Mapping Data

Experiment

• Experiment
  TEXT-QTL
• Chromosome
  4
• Reference
  J:244689 Velupillai P, et al., Polymorphisms in toll-like receptor 4 underlie susceptibility to tumor induction by the mouse polyomavirus. J Virol. 2012 Nov;86(21):11541-7
• ID
  MGI:6111052

Genes

Gene	Assay Type
Cytrq1	visible phenotype
Tlr4

Notes

• Experiment
  Inbred strains of mice vary greatly in terms of their susceptibility to tumor development and to acutely lethal infection by mouse polyomavirus (Py). PERA/EiJ (PE) mice are susceptible to tumor induction by polyomavirus, while C57BR/cdJ (BR) mice are resistant. Antigen-presenting cells from BR mice respond to the virus with interleukin-12 (IL-12) and those from PE mice with IL-10. The polarized cytokine responses underlie the development of effective anti tumor immunity in BR mice and the lack thereof in PE mice. The goal of the current study was to identify the genetic and immunological determinants of cytokine responses that underlie susceptibility to tumor induction by Py in the PE x BR host system.
  
  One hundred and fourteen newborn (PE x BR)F2 mice were infected with 10⁶ PFU of the PTA strain of polyomavirus. Spleen cells were taken one week after infection, cultured for 24 hours and assayed for IL-10 and IL-12 by ELISAs. The observed distribution of 27 PE-like, 61 F1-like and 26 BR-like responders was in agreement with the expected 1:2:1 ratio for a single gene governing the cytokine response with the PE allele acting in a codominant manner.
  
  A genome wide scan was carried out on DNA from 15 PE-like responders and 17 BR-like responders to map the gene governing the cytokine responses. A panel of 394 SNPs distributed across the 19 autosomes were used.
  
  A significant QTL, Cytrq1 (cytokine response QTL 1), mapped to Chromosome 4 peaking at SNP rs4224562 with a LOD score of 10.21, p<0.0001. All 17 BR-like responders were homozygous for the BR allele at rs4224562; the 15 PE-like responders were either homozygous or heterozygous for the PE allele at rs4224562, consistent with the dominance of the IL-10 response in PE mice. The 1.5 LOD support interval defined a region from 65.483 to 96.092 Mbp on Chr 4 that was likely to contain the cytokine response gene.
  
  Tlr4 mapped within the interval at 66.489-66.591 Mbp and was considered a logical candidate gene governing cytokine responses and tumor susceptibility in the PE x BR cross. The sequencing of parental Tlr4 genes confirmed the presence of multiple SNPs. The genotyping of F2 progeny revealed a complete concordance of parental Tlr4 allele-specific DNA sequences with the cytokine responses of F2 mice.