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

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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 F2 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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Acknowledgements

This study was supported in part by grants MH 51372, AA10760, AA11114, AA11043, and DA05228 from the United States Public Health Service and a grant from the Veterans Affairs Medical Research Service.

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Authors and Affiliations

  1. Research Service, Veterans Affairs Medical Center, Portland, Oregon, USA

    Robert Hitzemann, Maureen Lawler & Shannon Coulombe

  2. Department of Behavioral Neuroscience L470, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd, Portland, Oregon 97239, USA

    Robert Hitzemann, Barry Malmanger, Cheryl Reed, Barbara Hitzemann, Kari Buck, Brooks Rademacher, Nicole Walter & Yekatrina Polyakov

  3. Department of Pharmacology, University of Colorado Health Sciences Center, Denver, Colorado, USA

    James Sikela, Brenda Gensler & Sonya Burgers

  4. Center for Genomics and Bioinformatics, University of Tennessee Health Science Center, Memphis, Tennessee, USA

    Robert W. Williams

  5. Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York, USA

    Ken Manly

  6. Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, Ox3 7BN, UK

    Jonathan Flint

  7. Department of Genetics, University of Leicester, Leicester LE1 7RH, UK

    Christopher Talbot

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  1. Robert Hitzemann
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Correspondence to Robert Hitzemann.

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Hitzemann, R., Malmanger, B., Reed, C. et al. A strategy for the integration of QTL, gene expression, and sequence analyses . Mamm Genome 14, 733–747 (2003). https://doi.org/10.1007/s00335-003-2277-9

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