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Letter

Using Advanced Intercross Lines for High-Resolution Mapping of HDL Cholesterol Quantitative Trait Loci

¹ The Jackson Laboratory, Bar Harbor, Maine 04609, USA ² Genétiqué, Neurogenétiqué, comportement, CNRS, 45071 Orléans Cedex 2, France ³ GlaxoSmithKline, Centre de Recherches, 91951 Les Ulis Cedex, France ⁴ GlaxoSmithKline, Genetics and Discovery Alliances, Medicine Research Centre, Stevenage SG1 2NY, UK ⁵ Life Sciences Institute, the Hebrew University of Jerusalem, Jerusalem 91904, Israel ⁶ Institut de Neurosciences Physiologiques et Cognitives, INPC.CNRS, 13402 Marseille Cedex 20, France

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.

⁷ Corresponding author.
E-MAIL bjp{at}aretha.jax.org; FAX (207) 288-6078.

Article published online before print in June 2003.

[Supplemental material is available online at www.genome.org.]

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