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Fine mapping of a major locus on Chromosome 10 for exploratory and fear-like behavior in mice

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Abstract

Advanced intercross lines (AIL) and interval–specific congenic strains (ISCS) were used to fine map previously coarsely defined quantitative trait loci (QTL) on Chromosomes 1,10, and 19, influencing behaviors in the open Field (OF) and light–dark (LD) paradigms in mice. F12(A × B) AIL mice (N = 1130) were phenotyped, genotyped, and mapped. The ISCS were studied only in the telomeric Chromosome 10 region of interest, containing the exploratory and excitability QTL1 (Exq1). The Chromosome 10 Exq1 and Chromosome 19 Exq4 loci mapped robustly in the AIL. The most significant QTL findings (2.0 LOD score intervals; peak; LOD score) came from the TD15 and LD transitions traits, yielding estimated intervals of 2.2 cM for Exq1 (71.3–73.5 cM; peak 72.3 cM; LOD 11.9) and 9.0 cM for Exq4 (29.0–38.2 cM; peak 34 cM; LOD 4.2). The replicated QTLs on Chromosome 1 failed to map in this AIL population. The ISCS data confirmed Exq1 loci in general. However, the ISCS data were complex and less definitive for localizing the Exq1 loci. These exploratory and fear-like behaviors result from inheriting “many small things,” namely, QTL explaining 2%–7% of the phenotypic variance. These results highlight the challenges of positionally cloning loci of small effect for complex traits. In particular, fine-mapping success may depend on the genetic architecture underlying complex traits.

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Acknowledgments

We thank Ming You (Washington University) for insightful comments on the manuscript along with the anonymous reviewers. We appreciate our ILRI and UTSW colleagues for helpful conversations. We are extraordinarily grateful to the Mammalian Genotyping Service for skillfully genotyping the F12 population (James Weber, Marshfield Clinic). We appreciated Paul Neumann’s (Dalhousie University) idea in 1995 for the ISCS strategy, the Mouse Genome Project, Ken Manly for QTX Manager, Ensembl, and the Mouse Genome Informatics Project for providing the facilitating infrastructure for this work. This project has been generously supported by the Southwestern Medical Foundation, Texas Higher Education Coordinating Board ARP (010019-0081-1999), and National Institutes of Health R01-MH58882 (HG).

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  1. Neeman Mohibullah

    Present address: The Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N., Mailstop A1 - 162, P.O. Box 1902, WA, Seatle, 98109-1024, USA

Authors and Affiliations

  1. Department of Psychiatry and Integrative Biology, University of Texas Southwestern Medical Center, Dallas, Texas, 75390-9070, USA

    Shumin Zhang, Yigong Lou, Tara M. Amstein, Neeman Mohibullah, Devin Stancliffe & Howard K. Gershenfeld

  2. International Livestock Research Institute (I.L.R.I.), Naivasha Road, P.O. Box 30709, Nairobi, Kenya

    Monica Anyango, Alfred Osoti, Robert King & Fuad Iraqi

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  1. Shumin Zhang
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Correspondence to Shumin Zhang.

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Shumin Zhang, Yigong Lou and Howard Gershenfeld contributed equally to this work.

Abbreviations: ROI, Region of Interest; RI, recombinant inbred; AIL, advanced intercross line; ISCS, Interval-specific congenic strains; Sqrt, square root; QTL, quantitative trait loci; OF, open field; LOD, likelihood of the odds ratio score; Tde1, traveled distance epoch 1; TDe3, traveled distance epoch 3; TD15, traveled distance during 15 min; VM15, vertical movements during 15 min ; LD, light–dark transitions; AvgCtrT, average center time; Chr, chromosome; Exq, exploratory and excitability QTL.

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Zhang, S., Lou, Y., Amstein, T.M. et al. Fine mapping of a major locus on Chromosome 10 for exploratory and fear-like behavior in mice. Mamm Genome 16, 306–318 (2005). https://doi.org/10.1007/s00335-004-2427-8

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