Answer 28

Triple repeat expansion disorders

• Simple sequence repeats(SSR) in the genome tend to change over generations
  
  • SSR is di, tri, tetra

Examples: (AT repeats, CGG repeat)
-A child is likely to have the same number of repeats as his or her parents; but sometimes they change a little bit over generations

-These are most polymorphic areas of the genome

Question 29

What causes myotonic dystrophy?

Answer 29

Caused by a triplet repeat expansion in the DMPK gene

The expansion doesn’t affect the DMPK gene itself, instead, the expansion affects how many other genes are processed (and therefore expressed) in the tissues where it is expressed (the muscle )

Autosomal dominant transmission

Question 30

Describe the Myotonic dystrophy phenotype

Answer 30

Myotonic dystrophy has a pleiotropic phenotype

Characterized by wasting of the muscles, cataracts, heart conduction defects, endocrine changes, and myotonia

-Imability to relax muscle(myotonus) leads to muscle weakness and other symptoms

Question 31

What is myotonia?

Answer 31

Is reduced ability to relax after muscle contraction

Question 32

What is myoclonus?

Answer 32

A quick, involuntary muscle jerk

Question 33

Describe myotonic dystrophy as an example of anticipation

Answer 33

• As repeat gets longer, it becomes more unstable, and can expand more.
• In successive generations:
• Age of disorder onset can decrease and…
• Severity of the disorder can increase