Bio 362 Human Genetics Spring 2008
Down syndrome (DS) study sheet for April 1st
Background review material:
Vocabulary:
--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?
Relate the idea of maternal derivation to the information in Patterson Box 2 on page 7.
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.
What is the "judicious breeding" (p.6 of Patterson, left column) to make the Ms1Ts65 strain (see Fig 2 of Antonarakis)? Look up the primary source.
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.
Kahlem et al., 2004
NOTE: view Figure 3 at higher resolution at http://chr21.molgen.mpg.de/Down_Syndrome/Suppl-fig3.html
or http://www.genome.org/content/vol14/issue7/images/data/1258/DC1/Fig3internet.jpg
How was the exact breakpoint in T(16;17)65Dn determined?
How many genes were examined on the microarray? Into what categories can you divide those genes (and how many genes are in each category)?
Exactly how was the microarray experiment performed?
In the online version of Figure 3, find the entries for a few of the genes listed in the top right part of page 1260 to visualize the tissue-specific expression described in the text.
Using the online version of Figure 3, find examples of genes showing overexpression in the Ts65Dn mice.
How were the data analyzed to construct Figure 4? Is it valid to compute and compare slopes?
What is quantitative (real-time) PCR? Look it up in the textbook and online. Why did Kahlem et al. use this technique in addition to the microarray approach?
Is there good concordance between the microarray and qPCR results (see Figure 5)?
What was strange about the expression levels of genes listed in the left column of page 1263 (before the discussion section)? Find entries for some of these genes in the online version of Figure 3 to visualize what is described.
What mechanisms might explain the expression patterns of these genes?
Lyle et al., 2004
Supplementary data are available at http://www.genome.org/cgi/content/full/14/7/1268/DC1. At that site you can download a higher resolution version of Figure 2 in PDF form.
Compare this paper to the Kahlem et al. paper in terms of the number of genes studied, the source of the mRNA, and the technique used.
Into what categories can you divide the genes studied?
How was the qPCR performed?
For a few genes, compare the data between this paper and the Kahlem et al. paper.
In general, is there a dosage effect on the trisomic genes?
What does Figure 4 say about 1) dosage effects in the same tissue at different developmental stages, and 2) dosage effects on adjacent genes on the chromosome?
How do the data in this paper and the Kahlem et al. paper contribute to our models of Down syndrome mechanisms?
Altafaj et al., 2001 (questions from Philip and Laura):
1. What genetic abnormality enabled researchers to narrow down the chromosome and find what the called the "critical region?"
2. What made the DYRK1A gene a specific interest to the researchers?
3. What does DYRK1A encode and what is its function?
4. Fig 1: List all of the research methods used in B-F. What is the take home message of this figure and were all these results necessary to proove this?
5. Fig 2: What do the labels P7, P10, and P14 refer to? What do the authors claim each of the figures (A-C) proove about the neurodevelopment of the transgenic mice? Do you think the data support this?
6. Table 1: The authors claim this data describes "emotionality" of the mice. What do you take this to mean per the data presented? Do you think their intended meaning was lost in translation?
7. Fig 3: What is latency? Comparing A and B, do the neuromotor dissabilities lessen over the life of the mouse?
8. Fig 4: Explain the Morris Water Maze (including the various specific tests performed). Do you think the data presented here support the researchers’ assertions?
9. Do you agree with the researchers’ final sentence in the discussion? Why or why not?
