Original Contributions

Mammalian Genome

, Volume 15, Issue 11, pp 865-871

Refined histopathologic scoring system improves power todetect colitis QTL in mice

  • Andre BleichAffiliated withInstitute for Laboratory Animal Science and Central Animal Facility, Hannover Medical School
  • , Michael MählerAffiliated withInstitute for Laboratory Animal Science and Central Animal Facility, Hannover Medical School
  • , Claudia MostAffiliated withInstitute for Laboratory Animal Science and Central Animal Facility, Hannover Medical School
  • , Edward H. LeiterAffiliated withThe Jackson Laboratory
  • , Elisabeth Liebler–TenorioAffiliated withInstitute of Pathology, Hannover School of Veterinary Medicine
  • , Charles O. ElsonAffiliated withDepartment of Medicine, University of Alabama
  • , Hans J. HedrichAffiliated withInstitute for Laboratory Animal Science and Central Animal Facility, Hannover Medical School
  • , Brigitte SchlegelbergerAffiliated withInstitute for Cell and Molecular Pathology, Hannover Medical School
  • , John P. SundbergAffiliated withThe Jackson Laboratory Email author 

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Abstract

Induction of colitis in mice by a targeted mutation in the Il10 gene is inbred strain dependent. C3H/HeJBir (C3H) mice are colitis susceptible while C57BL/6J (B6) mice are resistant. Identification of quantitative trait loci (QTL) determining the differential strain responsiveness requires histopathologic scoring of multiple lesion subphenotypes in both cecum and colon. Here we show that ability to detect a major C3H-derived QTL on Chr 3 (cytokine deficiency–induced colitis susceptibility 1, Cdcs1) was critically dependent upon the degree of refinement of the histopathologic scoring system. QTL mapping was performed using a first-backcross population of interleukin-10-deficient mice and applying two different grading systems to assess lesion subphenotypes. The same histological specimens were scored by two independent pathologists using either a very detailed scoring system for four subphenotypes developed at The Jackson Laboratory (TJL) or a simpler scoring system developed at the Hannover Medical School (MHH). The more detailed TJL subphenotyping protocol increased power to identify Cdcs1 (a maximum LOD score of 4.28 versus a LOD score of 1.77 when using the abbreviated MHH subphenotyping scoring system). This study shows that for QTL mapping in a mouse model of colitis, in which histology represents the gold standard for phenotyping, ability to detect linkage is critically dependent upon the degree of refinement adopted for separately scoring the multiple histopathologic lesions comprising this complex phenotype.