Download what is happening to this weeks trendy gene/protein/cytokine?

Genomic approaches to
trypanosomiasis resistance
Trinity College
- some surprises
Dublin
Shirakawa Institute of Animal
Genetics
KARI-TRC
Shirakawa Institute of Animal
Genetics
Trinity College
Dublin
KARI-TRC
Copyright Mike Enfield
Livestock in heterogeneous
environments
There is extraordinary diversity in livestock (and crops)
across Africa.
This is TOTALLY different from the situation in the
West.
And reflects the ‘environment’ working on the genome.
Therefore there is information in the simple occurrence
of a given genotype in a given environment.
Trypanosomiasis
Is a fatal disease of livestock.
The livestock equivalent of
sleeping sickness in humans
T. congolense,
T. vivax
T brucei rhodesiense
T gambiense
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.
Contribution of 10 genes from Boran and N’Dama
cattle to reduction in degree of trypanosomosis
Boran (relatively susceptible)
N’Dama (tolerant)
15
10
5
0
-5
-10
-15
15
10
5
0
-5
-10
-15
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.
In mice, we mapped three genomic regions which determine
survival time following T. congolense infection
0
D17Mit46
D17Mit16
D5Mit233
D17Mit7
40
D5Mit114
D5Mit24
D1Nds2
MMU17
D1Mit102
80
D1Mit113
MMU5
120cM
D1Mit403
MMU1
PCA of Liver expression data
PCA of Liver expression data
Studying the tolerant/susceptible phenotype
STILL has the same problems!
• Separating cause from effect
• Separating relevant from irrelevant.
• Dominance of the ‘what is happening to this
weeks trendy gene/protein/cytokine?’
approach.
Analysis
(Fisher et al, NAR 35 (16)p5625-5633)
• What genes are differentially expressed
genomewide?
• What pathways are they members of?
• What pathways involve genes in the
QTL?
• What pathways are in both lists ?
• Prioritise the list by 'degree of change'
• Look at the biology of each network
Analysis
• It is important to stress that we do NOT
require (or even expect) QTG themselves to
be differentially expressed.
Cholesterol metabolism
C57 lite vs C57 regular survival following Trypanosome challenge
Patients in ICU under tight
glycaemic control
Total cholesterol (mmol/l)
3.4
Died
Survived
3.2
3
2.8
2.6
2.4
2.2
2
0
2
4
6
ICU day
8
10
This is nothing to do with
Trypanosomiasis - this is a
general response.
Total cholesterol (mmol/l)
3.4
Died
Survived
3.2
3
2.8
2.6
2.4
2.2
2
0
2
4
6
ICU day
8
10
Some conclusions
Overlaying QTL and expression data has been incredibly
informative. (But don’t assume your QTG will be differentially
expressed!)
Expression analysis in cow and mouse has revealed some
unexpected pathways and interactions.
We have learned a lot about host response to trypanosomes, but
also about:
How to survive a tryps infection
How to survive in an ICU in Northern England
Fundamentals of genome regulation.
It may be that much of biological variation will turn-out to result
from differential use of a small number of very general networks.
(Why are we surprised that QTL often (usually?) fall apart when
moved onto a new genetic background?)
If you do high quality science there will be high quality - but
unpredictable - outcomes.
Shirakawa Institute of Animal
Genetics
Trinity College
Dublin
KARI-TRC