Skip to main content
SpringerLink
Log in

Mind the gap: analysis of marker-assisted breeding strategies for inbred mouse strains

  • Original Contributions
  • Published:
Mammalian Genome Aims and scope Submit manuscript

Abstract

The development of congenic mouse strains is the principal approach for confirming and fine mapping quantitative trait loci, as well as for comparing the phenotypic effect of a transgene or gene-targeted disruption between different inbred mouse strains. The traditional breeding scheme calls for at least nine consecutive backcrosses before establishing a congenic mouse strain. Recent availability of genome sequence and high-throughput genotyping now permit the use of polymorphic DNA markers to reduce this number of backcrosses, and empirical data suggest that marker-assisted breeding may require as few as four backcrosses. We used simulation studies to investigate the efficiency of different marker-assisted breeding schemes by examining the trade-off between the number of backcrosses, the number of mice produced per generation, and the number of genotypes per mouse required to achieve a quality congenic mouse strain. An established model of crossover interference was also incorporated into these simulations. The quality of the strain produced was assessed by the probability of an undetected region of heterozygosity (i.e., “gaps”) in the recipient genetic background, while maintaining the desired donor-derived interval. Somewhat surprisingly, we found that there is a relatively high probability for undetected gaps in potential breeders for establishing a congenic mouse strain. Marker-assisted breeding may decrease the number of backcross generations required to generate a congenic strain, but only additional backcrossing will guarantee a reduction in the number and length of undetected gaps harboring contaminating donor alleles.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Beck JA, Lloyd S, Hafezparast M, Lennon-Pierce M, Eppig JT, et al. (2000) Genealogies of mouse inbred strains. Nat Genet 24: 23–25

    CAS  PubMed  Google Scholar 

  • Bennett B (2000) Congenic strains developed for alcohol- and drug-related phenotypes. Pharmacol Biochem Behav 67: 671–681

    Article  CAS  PubMed  Google Scholar 

  • Bennett B, Johnson TE (1998) Development of congenics for hypnotic sensitivity to ethanol by QTL-marker-assisted counter selection. Mamm Genome 9: 969–974

    Article  CAS  PubMed  Google Scholar 

  • Bergman ML, Duarte N, Campino S, Lundholm M, Motta V, et al. (2003) Diabetes protection and restoration of thymocyte apoptosis in NOD Idd6 congenic strains. Diabetes 52: 1677–1682

    CAS  PubMed  Google Scholar 

  • Blank RD, Campbell GR, Calabro A, D’Eustachio P (1988) A linkage map of mouse chromosome 12: localization of Igh and effects of sex and interference on recombination. Genetics 120: 1073–1083

    CAS  PubMed  Google Scholar 

  • Brockmann GA, Bevova MR (2002) Using mouse models to dissect the genetics of obesity. Trends Genet 18: 367–376

    Article  CAS  PubMed  Google Scholar 

  • Brodnicki TC, McClive P, Couper S, Morahan G (2000) Localization of Idd11 using NOD congenic mouse strains: elimination of Slc9a1 as a candidate gene. Immunogenetics 51: 37–41

    Article  CAS  PubMed  Google Scholar 

  • Brodnicki TC, Quirk F, Morahan G (2003) A susceptibility allele from a non-diabetes-prone mouse strain accelerates diabetes in NOD congenic mice. Diabetes 52: 218–222

    CAS  PubMed  Google Scholar 

  • Broman KW, Rowe LB, Churchill GA, Paigen K (2002) Crossover interference in the mouse. Genetics 160: 1123–1131

    PubMed  Google Scholar 

  • Burt RA, Marshall VM, Wagglen J, Rodda FR, Senyschen D, et al. (2002) Mice that are congenic for the char2 locus are susceptible to malaria. Infect Immun 70: 4750–4753

    Article  CAS  PubMed  Google Scholar 

  • Collins SC, Wallis RH, Wallace K, Bihoreau MT, Gauguier D (2003) Marker-assisted congenic screening (MACS): a database tool for the efficient production and characterization of congenic lines. Mamm Genome 14: 350–356

    Article  PubMed  Google Scholar 

  • Crabbe JC (2002) Alcohol and genetics: new models. Am J Med Genet 114: 969–974

    Article  PubMed  Google Scholar 

  • Esteban LM, Tsoutsman T, Jordan MA, Roach D, Poulton LD, et al. (2003) Genetic control of NKT cell numbers maps to major diabetes and lupus loci. J Immunol 171: 2873–2878

    CAS  PubMed  Google Scholar 

  • Estill SJ, Garcia JA (2000) A marker assisted selection protocol (MASP) to generate C57BL/6J or 129S6/SvEvTac speed congenic or consomic strains. Genesis 28: 164–166

    Article  CAS  PubMed  Google Scholar 

  • Fortin A, Stevenson MM, Gros P (2002) Complex genetic control of susceptibility to malaria in mice. Genes Immun 3: 177–186

    Article  CAS  PubMed  Google Scholar 

  • Foss E, Lande R, Stahl FW, Steinberg CM (1993) Chiasma interference as a function of genetic distance. Genetics 133: 681–691

    CAS  PubMed  Google Scholar 

  • Frisch M, Melchinger AE (2001) The length of the intact donor chromosome segment around a target gene in marker-assisted backcrossing. Genetics 157: 1343–1356

    CAS  PubMed  Google Scholar 

  • Grattan M, Mi QS, Meagher C, Delovitch TL (2002) Congenic mapping of the diabetogenic locus Idd4 to a 5.2-cM region of chromosome 11 in NOD mice: identification of two potential candidate subloci. Diabetes 51: 215–223

    CAS  PubMed  Google Scholar 

  • Hanson WD (1959) Early generation analysis of lengths of heterozygous chromosome segments around a locus held heterozygous with backcrossing or selfing. Genetics 44: 833–837

    Google Scholar 

  • Hospital F (2001) Size of donor chromosome segments around introgressed loci and reduction of linkage drag in marker-assisted backcross programs. Genetics 158: 1363–1379

    CAS  PubMed  Google Scholar 

  • Hospital F, Charcosset A (1997) Marker-assisted introgression of quantitative trait loci. Genetics 147: 1469–1485

    CAS  PubMed  Google Scholar 

  • Hospital F, Chevalet C, Mulsant P (1992) Using markers in gene introgression breeding programs. Genetics 132: 1199–1210

    CAS  PubMed  Google Scholar 

  • Hudgins CC, Steinberg RT, Klinman DM, Reeves MJ, Steinberg AD (1985) Studies of consomic mice bearing the Y chromosome of the BXSB mouse. J Immunol 134: 3849–3854

    CAS  PubMed  Google Scholar 

  • Iakoubova OA, Olsson CL, Dains KM, Ross DA, Andalibi A, et al. (2001) Genome-tagged mice (GTM): two sets of genome-wide congenic strains. Genomics 74: 89–104

    Article  CAS  PubMed  Google Scholar 

  • Kauppi L, Jeffreys AJ, Keeney S (2004) Where the crossovers are: recombination distributions in mammals. Nat Rev Genet 5: 413–424

    Article  CAS  PubMed  Google Scholar 

  • Koudande OD, Iraqi F, Thomson PC, Teale AJ, van Arendonk JA (2000) Strategies to optimize marker-assisted introgression of multiple unlinked QTL. Mamm Genome 11: 145–150

    CAS  PubMed  Google Scholar 

  • Lamhamedi-Cherradi SE, Boulard O, Gonzalez C, Kassis N, Damotte D, et al. (2001) Further mapping of the Idd5.1 locus for autoimmune diabetes in NOD mice. Diabetes 50: 2874–2878

    CAS  PubMed  Google Scholar 

  • Lander ES, Schork NJ (1994) Genetic dissection of complex traits. Science 265: 2037–2048

    CAS  PubMed  Google Scholar 

  • Laporte C, Ballester B, Mary C, Izui S, Reininger L (2003) The Sgp3 locus on mouse chromosome 13 regulates nephritogenic gp70 autoantigen expression and predisposes to autoimmunity. J Immunol 171: 3872–3877

    CAS  PubMed  Google Scholar 

  • Leiter EH, (2002) Mice with targeted gene disruptions or gene insertions for diabetes research: problems, pitfalls, and potential solutions. Diabetologia 45: 296–308

    Article  CAS  PubMed  Google Scholar 

  • Lin S, Speed TP (1996) Incorporating crossover interference into pedigree analysis using the chi 2 model. Hum Hered 46: 315–322

    CAS  PubMed  Google Scholar 

  • Markel P, Shu P, Ebeling C, Carlson GA, Nagle DL, et al. (1997) Theoretical and empirical issues for marker-assisted breeding of congenic mouse strains. Nat Genet 17: 280–284

    CAS  PubMed  Google Scholar 

  • McDevitt HO (2000) Discovering the role of the major histocompatibility complex in the immune response. Annu Rev Immunol 18: 1–17

    Article  CAS  PubMed  Google Scholar 

  • Montagutelli X (2000) Effect of the genetic background on the phenotype of mouse mutations. J Am Soc Nephrol 11: Suppl 16, S101–105

    PubMed  Google Scholar 

  • Moore KJ, Nagle DL (2000) Complex trait analysis in the mouse: The strengths, the limitations and the promise yet to come. Annu Rev Genet 34: 653–686

    Article  CAS  PubMed  Google Scholar 

  • Morahan G, Morel L (2002) Genetics of autoimmune diseases in humans and in animal models. Curr Opin Immunol 14: 803–811

    Article  CAS  PubMed  Google Scholar 

  • Nadeau JH (2001) Modifier genes in mice and humans. Nat Rev Genet 2: 165–174

    Article  CAS  PubMed  Google Scholar 

  • Nadeau JH, Singer JB, Matin A, Lander ES (2000) Analysing complex genetic traits with chromosome substitution strains. Nat Genet 24: 221–225

    Article  CAS  PubMed  Google Scholar 

  • Ochiai Y, Tamura Y, Saito Y, Matsuki A, Wakabayashi Y, et al. (2003) Mapping of genetic modifiers of thymic lymphoma development in p53-knockout mice. Oncogene 22: 1098–1102

    Article  CAS  PubMed  Google Scholar 

  • Podolin PL, Denny P, Lord CJ, Hill NJ, Todd JA, et al. (1997) Congenic mapping of the insulin-dependent diabetes (Idd) gene, Idd10, localizes two genes mediating the Idd10 effect and eliminates the candidate Fcgr1. J Immunol 159: 1835–1843

    CAS  PubMed  Google Scholar 

  • Rogner UC, Avner P (2003) Congenic mice: cutting tools for complex immune disorders. Nat Rev Immunol 3: 243–252

    Article  CAS  PubMed  Google Scholar 

  • Santiago-Raber ML, Baccala R, Haraldsson KM, Choubey D, Stewart TA, et al. (2003) Type-I interferon receptor deficiency reduces lupus-like disease in NZB mice. J Exp Med 197: 777–788

    Article  CAS  PubMed  Google Scholar 

  • Serreze DV, Chapman HD, Varnum DS, Hanson MS, Reifsnyder PC, et al. (1996) B lymphocytes are essential for the initiation of T cell-mediated autoimmune diabetes: analysis of a new “speed congenic” stock of NOD.Ig mu null mice. J Exp Med 184: 2049–2053

    Article  CAS  PubMed  Google Scholar 

  • Silver LM (1995) Mouse genetics: concepts and applications (New York: Oxford University Press)

    Google Scholar 

  • Singer JB, Hill AE, Burrage LC, Olszens KR, Song J, et al. (2004) Genetic dissection of complex traits with chromosome substitution strains of mice. Science 304: 445–448

    Article  CAS  PubMed  Google Scholar 

  • Snell GD (1948) Methods for the study of histocompatibility genes. J Genet 49: 87–108

    Google Scholar 

  • Stam P, Zeven AC (1981) The theoretical proportion of the donor genome in near-isogenic lines of self-fertilizers bred by backcrossing. Euphytica 30: 227–238

    Article  Google Scholar 

  • Tsuchihashi Z, Dracopoli NC (2002) Progress in high throughput SNP genotyping methods. Pharmacogenomics J 2: 103–110

    Article  CAS  PubMed  Google Scholar 

  • Visscher PM (1999) Speed congenics: accelerated genome recovery using genetic markers. Genet Res 74: 81–85

    Article  CAS  PubMed  Google Scholar 

  • Visscher PM, Haley CS, Thompson R (1996) Marker-assisted introgression in backcross breeding programs. Genetics 144: 1923–1932

    CAS  PubMed  Google Scholar 

  • Wakeland E, Morel L, Achey K, Yui M, Longmate J (1997) Speed congenics: a classic technique in the fast lane (relatively speaking). Immunol Today 18: 472–477

    Article  CAS  PubMed  Google Scholar 

  • Weil MM, Brown BW, Serachitopol DM (1997) Genotype selection to rapidly breed congenic strains. Genetics 146: 1061–1069

    CAS  PubMed  Google Scholar 

  • Winer S, Astsaturov I, Gaedigk R, Hammond-McKibben D, Pilon M, et al. (2002) ICA69(null) nonobese diabetic mice develop diabetes, but resist disease acceleration by cyclophosphamide. J Immunol 168: 475–482

    CAS  PubMed  Google Scholar 

  • Wither JE, Lajoie G, Heinrichs S, Cai YC, Chang N, et al. (2003) Functional dissection of lupus susceptibility loci on the New Zealand black mouse chromosome 1: evidence for independent genetic loci affecting T and B cell activation. J Immunol 171: 1697–1706

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank R.C.A. Symons for advice and comments. This work was supported by NIH grant GM59506-01.

Author information

Authors and Affiliations

  1. Division of Molecular Biology, Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands

    Nicola J. Armstrong

  2. Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, 3050, Australia

    Thomas C. Brodnicki & Terence P. Speed

  3. Department of Statistics, University of California, Berkeley, California, 94720, USA

    Terence P. Speed

Authors
  1. Nicola J. Armstrong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomas C. Brodnicki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Terence P. Speed
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nicola J. Armstrong.

Electronic Supplementary Material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Armstrong, N.J., Brodnicki, T.C. & Speed, T.P. Mind the gap: analysis of marker-assisted breeding strategies for inbred mouse strains. Mamm Genome 17, 273–287 (2006). https://doi.org/10.1007/s00335-005-0123-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00335-005-0123-y

Keywords

Search

Navigation