Genome wide expression consequences of a disease resistance QTL are strongly

influenced by the genetic background

Finding QTL genes in mice

Few genes of large effect Many genes of small effect

>2000 QTL mapped

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

% S

urvi

val

F6AJC57BL

Survival of F6 and parental strains

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

Microarray designResistant C57BL/6Susceptible AJ

Networks responding to infection

P53

Daxx in Tir1 QTL

C57BL/6 ETDDDDDDDDDDDDEDNEESEEEEEEEEEEKEATEDEDED129/J ETDDDDDDDDDDDDEDNEESEEEEEEEEEEKEATEDEDEDBALB/c ETDDDDD-DDDDDDEDNEESEEEEEEEEEEKEATEDEDEDA/J ETDDDDD-DDDDDDEDNEESEEEEEEEEEEKEATEDEDED

Fisher et al. NAR 2007 Vol. 35, No. 16 5625-5633

Polymorphism in p53 binding region

C57BL/6 regions in

Tir 1 congenicsTir1

Tir3Tir2

Congenic mice carrying C57BL/6 regions on A/J background

No genes are differentially expressed in both congenics and parentals

Parentals Tir1 congenics

417456

Liver

Parentals Tir1 congenics

5225883

Spleen

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

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 InstituteAlan ArchibaldSusan AndersonLaurence Hall

Genome wide expression consequences of a disease resistance QTL are strongly influenced by the genetic backgroundFinding QTL genes in miceSlide Number 3Trypanosoma infection response (Tir) loci C57/BL6 x AJ and C57/BL6 x BALB/CMicroarray designNetworks responding to infectionDaxx in Tir1 QTLCongenic mice carrying C57BL/6 regions on A/J background No genes are differentially expressed in both congenics and parentalsSlide Number 10Forms of gene regulation and discovery of QTGSlide Number 12Participants