Non-Mendelian Inheritance

Question 1

What is a contiguous gene syndrome? How does this relate to “dosage sensitivity?”

Answer 1

deletion or duplication of many genes, a large chromosome region. The effects of these changes are due to relative dosage of genes, as deletions and duplications can have variable phenotype effects.

Question 2

Contiguous gene syndromes:
Potocki-Lupski syndrome
Smith-Magenis syndrome
Symptoms of both? Which is due to deletion/duplication?

Answer 2

Deletion- Smith-Magenis syndrome: MR/ID, facial features, sleep disturbances

Duplication- Potocki-Lupski syndrome: MR, autism, hypotonia, heart defects

Question 3

Contiguous gene syndromes:
Charcot-Marie-Tooth disease
Is this deletion or duplication? Symptoms?
What about its opposite?

Answer 3

Deletion- Charcot-Marie-Tooth disease: Hereditary motor and sensory neuropathy (HMSN)

Duplication- Hereditary neuropathy with liability to pressure palsies (HNPP)

Question 4

Contiguous gene syndromes:

What would a deletion or duplication cause in the 22q11.2 gene?

Answer 4

Deletion- Digeorge syndrome: Heart defects, learning disability, unique face, cleft palate, delayed speech, feeding difficulties

Duplication- Cat eye syndrome: Vertical colobomas, anal atresia, heart defects, learning disability, scoliosis.

Question 5

Contiguous gene syndromes:
What would a deletion or duplication cause in the 1q21.1 gene?
What is this a great example of?

Answer 5

Dosage sensitivity!
Deletion- autism, *microcephaly

Duplication- autism, *macrocephaly

Question 6

What is the main mechanism that causes deletions and duplications? Basics on what happens?

Answer 6

Non-allelic homologous recombination (NAHR). Crossing-over in meiosis causes deletions or duplications due to misalignment.

Question 7

What specific type of deletion is seen in Digeorge syndrome?

Answer 7

Proximal deletion.

Question 8

Diagnosing contiguous gene disorders:

How does FISH work? Limitations?

Answer 8

Molecular probe attaches to specific DNA sequence. The fluorescence has two colors. The red and green will bind to one strand of DNA, and the subsequent strand will only have one of the colors bound to it. This indicates a deletion in that strand.

You have to be looking for a specific gene! It can’t blanket-diagnose a bunch of diseases.

Question 9

Diagnosing contiguous gene disorders:

Chromosome Microarray: How does it work? Limitations?

Answer 9

More powerful than FISH. Runs whole genome; you don’t have to have a sequence in mind. Red regions above the x-axis represent duplications, whereas green regions below the x-axis represent deletions.

It is an extremely sensitive test. It will likely show multiple duplications and deletions that mean nothing and show no problems at all.

Question 10

what enzyme methylates things at CPG islands? What does it methylate?

Answer 10

DNA methyltransferase. Methylates Cs.

Question 11

Just name the 3 ways that gene expression can be affected

Answer 11

DNA methylation
Chromatin remodeling/histone modification
X-inactivation

Question 12

What pathology is seen in the mutation of MECP2 gene? What does this help show the importance of?
Inheritance of this disease? Symptoms?

Answer 12

Shows importance of correct DNA methylation. Rett syndrome can be seen with a mutation in the MECP2 gene, which codes for Methyl-CPG-binding protein.

X-linked dominant, so lethal to males. Microcephaly and autism in females.

Question 13

What is the Lyon Hypothesis?

Answer 13

One of the X chromosomes in females is inactivated as a barr body. Adult female ends up a mosaic of 50% of cells having Xm inactivated, and the other half of cells Xp inactivated.

Question 14

When does X-inactivation (Xi) happen in humans? It is clonal and permanent. what does this mean?

Answer 14

Happens at fertilization, finishes within the week. Clonal and permanent means that each time a cell divides, it keeps the same X-chromosome inactivated, forever.

Question 15

1. where does X-inactivation start? What gene is it?
2. What does that key gene code for?
3. Explain the mechanism of Xi.

Answer 15

1. X-inactivation center (XiC), located at Xq13. The key gene is called XIST.
2. XIST codes for a functional non-coding RNA, meaning that it is never actually translated. But, it does serve a purpose in RNA form.
3. XIST RNA coats the X-chromosome that is to be inactivated. This leads to methylation of x-linked genes in it, and chromatin is condensed, silencing almost all of them.

Question 16

What percentage of genes escape Xi? How are they oriented?

Answer 16

15%. They are generally clustered together.

Question 17

What are two ways that Xi is not random?

Answer 17

1. Large deletions that include the XIC.

2. Translocation of the XiC to the other chromosome.

Question 18

Note: Both X chromosomes have an XIST gene; one is randomly activated to silence its chromosome.

Answer 18

.

Question 19

How can Xi cause a carrier female to show symptoms for an X-linked recessive disorder?

Answer 19

If there is a heavily skewed Xi pattern that favors the disease state, a carrier female will show symptoms.

Question 20

How can Xi cause an identical twin to show symptoms for a disease, but no the other?

Answer 20

If the inactivation happens before the twins split, and the zygote splits unevenly, then the twin with more of the disease X expressed will show the disease while the other will not.

Question 21

When does imprinting happen? Does it change?

Answer 21

Happens during gametogenesis. Imprinting does NOT change during an organism’s lifetime.

Question 22

What is the difference between paternally imprinted and paternally expressed?

Answer 22

Paternally imprinted means that a paternally-inherited gene is silenced. Paternally expressed means that a gene is only expressed if it is inherited from the father.

Question 23

What are the 3 ways prader-willi syndrome can happen?

Symptoms of prader-willi syndrome?

Answer 23

Large deletion of paternal 15q11.2 (75%)
Uniparental disomy of maternal chromosome 15 (25%)
Imprinting center defect (1%)
Neonatal hypotonia, significant developmental delay, hyperphagia and insatiable appetite, often obesity.

Question 24

What are the 3 ways angelman syndrome can happen?

What are the symptoms of angelman syndrome? Although multiple types, what is the deletion mechanism?

Answer 24

Maternal deletion 15q11.2 (60-70%)
Paternal UPD of chromosome 15 (5%)
UBE3A gene mutation (10-15%)

Maternal deletion of gene, and paternal genes are paternally imprinted. Severe devel. delay/intellectual disability. Microcephaly, speech impairment, seizures, ataxia/jerky movements, happy demeanor.

Question 25

Recurrence risk of UPD? What about for imprinting center mutations or gene mutations?

Answer 25

Low recurrence risk for deletions and UPD. However, up to 50% recurrence for imprinting center/gene mutations.

Question 26

What chromosome numbers are generally imprinted?

Answer 26

Chromosomes 7, 11, 14, 15

Question 27

Explain what UPD is (as seen in PWS or AS), and how that can cause issues.

Answer 27

In PWS, the cause could be maternal UPD. This means that the child got both genes from mom. Problem is, the 15q11.2 regions of both chromosomes are maternally imprinted and thus silenced.

Question 28

Explain how a paternal deletion could cause PWS, and what gene needs be deleted.

Answer 28

Deletion of paternal 15q11.2. Still inherits gene from mother, but it’s imprinted.

Question 29

AIC and PIC are both what? Deletions/errors in these locations could cause what?

Answer 29

Imprinting centers. PWS or AS.

Question 30

Explain the 3 causes of UPD.

Answer 30

1. Trisomy rescue- Non-disjunction in game formation. You then get two gametes fusing to form a zygote, that is now 3n for that chromosome. Non disjunction here gives you two somatic cell types, one with UPD (two of same chromosome) and one normal.
2. Monosomy rescue- Non-disjunction in forming gametes. Zygote forms as 1n for that chromosome. Somehow, it is able to duplicate, not sure how. You get monosomy, but due to that duplication the cell is UPD.
3. Gamete complementation- Non-disjunction in both gametes, with one gamete giving a UPD style 2 chromosomes, and the other giving none. Result is thus a zygote that is UPD.

Question 31

Epigenetics: Whole genome effect;

What happens if an embryo has only paternal genome?

Answer 31

Little or no fetal tissue, with overgrown placenta.

Hydatidiform mole.
complete mole- Non-viable egg with no DNA fertilized by sperm that duplicates its genome.

partial mole- monospermic or dispermic fertilization of viable egg leading to 3n or 4n embryo.

Question 32

Epigenetics: Whole genome effect;

What happens if an embryo has only a maternal genome?

Answer 32

Egg develops unfertilized with two copies of maternal genome. Does have some (although poor) fetal growth, but fibrotic placental tissue.

**Ovarian teratoma

Question 33

Endocrine disruptors and assisted repro. technologies can cause imprinting issues

Answer 33

note.

Question 34

duplication of Pw/Angelman gene causes what?

Answer 34

Duplication syndrome: Autism, seizures, increased risk of psychiatric/behavioral problems.