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The expanded BXD family of mice: A cohort for experimental systems genetics and precision medicine

View ORCID ProfileDavid G. Ashbrook, View ORCID ProfileDanny Arends, View ORCID ProfilePjotr Prins, View ORCID ProfileMegan K. Mulligan, View ORCID ProfileSuheeta Roy, View ORCID ProfileEvan G. Williams, Cathleen M. Lutz, Alicia Valenzuela, Casey J. Bohl, Jesse F. Ingels, Melinda S. McCarty, View ORCID ProfileArthur G. Centeno, View ORCID ProfileReinmar Hager, View ORCID ProfileJohan Auwerx, View ORCID ProfileSaunak Sen, View ORCID ProfileLu Lu, View ORCID ProfileRobert W. Williams
doi: https://doi.org/10.1101/672097
David G. Ashbrook
1Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA
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  • For correspondence: dashbrook@uthsc.edu rwilliams@uthsc.edu lulu@uthsc.edu
Danny Arends
2Lebenswissenschaftliche Fakultät, Albrecht Daniel Thaer-Institut, Humboldt-Universität zu Berlin, Invalidenstraße 42, 10115 Berlin, Germany
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Pjotr Prins
1Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA
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Megan K. Mulligan
1Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA
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Suheeta Roy
1Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA
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Evan G. Williams
3Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland
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Cathleen M. Lutz
4Mouse Repository and the Rare and Orphan Disease Center, The Jackson Laboratory, Bar Harbor, ME USA 04609
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Alicia Valenzuela
4Mouse Repository and the Rare and Orphan Disease Center, The Jackson Laboratory, Bar Harbor, ME USA 04609
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Casey J. Bohl
1Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA
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Jesse F. Ingels
1Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA
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Melinda S. McCarty
1Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA
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Arthur G. Centeno
1Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA
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Reinmar Hager
5Division of Evolution & Genomic Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Oxford Road, Manchester, M13 9PL, UK
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Johan Auwerx
6Laboratory of Integrative Systems Physiology, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland
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Saunak Sen
7Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
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Lu Lu
1Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA
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  • For correspondence: dashbrook@uthsc.edu rwilliams@uthsc.edu lulu@uthsc.edu
Robert W. Williams
1Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA
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  • For correspondence: dashbrook@uthsc.edu rwilliams@uthsc.edu lulu@uthsc.edu
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Abstract

The challenge of precision medicine is to model complex interactions among DNA variants, sets of phenotypes, and complex environmental factors and confounders. We have expanded the BXD family, creating a powerful and extensible test bed for experimental precision medicine and an ideal cohort to study gene-by-environmental interactions.

These BXD segregate for over 6 million variants, with a mean minor allele frequency close to 0.5. We have increased the family two-fold to 150 inbred strains, all derived from C57BL/6J and DBA/2J. We have also generated updated and comprehensive genotypes and an unrivaled deep phenome.

Approximately 10,000 recombinations have been located, allowing precision of quantitative trait loci mapping of ±2.0 Mb over much of the genome and ±0.5 Mb for Mendelian loci. The BXD phenome includes more than 100 ‘omics data sets and >7000 quantitative and clinical phenotypes, all of which is publicly available.

The BXD family is an enduring, collaborative, and replicable resource to test causal and mechanistic links between genomes and phenomes at many stages and under a wide variety of treatments and interventions.

Footnotes

  • Author email & ORCID David G. Ashbrook - dashbrook{at}uthsc.edu, Danny Arends - danny.arends{at}gmail.com, Pjotr Prins - jprins{at}uthsc.edu, Megan K. Mulligan - mkmulligan{at}uthsc.edu, Suheeta Roy - sroy12{at}uthsc.edu, Evan G. Williams - williams{at}imsb.biol.ethz.ch, Cathleen M. Lutz - cat.lutz{at}jax.org, Alicia Valenzuela - acv{at}jax.org, Casey J. Bohl - cbohl1{at}uthsc.edu, Jesse F. Ingels - jingels{at}uthsc.edu, Melinda McCarty - mmccarty{at}uthsc.edu, Arthur G. Centeno - acenteno{at}uthsc.edu, Reinmar Hager - reinmar.hager{at}manchester.ac.uk, Johan Auwerx - admin.auwerx{at}epfl.ch, Saunak Sen - sen{at}uthsc.edu - 0000-0003-4519-6361, Lu Lu - lulu{at}uthsc.edu, Robert W. Williams - rwilliams{at}uthsc.edu

  • Minor changes to figures, and full size versions of all figures now included in the pdf.

  • http://gn2.genenetwork.org

  • http://genenetwork.org

  • https://www.systems-genetics.org/

  • List of abbreviations
    AD
    Alzheimer’s Disease
    AI
    advanced intercross
    B6
    C57BL/6J mouse strain
    BLAST
    Basic Local Alignment Search Tool
    BXD
    BXD family of recombinant inbred strains of mice, produced by crossing the B6 and D2 parental strains
    CC
    Collaborative Cross
    Chr
    Chromosome
    cM
    centimorgan
    D2
    DBA/2J mouse strain
    DO
    Diversity Outbred
    DX
    diallel cross
    EMRs
    electronic medical records
    eQTL
    Expression quantitative trait locus
    F2
    Filial generation 2
    GEMMA
    Genome-wide Efficient Mixed Model Association
    GigaMUGA
    Giga Mouse Universal Genotyping Array
    GN
    GeneNetwork (http://genenetwork.org)
    GN2
    GeneNetwork2 (http://gn2.genenetwork.org)
    GWAS
    genome-wide association study
    H2ix̅
    heritability of isogenic strain means
    H2RIx̅
    heritability of recombinant inbred strain means
    HMDP
    Hybrid Mouse Diversity Panel
    IMPC
    International Mouse Phenotyping Consortium
    JAX
    The Jackson Laboratory
    Kb
    kilobase
    KOMP
    Knockout Mouse project
    LOD
    logarithm of odds
    LRS
    likelihood ratio statistic
    Mb
    Megabase
    MMRRC
    Mutant Mouse Resource & Research Centers
    MUGA
    Mouse Universal Genotyping Array
    nRecP
    number of observed recombinations from one position to the next
    nRecS
    number of observed recombinations per strain
    PheWAS
    phenome-wide association studies
    QT
    quantitative trait
    QTL
    quantitative trait locus
    r2
    Coefficient of determination
    RI
    Recombinant inbred
    RIXs
    Recombinant inbred intercrosses
    SE
    Standard error of the mean
    SNP
    single nucleotide polymorphism
    UTHSC
    University of Tennessee Health Science Center
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    The expanded BXD family of mice: A cohort for experimental systems genetics and precision medicine
    David G. Ashbrook, Danny Arends, Pjotr Prins, Megan K. Mulligan, Suheeta Roy, Evan G. Williams, Cathleen M. Lutz, Alicia Valenzuela, Casey J. Bohl, Jesse F. Ingels, Melinda S. McCarty, Arthur G. Centeno, Reinmar Hager, Johan Auwerx, Saunak Sen, Lu Lu, Robert W. Williams
    bioRxiv 672097; doi: https://doi.org/10.1101/672097
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    The expanded BXD family of mice: A cohort for experimental systems genetics and precision medicine
    David G. Ashbrook, Danny Arends, Pjotr Prins, Megan K. Mulligan, Suheeta Roy, Evan G. Williams, Cathleen M. Lutz, Alicia Valenzuela, Casey J. Bohl, Jesse F. Ingels, Melinda S. McCarty, Arthur G. Centeno, Reinmar Hager, Johan Auwerx, Saunak Sen, Lu Lu, Robert W. Williams
    bioRxiv 672097; doi: https://doi.org/10.1101/672097

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