Microbiology 204
Discussion Session #3 October 21, 2016
1-2:30PM S157
Faculty leader: Trevor Burt
Sharon et al., Genetic variation in MHC proteins is associated with T cell receptor expression biases. Nature Genetics, ng3625, epub ahead of print.
Everyone should read this paper before coming to class. You do not need to read the supplemental materials and supplemental figures (especially in this paper, where there are 32 Supplemental Figures!!!), although the Discussion Leader may choose to have the class discuss one or a few supplemental figures.
See below if you have an assignment, in which case you have some additional preparation for class. Assignments rotate among the students.
LEARNING OBJECTIVES:
To understand that MHC gene variation can have a direct effect on the types of TCRs that are selected during T cell development. To become familiar with genetic association mechanisms.
STUDENT ASSIGNMENTS
1. Discussion leader (see instruction page for advice on leading the discussion)
2. Virtually all autoimmune diseases are associated with specific MHC alleles. Give the class some examples of strong MHC (or HLA) association with various autoimmune diseases. Start with the disease ankylosing spondylitis. What is our main hypothesis of how different MHC alleles confer increased risk for autoimmune disease? How strong is the evidence to support this hypothesis?
3. For Fig. 1, explain the experimental approach for this study. What is an eQTL?
4. Fig. 2, is the meat of the paper. Describe these results. What is a Manhattan plot? Why don’t the TCRg and TCRd genes show some association with MHC? The Ig genes (Vl, Vk and VH) are shown as controls. Seems to me there is some signal with Vk?
5. Explain Fig. 3. In panel A, it is clear that there is more association of various TCR types with MHC II genes than MHC I genes. The authors offer a potential explanation. In general, what is more polymorphic in the human population, MHC I or MHC II? How do you think this should contribute to TCR diversity?
6. Fig. 4 shows that many of the specific amino acids in MHC I or MHC II that are associated with TCR bias are also known polymorphisms with human disease. Try to explain the statistical methods used in this figure. What is Bayesian analysis?
7. Explain Fig. 5. (pretty simple)
8. Perhaps the most interesting finding is the association of specific MHC amino acid residues known to be involved in various autoimmune diseases with a high propensity to select for certain TCR genes. Provide a hypothesis of how these interactions may lead to selection of pathogenic T cells in autoimmunity.
9. What is the acknowledged limitation of this study?
Student assignment #s
1. Germain Yong 10. Joe Hiatt
2. Didi Zhu 11. Theo Ross
3. Jeanmarie Gonzalez 12. Tina Solvik
4. Parinaz Fozouni 13. Ariane Panzer
5. Priya Mohindra
6. Camille Simoneau
7. Patrick Schupp
8. Elise Wollf
9. Cindy Tian
(NOTE : if you will miss a discussion session, inform Dr. Lowell in advance; if assignments have already been made, you should additionally make a trade with one of your classmates who does not have an assignment that week so that your assignment is covered).