Genetic reference panels are widely used to map complex, quantitative traits in model organisms. We have generated new high-resolution genetic maps of 259 mouse inbred strains from recombinant inbred strain panels (C57BL/6J × DBA/2J, ILS/IbgTejJ × ISS/IbgTejJ, and C57BL/6J × A/J) and chromosome substitution strain panels (C57BL/6J-Chr#, C57BL/6J-Chr#, and C57BL/6J-Chr#). We genotyped all samples using the Affymetrix Mouse Diversity Array with an average intermarker spacing of 4.3 kb. The new genetic maps provide increased precision in the localization of recombination breakpoints compared to the previous maps. Although the strains were presumed to be fully inbred, we found residual heterozygosity in 40% of individual mice from five of the six panels. We also identified de novo deletions and duplications, in homozygous or heterozygous state, ranging in size from 21 kb to 8.4 Mb. Almost two-thirds (46 out of 76) of these deletions overlap exons of protein coding genes and may have phenotypic consequences. Twenty-nine putative gene conversions were identified in the chromosome substitution strains. We find that gene conversions are more likely to occur in regions where the homologous chromosomes are more similar. The raw genotyping data and genetic maps of these strain panels are available at http://churchill-lab.jax.org/website/MDA.

Department of Anatomy and Neurobiology University of Tennessee Health Science Center Memphis Tennessee 38163

Division Biotechnology and Biomedicine Centre of the Academy of Sciences Institute of Molecular Genetics of the Academy of Sciences of the Czech Republic Vestec Prague 4 142 20 Czech Republic

Institut de Recherches Cliniques Montreal Quebec H2W 1R7 Canada

Institute for Behavioral Genetics Department of Genetics Lineberger Comprehensive Cancer Center University of North Carolina at Chapel Hill North Carolina 27599 7264

National Institute of Genetics Mishima 411 8540 Japan

The Jackson Laboratory Bar Harbor Maine 04609

University of Colorado at Boulder Colorado 80309

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Beck J. A., Lloyd S., Hafezparast M., Lennon-Pierce M., Eppig J. T., et al. , 2000.  Genealogies of mouse inbred strains. Nat. Genet. 24: 23–25. PubMed

Belknap J., 1998.  Effect of within-strain sample size on QTL detection and mapping using recombinant inbred mouse strains. Behav. Genet. 28: 29–38. PubMed

Broman K. W., 2005.  The genomes of recombinant inbred lines. Genetics 169: 1133–1146. PubMed PMC

Broman K. W., Sen S., 2009.  A Guide to QTL Mapping with R/qtl. Springer, New York.

Buchner D. A., Nadeau J. H., 2015.  Contrasting genetic architectures in different mouse reference populations used for studying complex traits. Genome Res. 25: 775–791. PubMed PMC

Chesler E. J., Gatti D. M., Morgan A. P., Strobel M., Trepanier L., et al. , 2016.  Diversity outbred mice at 21: maintaining allelic variation in the face of selection. G3 6: 3893–3902. PubMed PMC

Chinwalla A. T., Cook L. L., Delehaunty K. D., Fewell G. A., Fulton L. A., et al. , 2002.  Initial sequencing and comparative analysis of the mouse genome. Nature 420: 520–562. PubMed

Churchill G. A., Gatti D. M., Munger S. C., Svenson K. L., 2012.  The diversity outbred mouse population. Mamm. Genome 23: 713–718. PubMed PMC

Collaborative Cross Consortium , 2012.  The genome architecture of the Collaborative Cross mouse genetic reference population. Genetics 190: 389–401. PubMed PMC

Didion J. P., Yang H., Sheppard K., Fu C. P., McMillan L., et al. , 2012.  Discovery of novel variants in genotyping arrays improves genotype retention and reduces ascertainment bias. BMC Genomics 13: 34. PubMed PMC

Gregorova S., Divina P., Storchova R., Trachtulec Z., Fotopulosova V., et al. , 2008.  Mouse consomic strains: exploiting genetic divergence between Mus m. musculus and Mus m. domesticus subspecies. Genome Res. 18: 509–515. PubMed PMC

Himmelmann, L., 2010 HMM: HMM - Hidden Markov Models. R package version 1.0. Available at: https://CRAN.R-project.org/package=HMM. Accessed: April 8, 2016.

Juang B.-H., Rabiner L. R., 1990.  The segmental K-means algorithm for estimating parameters of hidden Markov models. IEEE Trans. Acoust. Speech Signal Process. 38: 1639–1641.

Keane T. M., Goodstadt L., Danecek P., White M. A., Wong K., et al. , 2011.  Mouse genomic variation and its effect on phenotypes and gene regulation. Nature 477: 289–294. PubMed PMC

Kumar V., Kim K., Joseph C., Kourrich S., Yoo S.-H., et al. , 2013.  C57BL/6N mutation in cytoplasmic FMRP interacting protein 2 regulates cocaine response. Science 342: 1508–1512. PubMed PMC

Liu J., Song H., Liu D., Zuo T., Lu F., et al. , 2014.  Extensive recombination due to heteroduplexes generates large amounts of artificial gene fragments during PCR. PLoS One 9: e106658. PubMed PMC

Morgan A. P., Didion J. P., Doran A. G., Holt J. M., McMillan L., et al. , 2016.  Whole genome sequence of two wild-derived Mus musculus domesticus inbred strains, LEWES/EiJ and ZALENDE/EiJ, with different diploid numbers. G3 (Bethesda) 6: 4211–4216. PubMed PMC

Nadeau J. H., Singer J. B., Matin A., Lander E. S., 2000.  Analysing complex genetic traits with chromosome substitution strains. Nat. Genet. 24: 221–225. PubMed

Nadeau J. H., Forejt J., Takada T., Shiroishi T., 2012.  Chromosome substitution strains: gene discovery, functional analysis, and systems studies. Mamm. Genome 23: 693–705. PubMed PMC

Nesbitt M. N., Skamene E., 1984.  Recombinant inbred mouse strains derived from A/J and C57BL/6J: a tool for the study of genetic mechanisms in host resistance to infection and malignancy. J. Leukoc. Biol. 36: 357–364. PubMed

Peirce J. L., Lu L., Gu J., Silver L. M., Williams R. W., 2004.  A new set of BXD recombinant inbred lines from advanced intercross populations in mice. BMC Genet. 5: 7. PubMed PMC

Shifman S., Bell J. T., Copley R. R., Taylor M. S., Williams R. W., et al. , 2006.  A high-resolution single nucleotide polymorphism genetic map of the mouse genome. PLoS Biol. 4: e395. PubMed PMC

Shorter J. R., Odet F., Aylor D. L., Pan W., Kao C.-Y., et al. , 2017.  Male infertility is responsible for nearly half of the extinction observed in the mouse Collaborative Cross. Genetics 206: 557–572. PubMed PMC

Simecek P., Churchill G. A., Yang H., Rowe L. B., Herberg L., et al. , 2015.  Genetic analysis of substrain divergence in non-obese diabetic (NOD) mice. G3 (Bethesda) 5: 771–775. PubMed PMC

Srivastava A., Morgan A. P., Najarian M. L., Sarsani V. K., Sigmon J. S., et al. , 2017.  Genomes of the mouse Collaborative Cross. Genetics 206: 537–556. PubMed PMC

Taft R. A., Davisson M., Wiles M. V., 2006.  Know thy mouse. Trends Genet. 22: 649–653. PubMed

Takada T., Mita A., Maeno A., Sakai T., Shitara H., et al. , 2008.  Mouse inter-subspecific consomic strains for genetic dissection of quantitative complex traits. Genome Res. 18: 500–508. PubMed PMC

Taudt A., Colomé-Tatché M., Johannes F., 2016.  Genetic sources of population epigenomic variation. Nat. Rev. Genet. 17: 319–332. PubMed

Taylor B. A., Bailey D. W., Cherry M., Riblet R., Weigert M., 1975.  Genes for immunoglobulin heavy chain and serum prealbumin protein are linked in mouse. Nature 256: 644–646. PubMed

Taylor B. A., Wnek C., Kotlus B. S., Roemer N., MacTaggart T., et al. , 1999.  Genotyping new BXD recombinant inbred mouse strains and comparison of BXD and consensus maps. Mamm. Genome 10: 335–348. PubMed

Welsh C. E., McMillan L., 2012.  Accelerating the inbreeding of multi-parental recombinant inbred lines generated by sibling matings. G3 (Bethesda) 2: 191–198. PubMed PMC

Williams R. W., Gu J., Qi S., Lu L., 2001.  The genetic structure of recombinant inbred mice: high-resolution consensus maps for complex trait analysis. Genome Biol. 2: RESEARCH0046. PubMed PMC

Williams R. W., Bennett B., Lu L., Gu J., DeFries J. C., et al. , 2004.  Genetic structure of the LXS panel of recombinant inbred mouse strains: a powerful resource for complex trait analysis. Mamm. Genome 15: 637–647. PubMed

Yang H., Ding Y., Hutchins L. N., Szatkiewicz J., Bell T. A., et al. , 2009.  A customized and versatile high-density genotyping array for the mouse. Nat. Methods 6: 663–666. PubMed PMC

Yang H., Wang J. R., Didion J. P., Buus R. J., Bell T. A., et al. , 2011.  Subspecific origin and haplotype diversity in the laboratory mouse. Nat. Genet. 43: 648–655. PubMed PMC