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

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Genome wide expression consequences of a disease
resistance QTL are strongly influenced by the
genetic background
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Finding QTL genes in mice

• Few genes of large effect
• Many genes of small effect
• gt2000 QTL mapped
• lt20 QTL genes identified (Flint 2005)
• Genes of large effect may be dependent on genetic
  background.

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Mouse models of Trypanosomiasis
Survival of F6 and parental strains

F
6
Survival
A
J
C
5
7
B
L
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1
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0
1
1
2
1
D
a
y
s

P
o
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t

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Trypanosoma infection response (Tir) loci
C57/BL6 x AJ and C57/BL6 x BALB/C
Iraqi et al Mammalian Genome 2000 11645-648
Kemp et al. Nature Genetics 1997 16194-196
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Microarray design
Resistant C57BL/6
Susceptible AJ
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Networks responding to infection
P53
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Daxx in Tir1 QTL
Polymorphism in p53 binding region
C57BL/6 ETDDDDDDDDDDDDEDNEESEEEEEEEEEEKEATEDEDED 1
29/J ETDDDDDDDDDDDDEDNEESEEEEEEEEEEKEATEDEDED BA
LB/c ETDDDDD-DDDDDDEDNEESEEEEEEEEEEKEATEDEDED A/J
ETDDDDD-DDDDDDEDNEESEEEEEEEEEEKEATEDEDED
Fisher et al. NAR 2007 Vol. 35, No. 16 5625-5633
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Congenic mice carrying C57BL/6 regions on A/J
background
Tir3
Tir2
C57BL/6 regions in
Tir 1 congenics
Tir1
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No genes are differentially expressed in both
congenics and parentals
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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

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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