title: Using advanced intercross lines for high-resolution mapping of HDL cholesterol quantitative trait loci.
abstract: Mapping quantitative trait loci (QTLs) with high resolution facilitates identification and positional cloning of the underlying genes. The novel approach of advanced intercross lines (AILs) generates many more recombination events and thus can potentially narrow QTLs significantly more than do conventional backcrosses and F2 intercrosses. In this study, we carried out QTL analyses in (C57BL/6J x NZB/BlNJ) x C57BL/6J backcross progeny fed either chow or an atherogenic diet to detect QTLs that regulate high-density lipoprotein cholesterol (HDL)concentrations, and in (C57BL/6J x NZB/BlNJ) F11 AIL progeny to confirm and narrow those QTLs. QTLs for HDL concentrations were found on chromosomes 1, 5, and 16. AIL not only narrowed the QTLs significantly more than did a conventional backcross but also resolved a chromosome 5 QTL identified in the backcross into two QTLs, the peaks of both being outside the backcross QTL region. We tested 27 candidate genes and found significant mRNA expression differences for 12 (Nr1i3, Apoa2, Sap, Tgfb2, Fgfbp1, Prom, Ppargc1, Tcf1, Ncor2, Srb1, App, and Ifnar). Some of these underlay the same QTL, indicating that expression differences are common and not sufficient to identify QTL genes. All the major HDL QTLs in our study had homologous counterparts in humans, implying that their underlying genes regulate HDL in humans.
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Wang
authors.forename: Isabelle
authors.initials: I
authors.lastname: Le Roy
authors.forename: Edwige
authors.initials: E
authors.lastname: Nicodeme
authors.forename: Renhua
authors.initials: R
authors.lastname: Li
authors.forename: Richard
authors.initials: R
authors.lastname: Wagner
authors.forename: Christina
authors.initials: C
authors.lastname: Petros
authors.forename: Gary A
authors.initials: GA
authors.lastname: Churchill
authors.forename: Stephen
authors.initials: S
authors.lastname: Harris
authors.forename: Ariel
authors.initials: A
authors.lastname: Darvasi
authors.forename: Jorge
authors.initials: J
authors.lastname: Kirilovsky
authors.forename: Pierre L
authors.initials: PL
authors.lastname: Roubertoux
authors.forename: Beverly
authors.initials: B
authors.lastname: Paigen
mesh_terms: D000818:Animals; D001018:Aortic Diseases / Q000097:blood / Q000235:genetics / Q000473:pathology; D001161:Arteriosclerosis / Q000097:blood / Q000235:genetics / Q000473:pathology; D002784:Cholesterol / Q000097:blood / Q000235:genetics; D008076:Cholesterol, HDL / Q000235:genetics*; D002874:Chromosome Mapping / Q000379:methods*; D003199:Computer Systems; D000090702:Constitutive Androstane Receptor; D003433:Crosses, Genetic; D004032:Diet; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D005838:Genotype; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008814:Mice, Inbred NZB; D010641:Phenotype; D016133:Polymerase Chain Reaction / Q000379:methods; D040641:Quantitative Trait Loci / Q000235:genetics*
chemical_list: D008076:Cholesterol, HDL; D000090702:Constitutive Androstane Receptor; D005819:Genetic Markers; C000716327:NR1I3 protein, human; C000716328:Nr1i3 protein, mouse; D002784:Cholesterol