Comparative genomics of Toll-like receptor signalling in five species
Oliver C Jann
2
Annemarie King
2
Nestor Lopez Corrales
1
Susan I Anderson
2
Kirsty Jensen
2
Tahar Ait-ali
2
Haizhou Tang
2
Chunhua Wu
0
Noelle E Cockett
0
Alan L Archibald
2
Elizabeth J Glass
2
0
Department of Animal, Dairy, and Veterinary Sciences, Utah State University
,
Logan, UT 844322-4700
USA
1
Public University of Navarra
,
Campus de Arrosadia s/n, 31006 Pamplona
,
Spain
2
The Roslin Institute and R(D)SVS, University of Edinburgh
,
Roslin, Midlothian, Edinburgh, EH25 9PS
,
UK
Background: Over the last decade, several studies have identified quantitative trait loci (QTL) affecting variation of immune related traits in mammals. Recent studies in humans and mice suggest that part of this variation may be caused by polymorphisms in genes involved in Toll-like receptor (TLR) signalling. In this project, we used a comparative approach to investigate the importance of TLR-related genes in comparison with other immunologically relevant genes for resistance traits in five species by associating their genomic location with previously published immune-related QTL regions. Results: We report the genomic localisation of TLR1-10 and ten associated signalling molecules in sheep and pig using in-silico and/or radiation hybrid (RH) mapping techniques and compare their positions with their annotated homologues in the human, cattle and mouse whole genome sequences. We also report medium-density RH maps for porcine chromosomes 8 and 13. A comparative analysis of the positions of previously published relevant QTLs allowed the identification of homologous regions that are associated with similar health traits in several species and which contain TLR related and other immunologically relevant genes. Additional evidence was gathered by examining relevant gene expression and association studies. Conclusion: This comparative genomic approach identified eight genes as potentially causative genes for variations of health related traits. These include susceptibility to clinical mastitis in dairy cattle, general disease resistance in sheep, cattle, humans and mice, and tolerance to protozoan infection in cattle and mice. Four TLR-related genes (TLR1, 6, MyD88, IRF3) appear to be the most likely candidate genes underlying QTL regions which control the resistance to the same or similar pathogens in several species. Further studies are required to investigate the potential role of polymorphisms within these genes.
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Background
The innate immune system is the first line of defence
against invading pathogens and is activated by conserved
pathogen associated molecular patterns (PAMPs).
Tolllike receptors (TLRs), a family of signalling molecules that
bind to PAMPs and consequently trigger an immune
response [1], play a major role within the innate immune
system. TLRs are found in all animals and even plant
homologues have been described [2], illustrating the
ancient origin of this gene family. Most mammalian
species share ten TLR genes (TLR1-10), each detecting PAMPs
with different molecular structures.
TLRs bind their ligands in a horseshoe-shaped leucine rich
repeat (LRR) domain, which enables a Toll/interleukin-1
receptor (TIR) domain to associate with adapter proteins
like the Toll/interleukin-1 receptor domain-containing
adapter protein (TIRAP), lymphocyte antigen 96 (LY96 or
MD2), or myeloid differentiation primary response
protein (MyD88) which binds with the interleukin-1
receptor-associated kinase 1 (IRAK-1). This binding activates
the tumour necrosis factor receptor-associated factor 6
(TRAF6), triggering a cascade which finally results in
nuclear factor-kappa B (NF-B) liberation, activating the
expression of pro-inflammatory genes (reviewed by
Werling & Jungi [3]). An additional molecule, the
Toll-interacting protein (TOLLIP), is involved in the regulation of
this process [4]. MyD88, TIRAP, IRAK-1 and TRAF6 are
also involved in TLR-induced apoptosis mediated by
caspase-8 (CASP8) (reviewed by Bannerman & Goldblum
[5]). The toll-like receptor adaptor molecules (TICAM-1
or TRIF and TICAM-2 or TRAM) have been shown to
activate TRAF6 and also to trigger interferon or (IFN-/)
responses [6,7]. The transcriptional regulation of type I
interferons is coordinated, at least in part, by interferon
regulatory factors 3 and 7 (IRF3/7). IRF3 and IRF7 can
also be activated by kinases which are regulated by
MyD88/TRAF6 [8]. The pre-eminence of TLRs and these
associated signalling molecules in the initial recognition
of pathogens suggests that they could be strong candidates
for animal health traits.
In humans, polymorphisms within genes coding for TLR
and associated signalling molecules are associated with a
predisposition to several diseases [9-11]. There is
increasing evidence pointing to the strong possibility that
polymorphisms in livestock TLR genes might affect immune
related traits [12-14] and might explain at least part of the
observed variation in disease resistance. A number of
immune-related quantitative trait loc (...truncated)