CHARACTERIZATION OF Ath17, A QUANTITATIVE TRAIT LOCUS FOR ATHEROSCLEROSIS SUSCEPTIBILITY BETWEEN C57BL/6J AND 129S1/SvImJ; SINGLE-NUCLEOTIDE POLYMORPHISMS HAVE IMPORTANT IMPLICATIONS ON IDENTIFYING ATHEROSCLEROSIS MODIFIER GENES

Although identifying quantitative trait loci (QTL) for atherosclerosis susceptibility in experimental murine models has helped us better understand the pathophysiology of atherosclerosis, identifying the genes underlying these QTL has been a slow and difficult process. We are currently in the process of identifying the gene that underlies Ath17, an atherosclerosis-susceptibility QTL we discovered in a (C57BL/6J×129S1/SvImJ)F2 intercross. Ath17 maps to a 6 cM interval region on chromosome 10 (D10Mit31, LOD score 6.6) and contains 46 annotated and 133 predicted genes. We searched the Celera Discovery System database for single nucleotide polymorphisms (SNPs) between C57BL/6J (B6) and 129S1/SvImJ in the Ath17 region and found defined blocks of high and low diversity and one polymorphic region of over 4 Mb surrounded by nonpolymorphic regions. Four of the genes, including the annotated Desrt, in the polymorphic region contained mis-sense mutations. The Desrt coding region contained four mis-sense mutations: B6 lysine to 129 glutamic acid at aa382, B6 asparagine to 129 serine at aa388, B6 threonine to 129 alanine at aa836, and B6 glycine to 129 serine at aa964. In addition, intron 5 of Desrt contained a SNP which co-localized with a putative transcription factor binding site. Desrt is a DNA binding protein, widely expressed in adult tissues, and likely plays a role in cell proliferation, differentiation, and development, making Dsert a strong candidate gene for Ath17. The murine SNP database dramatically reduced the percentage of the murine genome we had to search to find viable candidate genes for Ath17.