Bio 363 Human Genetics Spring 2013
Epigenetics--Beckwith-Wiedemann study sheet
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Robertson, 2005:
Focus only on the following four parts of the paper: introduction, the section on DNA methylation and imprinting disorders, Box 2, and the future perspectives section. Within the DNA methylation and imprinting disorders section, carefully read the overview as well as the subsections on Beckwith-Wiedemann, Prader-Willi, and Angelman syndromes; skim the rest.
From supplementary information S1, what do you infer is the mechanism by which methylation marks are interpreted as transcriptional repression?
What is CCCTC-binding factor, also known as CTCF?
How is loss of imprinting associated with cancer?
Why is DNA methylation an important issue in the context of assisted reproduction technologies? See Box 2, page 600.
From the text and Figure 2, figure out what happens on maternal and paternal alleles with regard to gene regulation in the Beckwith-Wiedemann, Prader-Willi, and Angelman syndrome regions.

Choufani et al., 2010 :
What are the symptoms of Beckwith-Wiedemann syndrome?
What is the structure of the genomic region associated with Beckwith-Wiedemann syndrome? (Also refer to the Roberston paper.) Be able to describe in detail how all the various genes in this region are regulated.
What are the different underlying mutations found in Beckwith-Wiedemann patients?
How are the Beckwith-Wiedemann syndrome mutations associated with different types of cancer?
What are new research directions in this field?

Sparago et al., 2004:
What subclass of mutations listed in the Weksberg paper, Table 1, do these patients have?
Of what part of the Beckwith-Wiedemann syndrome genomic region is Figure 1a a close-up view? What does each number/letter indicate?
What do the dots mean in some of the individuals in the pedigrees?
What underlying mutation is shown to exist in these patients? How was it shown? How did this mutation arise in the first place?
How are methylation differences shown in Figure 2a? Look up the HpaII enzyme to learn its specificity. Then refer to Figure 1a for the location of the restriction sites. What fragments do you predict if there is or isn't methylation?
What is bisulfite analysis? Look it up. in Figure 2b-d, what does each row of dots represent? What does it mean if a dot is filled in? How do these data indicate abnormal methylation in the patients? Look in the materials and methods of the Prawitt paper for more information on the logistics of how this is done.
What does Figure 2e say about what alleles of what genes are transcribed in the patients?
What point is argued in the correspondence, and how do you reconcile any conflicting results?

Prawitt et al., 2005:
How was uniparental disomy ruled out as the cause of Beckwith-Wiedemann syndrome in these patients?
What aberration did II.5 pass on to many of her children? Does it correlate with disease? How does the Southern blot in Figure 1 show this defect?
What does CTS stand for?
Does the bisulfite analysis indicate a methylation problem in the patients inheriting the microdeletion?
What chromosomal defect does correlate with disease? How was this defect determined?
What gene expression defect is caused by the microdeletion? By the additional chromosomal aberration?
How can a gene expression problem exist in the absence of a methylation defect?
What's the overall explanation for the pathogenesis of the disease in this family?

Correspondence between the authors of the two papers above:
What criticism do Prawitt et al. raise? How does the Sparago group respond and reconcile the differing findings? What new data do they supply?