International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


POSTER 82 - EPIGENETIC EVENTS INFLUENCE THE VARIATION IN INBRED MOUSE STRAIN INNATE IMMUNE RESPONSES

Wells CA 1, Aung H 1, Himes R 1, Forrest A 1, Ravasi T 1, Grimmond S 1, Kasukawa T 2, Carninci P 2, Hayashizaki Y 3, Hume D 1

1 IMB, University of QLD, Brisbane, Australia, 2 RIKEN Genome Sciences, Wako, Japan, 3 RIKEN Genome Sciences, Yokohama, Japan

Pathogenic challenges are one of the primary evolutionary drivers on mammalian genomes. An effective innate immune system must recognise pathogens and respond appropriately; too little and the pathogen will colonise the host, too much may generate local tissue damage or septic shock.  Inbred mice provide a spectrum of innate immune responses to a variety of pathogens, and we have demonstrated by microarray expression profiling that each strain exhibits a unique transcriptional response to a single pathogenic challenge, LPS.  This study demonstrates that macrophages derived from a single individual also demonstrate heterogeneity of responses to the same pathogenic challenge. We surveyed the genomic databases using RIKEN full-length cDNA clones and demonstrate that most participants in the Tlr4 signalling cascade are alternatively spliced, yielding functionally distinct products.  We propose that most receptors and signalling molecules recruited to innate immune pathways are regulated at an allelic level. Monoallelic expression of key signalling components, coupled with a cellular bias toward particular splice variants, provides a combinatorial molecular diversity within a population of macrophages from a single individual. We demonstrate that this heterogeneity is generated at a clonal level, so presenting a wide repertoire of defensive responses against new and evolving pathogens.

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