Trinity College Dublin

KARI-TRC

Shirakawa Institute of Animal Genetics

Genomic approaches to trypanosomiasis resistance

- some surprises

Trinity College Dublin

KARI-TRC

Shirakawa Institute of Animal Genetics

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 trypanosomosisBoran (relatively susceptible)

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.

N’Dama (tolerant)

-15-10-505

1015

-15-10-50

51015

MMU1

MMU17

MMU5

D17Mit16

D17Mit46

D17Mit7 D5Mit233

D5Mit24

D5Mit114

D1Mit102

D1Mit403

D1Nds2

D1Mit113

0

120cM

80

40

In mice, we mapped three genomic regions which determine survival time following T. congolense infection

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

2

2.2

2.4

2.6

2.8

3

3.2

3.4

0 2 4 6 8 10ICU day

Tot

al c

hole

ster

ol (

mm

ol/l)

Died Survived

Patients in ICU under tight glycaemic control

2

2.2

2.4

2.6

2.8

3

3.2

3.4

0 2 4 6 8 10ICU day

Tot

al c

hole

ster

ol (

mm

ol/l)

Died Survived

This is nothing to do with Trypanosomiasis - this is a

general response.

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.

Trinity College Dublin

KARI-TRC

Shirakawa Institute of Animal Genetics