title: An experimental assessment of in silico haplotype association mapping in laboratory mice.
abstract: BACKGROUND
  To assess the utility of haplotype association mapping (HAM) as a quantitative trait locus (QTL) discovery tool, we conducted HAM analyses for red blood cell count (RBC) and high density lipoprotein cholesterol (HDL) in mice. We then experimentally tested each HAM QTL using published crosses or new F2 intercrosses guided by the haplotype at the HAM peaks.
  
  
  RESULTS
  The HAM for RBC, using 33 classic inbred lines, revealed 8 QTLs; 2 of these were true positives as shown by published crosses. A HAM-guided (C57BL/6J x CBA/J)F2 intercross we carried out verified 2 more as true positives and 4 as false positives. The HAM for HDL, using 81 strains including recombinant inbred lines and chromosome substitution strains, detected 46 QTLs. Of these, 36 were true positives as shown by published crosses. A HAM-guided (C57BL/6J x A/J)F2 intercross that we carried out verified 2 more as true positives and 8 as false positives. By testing each HAM QTL for RBC and HDL, we demonstrated that 78% of the 54 HAM peaks were true positives and 22% were false positives. Interestingly, all false positives were in significant allelic association with one or more real QTL.
  
  
  CONCLUSIONS
  Because type I errors (false positives) can be detected experimentally, we conclude that HAM is useful for QTL detection and narrowing. We advocate the powerful and economical combined approach demonstrated here: the use of HAM for QTL discovery, followed by mitigation of the false positive problem by testing the HAM-predicted QTLs with small HAM-guided experimental crosses.
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Burgess-Herbert
authors.forename: Shirng-Wern
authors.initials: SW
authors.lastname: Tsaih
authors.forename: Ioannis M
authors.initials: IM
authors.lastname: Stylianou
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
authors.forename: Allison J
authors.initials: AJ
authors.lastname: Cox
authors.forename: Beverly
authors.initials: B
authors.lastname: Paigen
mesh_terms: D000483:Alleles; D000818:Animals; D008076:Cholesterol, HDL / Q000097:blood* / Q000235:genetics*; D019295:Computational Biology; D004906:Erythrocyte Count; D005260:Female; D006239:Haplotypes; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains / Q000235:genetics*; D040641:Quantitative Trait Loci
chemical_list: D008076:Cholesterol, HDL