Journal
MAMMALIAN GENOME
Volume 14, Issue 11, Pages 733-747Publisher
SPRINGER
DOI: 10.1007/s00335-003-2277-9
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Funding
- NATIONAL INSTITUTE OF MENTAL HEALTH [R01MH051372] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM [R01AA011114, R29AA011114, P60AA010760, P50AA010760] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [R01DA005228] Funding Source: NIH RePORTER
- NIAAA NIH HHS [AA10760, P60 AA010760, AA11114, AA11043] Funding Source: Medline
- NIDA NIH HHS [DA05228] Funding Source: Medline
- NIMH NIH HHS [MH51372] Funding Source: Medline
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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.
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