title: A strategy for the integration of QTL, gene expression, and sequence analyses.
abstract: Although hundreds if not thousands of quantitative trait loci (QTL) have been described for a wide variety of complex traits, only a very small number of these QTLs have been reduced to quantitative trait genes (QTGs) and quantitative trait nucleotides (QTNs). A strategy, Multiple Cross Mapping (MCM), is described for detecting QTGs and QTNs that is based on leveraging the information contained within the haplotype structure of the mouse genome. As described in the current report, the strategy utilizes the six F(2) intercrosses that can be formed from the C57BL/6J (B6), DBA/2J (D2), BALB/cJ (C), and LP/J (LP) inbred mouse strains. Focusing on the phenotype of basal locomotor activity, it was found that in all three B6 intercrosses, a QTL was detected on distal Chromosome (Chr) 1; no QTL was detected in the other three intercrosses, and thus, it was assumed that at the QTL, the C, D2, and LP strains had functionally identical alleles. These intercross data were used to form a simple algorithm for interrogating microsatellite, single nucleotide polymorphism (SNP), brain gene expression, and sequence databases. The results obtained point to Kcnj9 (which has a markedly lower expression in the B6 strain) as being the likely QTG. Further, it is suggested that the lower expression in the B6 strain results from a polymorphism in the 5'-UTR that disrupts the binding of at least three transcription factors. Overall, the method described should be widely applicable to the analysis of QTLs.
authors.affiliation: Research Service, Veterans Affairs Medical Center, Portland, Oregon, USA. hitzemann@ohsu.edu
authors.forename: Robert
authors.initials: R
authors.lastname: Hitzemann
authors.forename: Barry
authors.initials: B
authors.lastname: Malmanger
authors.forename: Cheryl
authors.initials: C
authors.lastname: Reed
authors.forename: Maureen
authors.initials: M
authors.lastname: Lawler
authors.forename: Barbara
authors.initials: B
authors.lastname: Hitzemann
authors.forename: Shannon
authors.initials: S
authors.lastname: Coulombe
authors.forename: Kari
authors.initials: K
authors.lastname: Buck
authors.forename: Brooks
authors.initials: B
authors.lastname: Rademacher
authors.forename: Nicole
authors.initials: N
authors.lastname: Walter
authors.forename: Yekatrina
authors.initials: Y
authors.lastname: Polyakov
authors.forename: James
authors.initials: J
authors.lastname: Sikela
authors.forename: Brenda
authors.initials: B
authors.lastname: Gensler
authors.forename: Sonya
authors.initials: S
authors.lastname: Burgers
authors.forename: Robert W
authors.initials: RW
authors.lastname: Williams
authors.forename: Ken
authors.initials: K
authors.lastname: Manly
authors.forename: Jonathan
authors.initials: J
authors.lastname: Flint
authors.forename: Christopher
authors.initials: C
authors.lastname: Talbot
mesh_terms: D000465:Algorithms; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D001921:Brain / Q000378:metabolism*; D003433:Crosses, Genetic; D015870:Gene Expression; D008124:Locomotion / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D018895:Microsatellite Repeats / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013057:Spectrum Analysis; D014466:Ultraviolet Rays