Skip to main content

Advertisement

SpringerLink
Log in

Heritability and coefficient of genetic variation analyses of phenotypic traits provide strong basis for high-resolution QTL mapping in the Collaborative Cross mouse genetic reference population

  • Published:
Mammalian Genome Aims and scope Submit manuscript

Abstract

Most biological traits of human importance are complex in nature; their manifestation controlled by the cumulative effect of many genetic factors interacting with one another and with the individual’s life history. Because of this, mouse genetic reference populations (GRPs) consisting of collections of inbred lines or recombinant inbred lines (RIL) derived from crosses between inbred lines are of particular value in analysis of complex traits, since massive amounts of data can be accumulated on the individual lines. However, existing mouse GRPs are derived from inbred lines that share a common history, resulting in limited genetic diversity, and reduced mapping precision due to long-range gametic disequilibrium. To overcome these limitations, the Collaborative Cross (CC) a genetically highly diverse collection of mouse RIL was established. The CC, now in advanced stages of development, will eventually consist of about 500 RIL derived from reciprocal crosses of eight divergent founder strains of mice, including three wild subspecies. Previous studies have shown that the CC indeed contains enormous diversity at the DNA level, that founder haplotypes are inherited in expected frequency, and that long-range gametic disequilibrium is not present. We here present data, primarily from our own laboratory, documenting extensive genetic variation among CC lines as expressed in broad-sense heritability (H2) and by the well-known “coefficient of genetic variation,” demonstrating the ability of the CC resource to provide unprecedented mapping precision leading to identification of strong candidate genes.

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.

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

Similar content being viewed by others

References

  • Ansorge WJ (2009) Next-generation DNA sequencing techniques. New Biotechnol 25(4):195–203

    Article  CAS  Google Scholar 

  • Aylor DL, Valdar W, Foulds-Mathes, Buus RJ, Verdugo RA, Baric RS, Ferris MT, Frelinger JA, Heise M, Frieman MB, Gralinski LE, Bell TA, Didion JD, Hua K, Nehrenberg DL, Powell CL, Steigerwalt J, Xie Y, Kalada S, Collins FS, Yang LV, Schwartz DA, Branstetter LA, Chesler EJ, Miller DR, Spence J, Yi Liu E, McMillan L, Sarkar A, Wang J, Wang W, Zhang Q, Broman KW, Korstanje R, Durrant C, Mott R, Iraqi FA, Pomp D, Threadgill D, de Pardo-Manuel Villena F, Churchil GA (2011) Genetic analysis of complex traits in the emerging collaborative cross. Genome Res 21:1213–1222

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Baker PJ, Roopenian DC (2002) Genetic susceptibility to chronic periodontal disease. Microbes Infect 4:1157–1167

    Article  CAS  PubMed  Google Scholar 

  • Baker PJ, Dixon M, Roopenian DC (2000) Genetic control of susceptibility to Porphyromonas gingivalis-induced alveolar bone loss in mice. Infect Immun 68:5864–5868

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Bottomley D, Ferris MT, Aicher LD et al (2012) Expression quantitative trait loci for extreme host response to Influenza A in pre-Collaborative Cross Mice. G3 2:213–221

    Article  Google Scholar 

  • Broman KW (2005) The genomes of recombinant inbred lines. Genetics 169(2):1133–1146

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Broman KW, Kim S, Sen S, Ané C, Payseur BA (2012) Mapping quantitative trait loci onto a phylogenetic tree. Genetics 192(1):267–279

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Brommage R (2003) Validation and calibration of DEXA body composition in mice. Am J Physiol Endocrinol Metab 285:454–459

    Google Scholar 

  • Buse JB, Ginsberg HN, Bakris GL, Clark NG, Costa F, Eckel R, Fonseca V, Gerstein HC, Grundy S, Nesto RW, Pignone MP, Plutzky J, Porte D, Redberg R, Stitzel KF, Stone NJ (2007) Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association. Circulation 115:114–126

    Article  PubMed  Google Scholar 

  • Chesler EJ, Miller DM, Branstetter LR, Galloway LD, Jackson BL et al (2008) The Collaborative Cross at Oak Ridge National Laboratory: developing a powerful resource for systems genetics. Mamm Genome 19:382–389

    Article  PubMed Central  PubMed  Google Scholar 

  • Churchill GA, Airey DC, Allayee H, Angel JM, Attie AD, Beatty J, Beavis WD, Belknap JK, Bennett B, Berrettini W, Bleich A, Bogue M, Broman KW, Buck KJ, Buckler E, Burmeister M, Chesler EJ, Cheverud JM, Clapcote S, Cook MN, Cox RD, Crabbe JC, Crusio WE, Darvasi A, Deschepper CF, Doerge RW, Farber CR, Forejt J, Gaile D, Garlow SJ, Geiger H, Gershenfeld H, Gordon T, Gu J, Gu W, de Haan G, Hayes NL, Heller C, Himmelbauer H, Hitzemann R, Hunter K, Hsu HC, Iraqi FA, Ivandic B, Jacob HJ et al (2004) The Collaborative Cross, a community resource for the genetic analysis of complex traits. Nat Genet 36:1133–1137

    Article  CAS  PubMed  Google Scholar 

  • Collaborative Cross Consortium, Iraqi FA, Mahajne M, Salaymah A, Sandovsky H, Tayem, Vered K, Balmer L, Hall M, Manship G, Morahan G, Petit K, Scholten J, Tweedie K, Weerasekera L, Cleak J, Durrant C, Goodstadt L, Mott R, Yalcin B, Aylor DL, Baric R, Bell TA, Bendt KM, Brooks JD, Buus RJ, Crowley JJ, Calaway JD, Calaway ME, Cholka A, Darr DB, Didion JP, Dorman A, Everett E, Ferris MT, Mathes WF, Fu CP, Gooch TJ, Goodson SG, Garlinski LE, Hansen SD, Heise M, Hoel J, Lee S, Lenarcic AB, Liu EY, McMillan L, Magnuson TR, Manly KF, O’Brien DA, Odet F, Pan W, de Pardo-Manuel Villena F, Perou C, Pomp D, Quackenbush CR, Robinson NN, Sharpless N, Shaw GD, Spence JS, Sullivan PF, Sun W, Tarantino LM, Valdar W, Wang J, Wang W, Welsh CE, Whitmore A, Wiltshire T, Wright F, Xie Y, Yu Zn, Zhabotynsky V, Zhang Z, Zou F, Powell C, Steigerwalt J, Threadgill DW, Chesler EJ, Churchill GA, Gatti DM, Svenson KL, Yang H, Shusterman A, Nashef A, Weiss EI, Houri-Haddad Y, Soller M, Schughart K, French JE, Collins FS, Crawford N, Hunter K, Kelada SNP, Peck BCE, Reilly K, Tavarez U, Bottomly D, Hitzeman R, McWeeney SK, Frelinger J, Phillippi J, Spritz RA, Benson AK, Kim J, Legge R, Low SJ, Ma F, Martinez I, Walter J, Williams RW, Aicher L, Katze M, Rosenzweig E, Broman KW (2012) The genome architecture of the Collaborative Cross mouse genetic reference population. Genetics 190(2):389–402

    Article  CAS  Google Scholar 

  • Cormier RT, Dove WF (2000) Dnmt1 N/1 reduces the net growth rate and multiplicity of intestinal adenomas in C57BL/6-Multiple intestinal neoplasia (Min)/1 mice independently of p53 but demonstrates strong synergy with the Modifier of Min 1AKR resistance allele. Cancer Res 60:3965–3970

    CAS  PubMed  Google Scholar 

  • Cormier RT, Bilger AJ, Lillich RB, Halberg KH (2000) The Mom1AKR intestinal tumor resistance region consists of Pla2g2a and a locus distal to D4Mit64. Oncogene 19:3182–3192

    Article  CAS  PubMed  Google Scholar 

  • Durrant C, Tayem H, Yalcin B, Cleak J, Goodstadt L, de Pardo-Manuel Villena F, Mott R, Iraqi FA (2011) Collaborative Cross mice and their power to map host susceptibility to Aspergillus fumigatus infection. Genome Res 21:1239–1248

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Falconer, Mackay, Falconer DS, Mackay FC (1996) Introduction to quantitative genetics. Longman, Essex

    Google Scholar 

  • Fearnhead NS, Britton MP, Bodmer WF (2001) The ABC of APC. Hum Mol Genet 10:721–733

    Article  CAS  PubMed  Google Scholar 

  • Fostira F, Thodi G, Sandaltzopoulos R, Fountzilas G, Yannoukakos D (2010) Mutational spectrum of APC and genotype-phenotype correlations in Greek FAP patients. BMC Cancer 10:389–396

    Article  PubMed Central  PubMed  Google Scholar 

  • Garcia-Gonzalez F, Simmons LW, Tomkins JL, Kotiaho JS, Evans JP (2012) Comparing evolvabilities: common errors surrounding the use and calculation of coefficients of additive genetic variation. Evolution 66:2341–2349

    Article  PubMed  Google Scholar 

  • Groden J, Thliveris A, Samowitz W, Carlson M, Gelbert L, Albertsen H, Joslyn G, Stevens J, Spirio L, Robertson M (1991) Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66:589–600

    Article  CAS  PubMed  Google Scholar 

  • Hernandez-Valladares M, Naessens J, Gibson JP, Musoke AJ, Rihet P, ole-MoiYoi OK, Iraqi FA (2004a) Confirmation and dissection of QTL controlling resistance to malaria in mice. Mamm Genome 15:390–398

    Article  PubMed  Google Scholar 

  • Hernandez-Valladares M, Rihet P, ole-MoiYoi OK, Iraqi FA (2004b) Mapping of a new quantitative trait locus for resistance to malaria in mice by a comparative approach of human chromosome 5q31-q33. Immunogenet 56:115–117

    Article  CAS  Google Scholar 

  • Houle D (1992) Evolvability and variability of quantitative traits. Genetics 130:195–204

    CAS  PubMed Central  PubMed  Google Scholar 

  • Iraqi F, Clapcot S, Kuman P, Heley C, Kemp S, Teale A (2000) Fine mapping of trypanosomiasis resistance QTLs in mice using advanced intercross lines. Mamm Genome 11:645–648

    Article  CAS  PubMed  Google Scholar 

  • Iraqi FA, Behnke JM, Menge DM, Lowe AM, Teale AJ, Gibson JP, Baker LR, Wakelin DR (2003) Mapping chromosomal regions controlling resistance to gastro-intestinal worms in mice. Mamm Genome 14:184–191

    Article  CAS  PubMed  Google Scholar 

  • Iraqi F, Churchill G, Mott R (2008) The Collaborative Cross, developing a resource for mammalian systems genetics: a status report of the Wellcome Trust cohort. Mamm Genome 19:379–381

    Article  PubMed  Google Scholar 

  • Keane TM, Goodstadt L, Danecek P, White MA, Wong K, Yalcin B, Heger A, Agam A, Slater G et al (2011) Mouse genomic variation and its effect on phenotypes and gene regulation. Nature 14 477(7364):289–294

    Article  CAS  Google Scholar 

  • Kelada SNP, Aylor DL et al (2012) Genetic analysis of hematological parameters in incipient lines of the Collaborative Cross G3(2):157–166

    Google Scholar 

  • Keynan Y, Rubinstein E (2007) The changing face of Klebsiella pneumoniae infection in the community. Int J Antimicrob Agent 30:385–389

    Article  CAS  Google Scholar 

  • Kovacs A, Ben-Jacob N, Tayem H, Halperin E, Iraqi FA, Gophna U (2011) Genotype is a stronger determinant than sex of the mammalian gut microbiota. Microb Ecol 61(2):423–428

    Article  PubMed  Google Scholar 

  • Mathes WF, Aylor DL, Miller DR, Churchill GA, Chesler EJ, de Villena F, Threadgill DW, Pomp D (2011) Architecture of energy balance traits in emerging lines of the Collaborative Cross. Am J Physiol Endocrinol Metab 300:E1124–E1134

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Morahan G, Balmer L, Monley D (2008) Establishment of “The Gene Mine”: a resource for rapid identification of complex trait genes. Mamm Genome 19(6):390–393

    Article  PubMed  Google Scholar 

  • Moser AR, Dove WF, Roth KA, Gordon JI (1992) The Min (multiple intestinal neoplasia) mutation: its effect on gut epithelial cell differentiation and interaction with a modifier system. J Cell Biol 716:1517–1526

    Article  Google Scholar 

  • Moser AR, Mattes EM, Dove WF, Lindstrom MJ, Haag JD, Gould MN (1993) Min, a mutation in the murine Apc gene, predisposes to mammary carcinomas and focal alveolar hyperplasias. PNAS 90:8977–8981

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mott R, Talbot CJ, Turri MG, Collins AC, Flint J (2000) A method for fine mapping quantitative trait loci in outbred animal stocks. PNAS 97:12649–12654

    Article  PubMed Central  PubMed  Google Scholar 

  • Ng SB, Buckingham KJ, Lee C, Bigham AW, Tabor HK, Dent KM, Huff CD, Shannon PT, Jabs EW, Nickerson DA, Shendure J, Bamshad MJ (2010) Exome sequencing identifies the cause of a mendelian disorder. Nat Genet 42(1):30–35

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Petkova SB, Yuan R, Tsaih SW, Schott W, Roopenian DC, Paigen B (2008) Genetic influence on immune phenotype revealed strain-specific variations in peripheral blood lineages. Physiol Genomics 34:304–314

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Philip VM, Sokoloff G, Ackert-Bicknell CL et al (2011) Genetic analysis in the Collaborative Cross breeding population. Genome Res 2011:1223–1238

    Article  Google Scholar 

  • Polak D, Wilensky A, Shapira L, Halabi A, Goldstein D, Weiss EI et al (2009) Mouse model of experimental periodontitis induced by Porphyromonas gingivalis/Fusobacterium nucleatum infection: bone loss and host response. J Clin Periodontol 36(5):406–410

    Article  PubMed  Google Scholar 

  • Roberts A, de Pardo-Manuel Villena F, Wang W, McMillan L, Threadgill DW (2007) The polymorphism architecture of mouse genetic resources elucidated using genome-wide resequencing data: implications for QTL discovery and systems genetics. Mamm Genome 18(6–7):473–481

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Shusterman A, Durrant C, Mott R, Schaefer A, Weiss EI, Iraqi FA, Houri-Haddad Y (2013a) Host susceptibility to periodontitis: mapping murine genomic regions. J Dent Res 92:438–443

    Article  CAS  PubMed  Google Scholar 

  • Shusterman A, Salyma Y, Nashef A, Soller M, Wilensky A, Mott R, Weiss EI, Houri-Haddad Y, Iraqi FA (2013b) Genotype is an important determinant factor of host susceptibility to periodontitis in the Collaborative Cross and inbred mouse populations. BMC Genet 14:68–79

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Silver LM (1995) Mouse genetics: concepts and applications. Oxford University Press, Oxford

    Google Scholar 

  • Threadgill DW, Hunt KW, Williams RW (2002) Genetic dissection of complex and quantitative traits: from fantasy to reality via a community effort. Mamm Genome 16:344–355

    Google Scholar 

  • Valdar W, Flint J, Mott R (2006) Simulating the collaborative cross: power of QTL detection and mapping resolution in large sets of recombinant inbred strains of mice. Genetics 172:1783–1797

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Voelkerding KV et al (2009) Next-generation sequencing: from basic research to diagnostics. Clin Chem 55:641–658

    Article  CAS  PubMed  Google Scholar 

  • Welsh CE, Miller RD, Manly KF, Wang J, McMillan L, Morahan G, Mott R, Iraqi FA, Threadgill DW, Pardo-Manuel de Villena F (2012) Status and access to the Collaborative Cross population. Mamm Genome 23:706–712

    Article  PubMed Central  PubMed  Google Scholar 

  • Wilensky A, Gabet Y, Yumoto H, Houri Haddad Y, Shapira L (2005) Three-dimensional quantification of alveolar bone loss in Porphyromonas gingivalis infected mice using Micro-CT. J Periodontol 76(8):1282–1286

    Article  PubMed  Google Scholar 

  • Yalcin B, Flint J, Mott R (2005) Using progenitor strain information to identify quantitative trait nucleotides in outbred mice. Genetics 171:673–681

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yang H, Ding Y, Hutchins LN, Szatkiewicz J, Bell TA, Paigen BJ, Graber JH, de Villena FP, Churchill GA (2009) A customized and versatile high-density genotyping array for the mouse. Nat Methods 6(9):663–666

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Wellcome Trust grants 085906/Z/08/Z, 083573/Z/07/Z, and 075491/Z/04, Israeli Science Foundation grant (ISF)/429/09, Hendrech and Eiran Gotwert Fund for studying diabetes, and Merian and George Saiah Fund for studying infectious diseases. We thank Tel-Aviv University for their core funding and technical support and the Israeli Counsel for Higher Education for financial supporting Prof. Iraqiıs lab.

Author information

Authors and Affiliations

  1. Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, 69978, Tel Aviv, Israel

    Fuad A. Iraqi, Hanifa Athamni, Alexandra Dorman & Yasser Salymah

  2. Welcome Trust human Genome center, University of Oxford, Oxford, UK

    Ian Tomlinson & Richard Mott

  3. Department of Prosthodontics, Dental School at Hadassah, Hebrew University, Jerusalem, Israel

    Aysar Nashif, Ariel Shusterman, Ervin Weiss & Yael Houri-Haddad

  4. Department of Genetics, Silberman Institute of Life Sciences, Hebrew University, Edmund Safra Campus, Givat Ram, Jerusalem, Israel

    Morris Soller

Authors
  1. Fuad A. Iraqi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hanifa Athamni
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alexandra Dorman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yasser Salymah
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ian Tomlinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Aysar Nashif
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ariel Shusterman
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ervin Weiss
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yael Houri-Haddad
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Richard Mott
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Morris Soller
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fuad A. Iraqi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Iraqi, F.A., Athamni, H., Dorman, A. et al. Heritability and coefficient of genetic variation analyses of phenotypic traits provide strong basis for high-resolution QTL mapping in the Collaborative Cross mouse genetic reference population. Mamm Genome 25, 109–119 (2014). https://doi.org/10.1007/s00335-014-9503-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00335-014-9503-5

Keywords

Search

Navigation