Bio 363 Human Genetics Spring 2013
Down syndrome (DS) study sheet
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Background review material:
--euploid vs. aneuploid
--polyploid, monoploid (into which of the above two categories do these terms fit into?)
--nullisomic, monosomic, trisomic (ditto?)
How does monosomy arise? How does trisomy arise?
What are the clinical consequences of monosomy and trisomy? Is it different with different chromosomes?
What is a Robertsonian translocation? What happens during meiosis in a person with this kind of chromosomal rearrangement?
In what different ways can DS arise?
What are the symptoms of DS?

Antonarakis et al., 2004
What are all the ways to test a fetus for Down syndrome?
How was it shown that extra copies of chromosome 21 are normally maternally derived?
What are the mouse models for DS? Be able to draw the chromosomes in each strain. Explain the concept of synteny in the context of these strains.
How many genes are estimated to be on chromosome 21? How have recent studies of the transcriptome called the number into question? What's the significance of the many non-coding RNAs?
What is the critical region, and how was it determined?
How can protein dosage imbalance lead to phenotype alterations? Give examples.
Are all the genes in the trisomic region of mouse models expressed at 1.5x the normal level? Why or why not? (speculate..)
Prioritize the future directions listed near the end of the paper.

Prandini et al., 2007
What did the authors show in a previous study (top of second column, first page), and how does that complicate studies of Down syndrome gene expression?
By what criteria do the authors aim to classify genes, and how is this classification relevant to hypotheses concerning the variability of Down syndrome severity?
Outline the procedure used. What kinds of cells? How many lines of each type? What controls? How was gene expression measured? Which genes were excluded from analysis and why?
(For this paper it’s more useful to read the methods section than it is with other papers)
Try to infer what it means for a gene to meet the efficiency criteria.
Look up Table 3 at the journal web site.
Fig 1: How does panel A help illustrate which genes were chosen for full analysis? How well does panel B illustrate the overall results? The genes are shown in the order they exist on the chromosome—what additional result does that show?
Did Chr 21 genes give different results from non-Chr 21 genes? (Which was the exception and how do you explain it?)
What HSA21 gene shows really different expression in DS?
Fig 2: What is a coefficient of variation? Does a high or low number mean that the expression levels are very similar across all cell lines in a category? What does it mean that the genes with low CV values have a higher level of statistical significance (based on KW score) when comparing normal to DS expression levels?
Fig 3 and 4: What does a D score indicate? Pick a couple of examples in figure 3, eyeball the overlap in expression levels, and then see how the D scores correspond in Fig 4.
How do the authors try to connect the gene groupings in Fig 4 with different aspects of the Down Syndrome phenotype?

Korbel et al., 2009  
What are segmental trisomies?
Is this paper looking at gene expression or simply DNA copy number?
Fig 1: How does FISH work? How does a quantitative Southern blot work? Results from these techniques on this patient are in panel C. What additional technique led to the data in panel D? Do the data in C and D correspond? What “gap in the duplicated region” was apparent in D but not in C?
Fig 2: Note that the figure legend describes the figure as if it were rotated 90 degrees to put the text right side up. “Left” and “right” columns refer to the pair of columns per patient.
What sorts of complex chromosomal rearrangements were found?
For the last part of the paper, just focus on panels A and B of Fig 3, and the accompanying text about DSCHD only. Don’t try to figure out the specifics of the Bayesian analysis. How was the critical region for the DSCHD aspect of Down syndrome narrowed down using both mice and humans? How many genes are in the narrowed-down region, and what interesting ones are included?
What are some of the big picture conclusions at the end of the paper?