Non-Mendelian Inheritance Flashcards
What is a contiguous gene syndrome? How does this relate to “dosage sensitivity?”
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.
Contiguous gene syndromes:
Potocki-Lupski syndrome
Smith-Magenis syndrome
Symptoms of both? Which is due to deletion/duplication?
Deletion- Smith-Magenis syndrome: MR/ID, facial features, sleep disturbances
Duplication- Potocki-Lupski syndrome: MR, autism, hypotonia, heart defects
Contiguous gene syndromes:
Charcot-Marie-Tooth disease
Is this deletion or duplication? Symptoms?
What about its opposite?
Deletion- Charcot-Marie-Tooth disease: Hereditary motor and sensory neuropathy (HMSN)
Duplication- Hereditary neuropathy with liability to pressure palsies (HNPP)
Contiguous gene syndromes:
What would a deletion or duplication cause in the 22q11.2 gene?
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.
Contiguous gene syndromes:
What would a deletion or duplication cause in the 1q21.1 gene?
What is this a great example of?
Dosage sensitivity!
Deletion- autism, *microcephaly
Duplication- autism, *macrocephaly
What is the main mechanism that causes deletions and duplications? Basics on what happens?
Non-allelic homologous recombination (NAHR). Crossing-over in meiosis causes deletions or duplications due to misalignment.
What specific type of deletion is seen in Digeorge syndrome?
Proximal deletion.
Diagnosing contiguous gene disorders:
How does FISH work? Limitations?
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.
Diagnosing contiguous gene disorders:
Chromosome Microarray: How does it work? Limitations?
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.
what enzyme methylates things at CPG islands? What does it methylate?
DNA methyltransferase. Methylates Cs.
Just name the 3 ways that gene expression can be affected
DNA methylation
Chromatin remodeling/histone modification
X-inactivation
What pathology is seen in the mutation of MECP2 gene? What does this help show the importance of?
Inheritance of this disease? Symptoms?
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.
What is the Lyon Hypothesis?
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.
When does X-inactivation (Xi) happen in humans? It is clonal and permanent. what does this mean?
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.
- where does X-inactivation start? What gene is it?
- What does that key gene code for?
- Explain the mechanism of Xi.
- X-inactivation center (XiC), located at Xq13. The key gene is called XIST.
- XIST codes for a functional non-coding RNA, meaning that it is never actually translated. But, it does serve a purpose in RNA form.
- 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.
What percentage of genes escape Xi? How are they oriented?
15%. They are generally clustered together.
What are two ways that Xi is not random?
- Large deletions that include the XIC.
2. Translocation of the XiC to the other chromosome.
Note: Both X chromosomes have an XIST gene; one is randomly activated to silence its chromosome.
.
How can Xi cause a carrier female to show symptoms for an X-linked recessive disorder?
If there is a heavily skewed Xi pattern that favors the disease state, a carrier female will show symptoms.
How can Xi cause an identical twin to show symptoms for a disease, but no the other?
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.
When does imprinting happen? Does it change?
Happens during gametogenesis. Imprinting does NOT change during an organism’s lifetime.
What is the difference between paternally imprinted and paternally expressed?
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.
What are the 3 ways prader-willi syndrome can happen?
Symptoms of prader-willi syndrome?
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.
What are the 3 ways angelman syndrome can happen?
What are the symptoms of angelman syndrome? Although multiple types, what is the deletion mechanism?
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.
