1. Trinity College Dublin
KARI-TRC
Shirakawa Institute of Animal Genetics
Functional genomics to identify genes and networks influencing survival following Trypanosome challenge.

2. Functional genomics to identify genes and networks influencing survival following Trypanosome challenge.
Shirakawa Institute of Animal Genetics
Trinity College Dublin
KARI-TRC

4. Mouse model
X =
C57BL6 resistant
Balb/c susceptible

5. phenomenology - (1) subjective or phenomenal experience (2) a systematic study of consciousness from a first-person perspective originated by Husserl. See phenomenological critique of representationalism
In the philosophy of mind there exists continuing debate about the validity and usefulness of this approach to the study of consciousness.
In the philosophy of trypanotolerance …………………..

6. Trypanotolerance research. 30 years of stamp collecting ?

7. Studying the tolerant/susceptible phenotype has problems:
Separating cause from effect
Separating relevant from irrelevant.
Dominance of the ‘what is happening to this weeks trendy gene/protein/cytokine?’ approach.

8. Studying tolerance susceptibility any way has problems:
We have no idea of the mechanisms
We have no idea of effector tissue
(or maybe too many ideas)
We have no in vitro model

9. M. Soller and J.S. Beckmann, FAO Consultation Report, March 1987
‘Mapping trypanotolerance loci of the N’Dama would allow the rapid introgression of desired traits from other breeds into the N’Dama, while retaining the trypanotolerance traits; or the rapid introgression of the trypanotolerance trait from the N’Dama to other breeds. Mapping of trypanotolerance loci would also be the first step in their eventual cloning and manipulation through genetic engineering techniques’
CCER June 2002

11. Contribution of 10 genes from Boran and N’Dama cattle to reduction in degree of trypanosomosis
Boran (susceptible)
N’Dama (tolerant)
The N’Dama and Boran each contribute trypanotolerance alleles at 5 of the 10 most significant QTL, indicating that a synthetic breed could have even higher tolerance than the N’Dama.

12. In mice, we mapped three genomic regions which determine survival time following T. congolense infection
D17Mit46
D17Mit16
D5Mit233
D17Mit7 40
D5Mit114
D5Mit24
D1Nds2
MMU17
D1Mit102 80
D1Mit113
D1Mit403
MMU5
MMU1
120cM

13. The mapping data gives us a point of attack for a functional approach.
What are these genes ?
How do they affect survival ?
What response pathways are common to mouse/cow/human ?
What does that tell us about how to survive trypanosome challenge ?
The mapping data gives us a point of attack for a functional approach.

14. Functional genomics technology allows us to look at what genes respond to infection And especially what genes respond differently to infection

15. Expression analysis of cow and mouse, resistant and susceptible.

16. Expression analysis of cow and mouse, resistant and susceptible
Expression analysis of cow and mouse, resistant and susceptible. Back to stamp collecting?

17. Expression studies Cow. N’dama vs Boran time course
Expression studies Cow N’dama vs Boran time course N’dama x Boran backcross Mouse C57 vs A/J & Balb/c time course C57*A/J congenics (C57*A/J BAC transgenics)

18. Mouse time course. Liver.

19. Congenics
Lines fixed for alternative ‘alleles’ of each QTL on a susceptible background.
Day 0
liver

27. MMU17 MMU5 MMU1 D17Mit46 D17Mit16 D5Mit233 D17Mit7 40 D5Mit114 D5Mit24
D17Mit46
D17Mit16
D5Mit233
D17Mit7 40
D5Mit114
D5Mit24
D1Nds2
MMU17
D1Mit102 80
D1Mit113
D1Mit403
MMU5
MMU1
120cM

28. Cxcl1 - inflammatory response

29. This is NOT a gene hunt!
We are trying to understand the biology of the system.

30. This is NOT a gene hunt!
We are trying to understand the biology of the system.
But!
How do we know when we have the gene we were not looking for?

31. What to do with candidate genes
All the obvious things
Plus
Exploit the unique populations of cattle
‘Recently’ admixed resistant * susceptible
Multiple resistant breeds
Multiple resistant species (sheep, goat, wildlife)

32. Data exchange issues Shirakawa Institute of Animal Genetics
Trinity College Dublin
KARI-TRC
Shirakawa Institute of Animal Genetics
Data exchange issues

34. Shirakawa Institute of Animal Genetics
Trinity College Dublin
KARI-TRC