TY - JOUR
T1 - Genetics of colitis susceptibility in IL-10-deficient mice
T2 - Backcross versus F2 results contrasted by principal component analysis
AU - Mähler, Michael
AU - Most, Claudia
AU - Schmidtke, Sybille
AU - Sundberg, John P.
AU - Li, Renhua
AU - Hedrich, Hans Jürgen
AU - Churchill, Gary A.
N1 - Funding Information:
We thank Ina Köhn (Medical School Hanover), Petra Stutmann (School of Veterinary Medicine Hanover), and Mark Farmer (The Jackson Laboratory) for technical assistance; Elisabeth Liebler-Tenorio (School of Veterinary Medicine Hanover) for histologic consultation; and Ed Leiter (The Jackson Laboratory) for providing the F2 raw data and for helpful discussion. This work was supported by grants from the Deutsche Forschungsgemeinschaft (Sonderforschungsbereich 280, Teilprojekt C 16; M.M., H.J.H.), the National Institute of Health (DK44240; J.P.S), and the National Cancer Institute (CA34196; J.P.S., G.A.C.).
PY - 2002/9
Y1 - 2002/9
N2 - Interleukin-10-deficient (Il10-/-) mice on a C3H/HeJBir genetic background develop more severe colitis than those on a C57BL/6J background. We performed genome screens for quantitative trait loci (QTLs) regulating colitis susceptibility in this model system using two first backcross populations derived from these two strains. To reduce the complexity of this analysis, the information from numerous histologic phenotypes was summarized by principal component analysis. A similar approach was applied to previously published data from an F2 intercross (involving the same progenitor strains), which allowed us to ascertain all six previously reported cytokine-deficiency-induced colitis susceptibility loci (Cdcs1-6) with main and/or interacting effects on chromosomes 3, 1, 2, 8, 17, and 18. The colitogenic effect of Cdcs1 was confirmed in the backcross to C3H/HeJBir-Il10-/-. Its effect was epistatically modified by another locus on chromosome 12. In addition, three main effect QTLs on chromosomes 4, 5, and 12 were identified in the backcross to C57BL/6J-Il10-/-. Analyses of the modes of inheritance in these crosses revealed colitogenic contributions by both parental genomes. These findings show the complexity of inheritance underlying susceptibility to colitis and illustrate why detection of human inflammatory bowel disease loci has proven to be so difficult.
AB - Interleukin-10-deficient (Il10-/-) mice on a C3H/HeJBir genetic background develop more severe colitis than those on a C57BL/6J background. We performed genome screens for quantitative trait loci (QTLs) regulating colitis susceptibility in this model system using two first backcross populations derived from these two strains. To reduce the complexity of this analysis, the information from numerous histologic phenotypes was summarized by principal component analysis. A similar approach was applied to previously published data from an F2 intercross (involving the same progenitor strains), which allowed us to ascertain all six previously reported cytokine-deficiency-induced colitis susceptibility loci (Cdcs1-6) with main and/or interacting effects on chromosomes 3, 1, 2, 8, 17, and 18. The colitogenic effect of Cdcs1 was confirmed in the backcross to C3H/HeJBir-Il10-/-. Its effect was epistatically modified by another locus on chromosome 12. In addition, three main effect QTLs on chromosomes 4, 5, and 12 were identified in the backcross to C57BL/6J-Il10-/-. Analyses of the modes of inheritance in these crosses revealed colitogenic contributions by both parental genomes. These findings show the complexity of inheritance underlying susceptibility to colitis and illustrate why detection of human inflammatory bowel disease loci has proven to be so difficult.
KW - Colitis
KW - Environment
KW - Genetics
KW - Inflammatory bowel disease
KW - Interleukin-10
KW - Knockout
KW - Linkage
KW - Mouse
KW - Quantitative trait
UR - http://www.scopus.com/inward/record.url?scp=0036727184&partnerID=8YFLogxK
U2 - 10.1006/geno.2002.6840
DO - 10.1006/geno.2002.6840
M3 - Article
C2 - 12213197
AN - SCOPUS:0036727184
SN - 0888-7543
VL - 80
SP - 274
EP - 282
JO - Genomics
JF - Genomics
IS - 3
ER -