Genetic Dissection of Quantitative Trait Loci Specifying Sedative/Hypnotic Sensitivity to Ethanol: Mapping With Interval-Specific Congenic Recombinant Lines

Authors

  • Beth Bennett,

    Corresponding author
    1. Institute for Behavioral Genetics (BB, MB, LG, PC-L, TEJ) and the Department of Psychology (TEJ), University of Colorado, Boulder, Colorado.
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  • Mary Beeson,

    1. Institute for Behavioral Genetics (BB, MB, LG, PC-L, TEJ) and the Department of Psychology (TEJ), University of Colorado, Boulder, Colorado.
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  • Lena Gordon,

    1. Institute for Behavioral Genetics (BB, MB, LG, PC-L, TEJ) and the Department of Psychology (TEJ), University of Colorado, Boulder, Colorado.
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  • Phyllis Carosone-Link,

    1. Institute for Behavioral Genetics (BB, MB, LG, PC-L, TEJ) and the Department of Psychology (TEJ), University of Colorado, Boulder, Colorado.
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  • Thomas E. Johnson

    1. Institute for Behavioral Genetics (BB, MB, LG, PC-L, TEJ) and the Department of Psychology (TEJ), University of Colorado, Boulder, Colorado.
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  • Supported by Grants KO2-AA0195, P50-AA03527, and RO1-AA008940.

Beth Bennett, PhD, Institute for Behavioral Genetics, Box 447, University of Colorado, Boulder, CO 80309–0447; Fax: 303–492–8063; E-mail: bennettb@colorado.edu.

Abstract

Background Linkage studies alone do not produce sufficient resolution to narrow the location of a quantitative trait locus (QTL) to a small-enough chromosomal region for gene identification. One solution to this problem is to use interval-specific congenic recombinant (ISCR) lines to narrow the chromosomal interval known to contain the QTL. In previous work, we mapped four QTLs for differential ethanol sensitivity in the inbred long-sleep (ILS) and inbred short-sleep (ISS) strains and generated reciprocal congenic strains in which each full QTL interval from ILS was bred onto the ISS background and vice versa.

Methods ISCR lines were derived by identifying mice carrying recombination events in the congenic interval during backcrossing of the ISS.ILS. Lore congenics to ISS. Recombinant mice were backcrossed to ISS, and progeny carrying the ISCR chromosome were identified and tested to determine whether the ISCR region carried the donor Lore QTL.

Results We developed multiple ISCR lines for each Lore QTL, in which the QTL interval was broken into a number of smaller intervals. For all four QTLs, we reduced the size of the interval, in one case to 3.7 cM.

Conclusions Use of ISCR lines can narrow each Lore candidate region to a few centimorgans. Such an interval size is conducive to brute-force approaches to identify candidate genes, entailing bioinformatics, gene expression, and DNA sequencing strategies.

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