International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


POSTER 47 - GENOME-WIDE ASSOCIATION ANALYSIS IDENTIFIES NOVEL MODIFIER LOCI OF HIRSCHSPRUNG DISEASE IN SOX10DOM MICE

Owens SE 1, Broman KW 2, Smith JR 1, Southard-Smith EM 1

1 Vanderbilt University, Nashville, United States, 2 Johns Hopkins University, Baltimore, United States

Hirschsprung disease (HSCR) is caused by abnormal development of the neural crest cells that comprise the enteric nervous system, resulting in an absence or reduction of enteric ganglia in a variable portion of the distal gastrointestinal tract.

Dominant megacolon (Sox10Dom) mice model the aganglionic megacolon seen in HSCR, and SOX10 mutations have been identified in a subset of HSCR patients. Sox10Dom heterozygote mice on a mixed genetic background (B6C3F1) mimic the variable severity of aganglionosis in HSCR patients, and this variation is influenced by genetic background.

To establish linkage to modifier genes that modulate the severity of aganglionosis in Sox10Dom mice we performed a genome-wide scan. Penetrance and extent of intestinal aganglionosis was quantified by whole-mount acetylcholinesterase (AChE) histochemistry on gastrointestinal tracts from postnatal day 7-10 backcross (n=204) and intercross (n=1092) progeny. Mice from the extremes of the phenotype distribution, along with mice in which aganglionosis was not penetrant, were genotyped by fluorescence polarization methods to distinguish 104 SNP markers at an average spacing of 19 cM throughout the genome.  Using R/qtl, nonparametric interval mapping identified five loci with significant linkage results.  All five loci are modifiers of penetrance, and two also contribute to the difference in severity of aganglionosis.  Epistatic interactions between modifiers and effects of gender and imprinting will be presented.

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