Bio 363 Human Genetics Spring 2013
Narcolepsy study sheet
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Chabas et al., 2003
For background information on MHC/HLA loci and allele nomenclature, see .
What are the normal stages of sleep? What goes wrong in narcolepsy?
What is the structure and function of class II MHC proteins? In what cells are they expressed?
What is relative risk?
In a very general sense, what do tables 1 and 2 suggest about different MHC genotypes and their link to narcolepsy?
Can you figure out how relative risks were calculated in table 2?
What do twin studies suggest about narcolepsy susceptibility?
Where in the brain is hypocretin made? Where are hypocretin receptors expressed?
After you've read the Lin paper, compare its text with the canine narcolepsy section of this review.
What mutations were found in different narcoleptic dogs (see Fig 3)?
How is the HLA DQA1*0102 DQB1*0602 association with human narcolepsy related to the hypocretin story??

Kornum et al., 2011
What have the been the advances and curious findings regarding genetic predispositions and triggers for autoimmunity and narcolepsy in recent years?

Lin et al., 1999
Explain in general why backcrosses (see top of second page) were necessary to prepare for this linkage study.
The researchers thought they found linkage to an immunoglobulin gene, but what was actually the case?
How did they use the idea of synteny to help with their chromosome walking efforts?
Once they had isolated the DNA across the region, what additional features were found to help with finer mapping?
What are all the features depicted in Figure 2?
For the dogs mentioned in the middle of Figure 2, what does it mean for the assocated line to be blunt at one end and have an arrow at the other end?
Which two dogs initially defined the genomic region of interest?
Which dogs further narrowed the region of interest? How many known genes were in that region?
How did Southern blotting initially suggest that there were mutations in HCRTR2?
How did PCR help clarify the nature of the mutation? What were the templates used in the different panels of Figure 5?
What are the different mutations in narcoleptic Dobermans and Labradors?
What was intriguing about the hypocretin system?
Don't try to muddle through all the brain anatomy in the discussion. Just get a general sense of whether hypocretin-synthesizing neurons are widespread or localized in the brain, and whether the regions they project to are widespread or localized.

Hallmeyer et al., 2009
Sketch a flow chart of the logistical steps taken by the researchers. What samples were collected and how were they tested?
By what criterion was the sample population limited?
Eyeball the numbers in Table 1 to see how the data suggest an association.
Look up the Mantel-Haenzel test to get a general sense of how it works, but otherwise don't get bogged down in the statistical methods.
Look up VJ and VDJ recombination to understand how genes for antibody and T cell receptor subunits are processed during lymphocyte maturation.
What are the speculations regarding the mechanism of how these polymorphisms might increase narcolepsy risk?