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High-resolution mapping of quantitative trait loci in outbred mice

Abstract

Screening the whole genome of a cross between two inbred animal strains has proved to be a powerful method for detecting genetic loci underlying quantitative behavioural traits1,2,3,4,5,6,7, but the level of resolution offered by quantitative trait loci (QTL) mapping is still too coarse to permit molecular cloning of the genetic determinants8. To achieve high-resolution mapping, we used an outbred stock of mice for which the entire genealogy is known. The heterogeneous stock (HS) was established 30 years ago from an eight-way cross of C57BL/6, BALB/c, RIII, AKR, DBA/2, I, A/J and C3H inbred mouse strains9. At the time of the experiment reported here, the HS mice were at generation 58, theoretically offering at least a 30-fold increase in resolution for QTL mapping compared with a backcross or an F2 intercross10,11. Using the HS mice we have mapped a QTL influencing a psychological trait in mice to a 0.8-cM interval on chromosome 1. This method allows simultaneous fine mapping of multiple QTLs, as shown by our report of a second QTL on chromosome 12. The high resolution possible with this approach makes QTLs accessible to positional cloning.

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Figure 1: The location of a genetic effect on two open-field measures (OFA, OFD) and EMO (which represents their negative correlation).
Figure 2: A region of 1.4 cM on chromosome 1 that contains the QTL. The results of two analyses are shown: the curve is the output of MAPMAKER-QTL and the black squares indicate the ANOVA results for each marker.

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Acknowledgements

We thank A. Darvasi and L. Cardon for help with the analyses, J. DeFries for comments on the manuscript and S. Brown and the MRC Mammalian Genetics Unit at Harwell, Oxfordshire for help. This work was supported by the Wellcome Trust (C.J.T., A.N. and J.F.).

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Correspondence to Jonathan Flint.

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Talbot, C., Nicod, A., Cherny, S. et al. High-resolution mapping of quantitative trait loci in outbred mice. Nat Genet 21, 305–308 (1999). https://doi.org/10.1038/6825

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