Abstract
A chromosome substitution strain (CSS) is an inbred strain in which one chromosome has been substituted from a different inbred strain by repeated backcrossing. A complete CSS set has one strain representing each chromosome against a uniform background, thus allowing genome-wide scans to be carried out for quantitative trait loci (QTLs) influencing any trait of interest. A one-way ANOVA by strain is first carried out, followed by planned comparisons using Dunnett’s method. A QTL is detected and mapped to a chromosome when a significant difference is observed in a background strain vs CSS comparison. The most efficient ratio of background to CSS mice in any one comparison is 4.5:1, and the threshold for p < .05 genome-wide significance is estimated to be p = .003 to .004, a much less stringent criterion than any other mammalian mapping population. The use of false discovery rates tends to further reduce threshold stringency. Comparisons are made to the widely used conventional F2 intercross, and both advantages and disadvantages are noted. The proportion of the trait variance due to a QTL is often much larger than the same QTL in an F2, and the number of generations to attain fine mapping is greatly reduced. To serve as guidelines for planning experiments, methods to estimate sample sizes for QTL detection are presented for the initial genome scan and for subsequent fine mapping.
Similar content being viewed by others
References
DW Bailey (1981) Recombinant inbred strains and bilineal congenic trains. HL Foster JD Small JG Fox (Eds) The mouse in Biomedical Research. Vol I., Academic Press New York 223–239
RE Bechhofer AC Tamhane (1983) ArticleTitleDesign of experiments for comparing treatments with a control: tables of optimal allocation of observations. Technometrics 25 87–95
JK Belknap (1998) ArticleTitleEffect of within-strain sample size on QTL detection and mapping using recombinant inbred mouse strains. Behav Genet 28 29–37 Occurrence Handle1:STN:280:DyaK1c3jsVOhtQ%3D%3D Occurrence Handle9573644
JK Belknap AL Atkins (2001) ArticleTitleThe replicability of quantitative trait loci (QTLs) for murine alcohol preference drinking behavior across eight different studies. Mamm Genome 12 893–899 Occurrence Handle1:CAS:528:DC%2BD3MXosFGgtLc%3D Occurrence Handle11707775
Y Benjamini Y Hochberg (1995) ArticleTitleControlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat Soc B 57 289–300
B Bennett M Beeson L Gordon P Carosone-Link TE Johnson (2002) ArticleTitleGenetic dissection of quantitative trait loci specifying sedative/hypnotic sensitivity to ethanol: mapping with interval-specific congenic recombinant lines. Alcohol Clin Exp Res 26 1615–1624 Occurrence Handle1:CAS:528:DC%2BD38XoslSltbk%3D Occurrence Handle12436049
SE Bergeson ML Helms LA O’Toole MW Jarvis HS Hain et al. (2001) ArticleTitleQuantitative trait loci influencing morphine antinociception in four mapping populations. Mamm Genome 12 546–553 Occurrence Handle1:CAS:528:DC%2BD3MXks1ajs7o%3D Occurrence Handle11420618
JH Bruell (1971) Dominance and segregation in the inheritance of quantitative behavior in mice. M Manosevitz G Lindzey DD Thiessen (Eds) Behavioral Genetics: Method and Research Appleton-Century-Crofts New york 92–109
GT Cicila MR Garrett SJ Lee J Liu H Dene et al. (2001) ArticleTitleHigh-resolution mapping of the blood pressure QTL on Chromosome 7 using Dahl rat congenic strains. Genomics 72 51–60 Occurrence Handle10.1006/geno.2000.6442 Occurrence Handle1:CAS:528:DC%2BD3MXhslyjtL4%3D Occurrence Handle11247666
A Darvasi (1997) ArticleTitleInterval-specific congenic strains (ISCS): an experimental design for mapping a QTL into a 1-centimorgan interval. Mamm Genome 8 163–167
A Darvasi (1998) ArticleTitleExperimental strategies for the genetic dissection of complex traits in animal models. Nat Genet 18 19–24 Occurrence Handle1:CAS:528:DyaK1cXivFWgtQ%3D%3D Occurrence Handle9425894
A Darvasi M Soller (1992) ArticleTitleSelective genotyping for determination of linkage between a marker locus and a quantitative trait locus. Theor Appl Genet 85 353–359
A Darvasi M Soller (1997) ArticleTitleA simple method to calculate resolving power and confidence interval of QTL map location. Behav Genet 27 125–132 Occurrence Handle1:STN:280:ByiB1M%2Fpt1E%3D Occurrence Handle9145551
P Demant AM Hart (1986) ArticleTitleRecombinant congenic strains—a new tool for analyzing genetic traits determined by more than one gene. Immunogenetics 24 416–422 Occurrence Handle1:STN:280:BiiD1c3htFM%3D Occurrence Handle3793154
P Denny CJ Lord NJ Hill JV Goy ER Levy et al. (1997) ArticleTitleMapping of the IDDM locus idd3 to a 0.35 cM interval containing the II-2 gene. Diabetes 46 695–700
CW Dunnett (1955) ArticleTitleA multiple comparison procedure for comparing several treatments with a control. J Am Stat Assoc 50 1096–1121
C Fehr RL Shirley JK Belknap JC Crabbe KJ Buck (2002) ArticleTitleCongenic mapping of alcohol and pentobarbital withdrawal liability loci to < 1 centiMorgan interval of murine chromosome 4: identification of Mpdz as a candidate gene. J. Neuros 22 3730–3738 Occurrence Handle1:CAS:528:DC%2BD38Xjs1SlsrY%3D
A Fortin E Diez D Rochefort L Laroche D Malo GA Rouleau P Gros E Skamene (2001) ArticleTitleRecombinant congenic strains derived from A/J and C57BL/6J: a tool for genetic dissection of complex traits. Genomics 74 21–35 Occurrence Handle10.1006/geno.2001.6528 Occurrence Handle1:CAS:528:DC%2BD3MXjslKhtbc%3D Occurrence Handle11374899
Y Hochberg AC Tamhane (1987) Multiple Comparison Procedures. J. Wiley & Sons New york
MJ Kearsey HS Pooni (1996) The Genetical Analysis of Quantitative Traits Chapman and Hall London
ES Lander L Kruglyak (1995) ArticleTitleGenetic dissection of complex traits: Guidelines for interpreting and reporting linkage results. Nat Genet 11 241–247 Occurrence Handle1:CAS:528:DyaK2MXptlSjs74%3D Occurrence Handle7581446
H Lee JCM Dekkers M Soller M Malek RL Fernando MF Rothschild (2002) ArticleTitleApplication of the false discovery rate to quantitative trait loci interval mapping with multiple traits. Genetics 161 905–914 Occurrence Handle12072484
TFC Mackay (2001) ArticleTitleThe genetic architecture of quantitative traits. Ann a Rev Genet 225 303–339 Occurrence Handle10.1146/annurev.genet.35.102401.090633
RG Miller (1981) Simultaneous Statistical Inference. Springer Verlag New york
JH Nadeau JB Singer A Matin ES Lander (2000) ArticleTitleAnalyzing complex genetic traits with chromosome substitution strains. Nat Genet 24 221–225 Occurrence Handle10.1038/73427 Occurrence Handle1:CAS:528:DC%2BD3cXhvFaqtrs%3D Occurrence Handle10700173
WR Rice (1989) ArticleTitleAnalyzing tables of statistical tests. Evolution 43 223–225
R Rosenthal (1994) Parametric measures of effect size. H Cooper LV Hedges (Eds) The Handbook of Research Synthesis, Russell Sage New york 231–244
RR Sokal FJ Rohlf (1995) Biometry, Freeman San Francisco, CA 794–797
JD Storey (2002) ArticleTitleA direct approach to false discovery rates. J R Stat Soc B 64 479–498 Occurrence Handle10.1111/1467-9868.00346
CJ Talbot A Nicod SS Cherny DW Fulker AC Collins J Flint (1999) ArticleTitleHigh resolution mapping of quantitative trait loci in outbred mice. Nat Genet 21 305–308 Occurrence Handle10.1038/6825 Occurrence Handle1:CAS:528:DyaK1MXitVCitLc%3D Occurrence Handle10080185
E Wakeland L Morel K Achey M Yui J Longmate (1997) ArticleTitleSpeed congenics: a classic technique in the fast lane (relatively speaking). Immunol Today 18 472–477 Occurrence Handle10.1016/S0167-5699(97)01126-2 Occurrence Handle1:CAS:528:DyaK2sXmvFegu7g%3D Occurrence Handle9357138
RW Williams J Gu S Qi L Lu (2001) ArticleTitleThe genetic structure of recombinant inbred mice: high-resolution consensus maps for complex trait analysis. Genome Biol 2 Occurrence Handle11521680
Acknowledgements
This work was supported by grants AA10760, AA06243, DA10913, DA05228, Merit Review Program #350, and a Senior Career Scientist Award from the Department of Veterans Affairs.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Belknap, J.K. Chromosome substitution strains: some quantitative considerations for genome scans and fine mapping . Mamm Genome 14, 723–732 (2003). https://doi.org/10.1007/s00335-003-2264-1
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/s00335-003-2264-1