Genome wide expression consequences of a disease resistance QTL are strongly influenced by the genetic background. The document discusses finding QTL genes in mice, with few genes having a large effect and many having small effects. It also discusses mouse models of trypanosomiasis and survival differences between parental strains and an F6 generation. Trypanosoma infection response loci were mapped between C57BL/6 and AJ and C57BL/6 and BALB/c mouse strains. A microarray study looked at gene expression differences between resistant C57BL/6 and susceptible AJ mice. The Daxx gene was found to be located within a Trypanosoma infection response QTL and had a polymorphism in its p53

1. Genome wide expression consequences
of a disease resistance QTL are strongly
influenced by the genetic background

2. Finding QTL genes in mice
• Few genes of large effect
• Many genes of small effect
• >2000 QTL mapped
• <20 QTL genes identified (Flint 2005)
• Genes of large effect may be dependent on
genetic background.

3. Mouse models of
Trypanosomiasis
Survival of F6 and parental strains
0
10
20
30
40
50
60
70
80
90
100
1 21 41 61 81 101 121
Days Post Challenge
%Survival
F6
AJ
C57BL
Survival of F6 and parental strains

4. Trypanosoma infection
response (Tir) loci
C57/BL6 x AJ and C57/BL6 x BALB/C
Iraqi et al Mammalian Genome 2000 11:645-648
Kemp et al. Nature Genetics 1997 16:194-196

5. Microarray design
Resistant C57BL/6Susceptible AJ

6. Networks responding to infection
P53

7. Daxx in Tir1 QTL
C57BL/6 ETDDDDDDDDDDDDEDNEESEEEEEEEEEEKEATEDEDED
129/J ETDDDDDDDDDDDDEDNEESEEEEEEEEEEKEATEDEDED
BALB/c ETDDDDD-DDDDDDEDNEESEEEEEEEEEEKEATEDEDED
A/J ETDDDDD-DDDDDDEDNEESEEEEEEEEEEKEATEDEDED
Fisher et al. NAR 2007 Vol. 35, No. 16 5625-5633
Polymorphism in p53 binding region

8. C57BL/6 regions in
Tir 1 congenics
Tir1
Tir3
Tir2
Congenic mice carrying C57BL/6
regions on A/J background

9. No genes are differentially expressed in
both congenics and parentals
Parentals Tir1 congenics
417456
Liver
Parentals Tir1 congenics
5225883
Spleen

11. Forms of gene regulation and
discovery of QTG
• Direct regulation:- eg transcription factor
(SREBP)
– Polymorphisms might cause reproducible
phenotype
• Indirect regulation:- eg negative
feedback of cholesterol levels on
cholesterol synthesis pathway
– Polymorphisms less likely to cause
reproducible phenotype

13. Participants
• ILRI, Nairobi
• Morris Agaba
• John Gibson
• Olivier Hanotte
• Hassan Musa
• Joel Mwakya
• Daniel Mwanga
• Jan Naessens
• Joseph Nganga
• Moises Ogugu
• John Wambugu
• Lilliam Wambua
• University of
Manchester
• Andy Brass
• Helen Hulme
• Paul Fisher
• Leo Zeef
• Leanne Wardlesworth
• University of Liverpool
• Anthea Broadhead
• Derek Daly
• Steve Kemp
• Harry Noyes
• Katie Rennie
• Luke Thomas
• Kate Goodheart
Roslin Institute
Alan Archibald
Susan Anderson
Laurence Hall