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 <20 QTL genes identified (Flint 2005) Genes of large effect may be dependent on genetic background.

Mouse models of Trypanosomiasis Days Post Challenge % Survival F6 AJ C57BL 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 : Kemp et al. Nature Genetics :

Microarray design Resistant C57BL/6Susceptible AJ

Networks responding to infection P53

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 Polymorphism in p53 binding region

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

No genes are differentially expressed in both congenics and parentals ParentalsTir1 congenics Liver ParentalsTir1 congenics 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 Institute Alan Archibald Susan Anderson Laurence Hall