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 F 2 intercrosses. In this study, we carried out QTL analyses in (C57BL/6J × NZB/BlNJ) × 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 × NZB/BlNJ)F 11 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.

Using an advanced intercross line to identify quantitative trait loci controlling immune response during collagen-induced arthritis

“…Indeed, this approach was successfully applied to refine QTLs in several studies. Since the propositon of AIL in 1995, eight AIL have been generated, including five mouse lines, [2][3][4][5][6] one rat line, 7,8 one chicken line 9 and one mosquito line. 10 All were used to refine QTLs that were originally identified in the F2 progeny with big CIs.…”

Simulating the Collaborative Cross: Power of Quantitative Trait Loci Detection and Mapping Resolution in Large Sets of Recombinant Inbred Strains of Mice

“…For instance, detection and fine mapping can be achieved within a population of manageable size by making use of historical recombinants. Advanced intercross lines (AILs), populations made from F 2 's by repeated intercrossing within a large population, have the simple genetic background necessary for unambiguous assignment of identity by descent along with the highly recombinant haplotype structure that allows high mapping resolution (Darvasi and Soller 1995;Wang et al 2003). Heterogeneous stocks (HS) are a generalization of AILs, derived from a cross of eight inbred mouse lines (McClearn et al 1970;Demarest et al 2001).…”

Current Gene‐Mapping Strategies in Experimental Models of Multiple Sclerosis

“…QTL mapping in AIL has been reported in experimental models related to resistance to parasites [46], lung tumour [70] and cardiovascular disease [47]. We have fine-mapped EAE-regulatory QTLs using an AIL (Jagodic et al, J Immunol 2004, in press) [65].…”

“…F2-and backcrosses should, therefore, be considered to be appropriate for a primary identification of regulatory QTLs, as they have enough statistical power for QTL detection. Further complications using linkage analysis in F2 populations are: (i) a single QTL may comprise several adjacent QTLs [46,47]; (ii) nearby QTLs with opposing effects may not be detected [48] and (iii) a detected QTL may be incorrectly positioned [47,49].…”