Fine mapping of polymorphic alcohol-related quantitative trait loci candidate genes using interval-specific congenic recombinant mice

Marissa A. Ehringer, Jessica Thompson, Otakuye Conroy-Ben, Fan Yang, Raquel Hink, Beth Bennett, Thomas E. Johnson, James M. Sikela

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Background: The inbred long-sleep (ILS) and inbred short-sleep (ISS) strains of mice are widely studied as a model of initial sensitivity to alcohol. Recently, a large comparative DNA sequencing study of candidate genes located within the four Lore quantitative trait loci (QTLs) associated with the ethanol-induced loss of righting reflex in ILS and ISS mice has identified eight genes that contain coding region differences corresponding to amino acid changes. Here, recently developed interval-specific congenic recombinant mice (ISCRs) have been used to map these genes in relationship to newly narrowed QTL regions. Methods: Regions of candidate genes containing DNA differences corresponding to previously identified amino acid changes between ISS and ILS mice were amplified from either genomic DNA or complementary DNA from ISCR mice using polymerase chain reaction. The products were purified and directly sequenced to determine the genotypes for each polymorphism. On the basis of these genotypic data, each candidate gene was determined to be located either within or outside of recently narrowed Lore QTL intervals. Results: Of these eight candidates with protein-coding differences, five are now excluded from their respective Lore intervals. The other three (Znf142, Ptprn, and Znf133) have been localized to the narrowed QTL intervals. Conclusions: These three central nervous system genes (Znf142, Ptprn, and Znf133) represent promising candidates for involvement in the differential sensitivity to alcohol exhibited between ILS and ISS mice. This study also demonstrates how the combination of high-throughput comparative gene sequencing and concomitant genetic fine mapping of QTL regions with ISCRs can be an effective tool for accelerating the process of moving from QTL to gene.

Original languageEnglish (US)
Pages (from-to)1603-1608
Number of pages6
JournalAlcoholism: Clinical and Experimental Research
Volume26
Issue number11
StatePublished - Nov 1 2002
Externally publishedYes

Fingerprint

Congenic Mice
Quantitative Trait Loci
Sleep
Genes
Alcohols
DNA
Righting Reflex
Amino Acids
Polymerase chain reaction
Neurology
Polymorphism
DNA Sequence Analysis
Ethanol
Central Nervous System
Complementary DNA
Genotype
Throughput
Polymerase Chain Reaction

Keywords

  • Alcohol Sensitivity
  • Candidate Genes
  • QTL Mapping

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Toxicology

Cite this

Fine mapping of polymorphic alcohol-related quantitative trait loci candidate genes using interval-specific congenic recombinant mice. / Ehringer, Marissa A.; Thompson, Jessica; Conroy-Ben, Otakuye; Yang, Fan; Hink, Raquel; Bennett, Beth; Johnson, Thomas E.; Sikela, James M.

In: Alcoholism: Clinical and Experimental Research, Vol. 26, No. 11, 01.11.2002, p. 1603-1608.

Research output: Contribution to journalArticle

Ehringer, Marissa A. ; Thompson, Jessica ; Conroy-Ben, Otakuye ; Yang, Fan ; Hink, Raquel ; Bennett, Beth ; Johnson, Thomas E. ; Sikela, James M. / Fine mapping of polymorphic alcohol-related quantitative trait loci candidate genes using interval-specific congenic recombinant mice. In: Alcoholism: Clinical and Experimental Research. 2002 ; Vol. 26, No. 11. pp. 1603-1608.
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