Shannon Coulombe | PubMed Health

PubMed2006

Further studies on using multiple-cross mapping (MCM) to map quantitative trait loci.

We have completed whole-genome scans for quantitative trait loci (QTLs) associated with acute ethanol-induced activation in 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 strains. The goal was to test the hypothesis that given the relatively simple structure of the laboratory mouse genome, the same QTLs will be detected in multiple crosses which in turn will provide support for the strategy of multiple-cross mapping (MCM). QTLs with LOD scores greater than 4 were detected on Chrs 1, 2, 3, 8, 9, 13, 14, and 16. Only for the QTL on distal Chr 1 was there convincing evidence that the same or at least a very similar QTL was detected in multiple crosses. We also mapped the Chr 2 QTL directly in heterogeneous stock (HS) animals derived from the four inbred strains. At G(19) the QTL was mapped to an approximately 3-Mbp interval and this interval was associated with a haplotype block with a largely biallelic structure: B6-L:C-D2. We conclude that mapping in HS animals not only provides significantly greater QTL resolution, at least in some cases it provides significantly more information about the QTL haplotype structure.

Animals↗

PubMed2003

A strategy for the integration of QTL, gene expression, and sequence analyses.

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.

Algorithms↗