TY - JOUR
T1 - Using advanced intercross lines for high-resolution mapping HDL cholesterol quantitative trait loci
AU - Wang, Xiaosong
AU - Le Roy, Isabelle
AU - Nicodeme, Edwige
AU - Li, Renhua
AU - Wagner, Richard
AU - Petros, Christina
AU - Churchill, Gary A.
AU - Harris, Stephen
AU - Darvasi, Ariel
AU - Kirilovsky, Jorge
AU - Roubertoux, Pierre L.
AU - Paigen, Beverly
PY - 2003/7/1
Y1 - 2003/7/1
N2 - 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 × NZB/BINJ) × 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/BINJ)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 (Nrli3, 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.
AB - 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 × NZB/BINJ) × 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/BINJ)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 (Nrli3, 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.
UR - http://www.scopus.com/inward/record.url?scp=0037810502&partnerID=8YFLogxK
U2 - 10.1101/gr.1185803
DO - 10.1101/gr.1185803
M3 - Article
C2 - 12805272
AN - SCOPUS:0037810502
SN - 1088-9051
VL - 13
SP - 1654
EP - 1664
JO - Genome Research
JF - Genome Research
IS - 7
ER -