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Functional genetic analysis of mouse chromosome 11

Abstract

Now that the mouse and human genome sequences are complete, biologists need systematic approaches to determine the function of each gene1,2. A powerful way to discover gene function is to determine the consequence of mutations in living organisms. Large-scale production of mouse mutations with the point mutagen N-ethyl-N-nitrosourea (ENU) is a key strategy for analysing the human genome because mouse mutants will reveal functions unique to mammals, and many may model human diseases3. To examine genes conserved between human and mouse, we performed a recessive ENU mutagenesis screen that uses a balancer chromosome, inversion chromosome 11 (refs 4, 5). Initially identified in the fruitfly, balancer chromosomes are valuable genetic tools that allow the easy isolation of mutations on selected chromosomes6. Here we show the isolation of 230 new recessive mouse mutations, 88 of which are on chromosome 11. This genetic strategy efficiently generates and maps mutations on a single chromosome, even as mutations throughout the genome are discovered. The mutations reveal new defects in haematopoiesis, craniofacial and cardiovascular development, and fertility.

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Figure 1: A balancer chromosome screen for the conserved region of mouse chromosome 11/human chromosome 17.
Figure 2: Lethal mutants affect gastrulation and cardiovascular development.
Figure 3: A new Slc4a1 missense mutation.

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References

  1. Mouse Genome Sequencing Consortium. Initial sequencing and comparative analysis of the mouse genome. Nature 420, 520–562 (2002)

    Article  Google Scholar 

  2. International Human Genome Sequencing Consortium. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001)

    Article  Google Scholar 

  3. Justice, M. J. in Genetics and Transgenics: A Practical Approach (eds Jackson, I. & Abbott, C.) 185–215 (Oxford Univ. Press, Oxford, 1999)

    Google Scholar 

  4. Zheng, B. et al. Engineering a balancer chromosome in the mouse. Nature Genet. 22, 375–378 (1999)

    Article  CAS  Google Scholar 

  5. Zheng, B., Mills, A. A. & Bradley, A. A system for rapid generation of coat color-tagged knockouts and defined chromosomal rearrangements in mice. Nucleic Acids Res. 27, 2354–2360 (1999)

    Article  CAS  Google Scholar 

  6. Muller, H. J. Genetic variability, twin hybrids, and constant hybrids, in a case of balanced lethal factors. Genetics 3, 422–499 (1918)

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Kasarskis, A., Manova, K. & Anderson, K. V. A phenotype-based screen for embryonic lethal mutations in the mouse. Proc. Natl Acad. Sci. USA 95, 7485–7490 (1998)

    Article  ADS  CAS  Google Scholar 

  8. Hentges, K., Thompson, K. & Peterson, A. The flat-top gene is required for the expansion and regionalization of the telencephalic primordium. Development 126, 1601–1609 (1999)

    CAS  PubMed  Google Scholar 

  9. Herron, B. J. et al. Efficient generation and mapping of recessive developmental mutations using ENU mutagenesis. Nature Genet. 30, 185–189 (2002)

    Article  CAS  Google Scholar 

  10. Kamath, R. S. et al. Systematic functional analysis of the Caenorhabditis elegans genome using RNAi. Nature 421, 231–237 (2003)

    Article  ADS  CAS  Google Scholar 

  11. Miklos, G. L. & Rubin, G. M. The role of the genome project in determining gene function: insights from model organisms. Cell 86, 521–529 (1996)

    Article  CAS  Google Scholar 

  12. Shedlovsky, A., King, T. R. & Dove, W. F. Saturation germ line mutagenesis of the murine t region including a lethal allele at the quaking locus. Proc. Natl Acad. Sci. USA 85, 180–184 (1988)

    Article  ADS  CAS  Google Scholar 

  13. Rinchik, E. M. & Carpenter, D. A. N-ethyl-N-nitrosourea mutagenesis of a 6- to 11-cM subregion of the Fah-Hbb interval of mouse chromosome 7: completed testing of 4,557 gametes and deletion mapping and complementation analysis of 31 mutations. Genetics 152, 373–383 (1999)

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Conway, S. J., Kruzynska-Frejtag, A., Kneer, P. L., Machnicki, M. & Koushik, S. V. What cardiovascular defect does my prenatal mouse mutant have, and why? Genesis 35, 1–21 (2003)

    Article  Google Scholar 

  15. Nusslein-Volhard, C., Frohnhofer, H. G. & Lehmann, R. Determination of anteroposterior polarity in Drosophila. Science 238, 1675–1681 (1987)

    Article  ADS  CAS  Google Scholar 

  16. Barrow, J. R. & Capecchi, M. R. Targeted disruption of the Hoxb-2 locus in mice interferes with expression of Hoxb-1 and Hoxb-4. Development 122, 3817–3828 (1996)

    CAS  PubMed  Google Scholar 

  17. Hitotsumachi, S., Carpenter, D. A. & Russell, W. L. Dose-repetition increases the mutagenic effectiveness of N-ethyl-N-nitrosourea in mouse spermatogonia. Proc. Natl Acad. Sci. USA 82, 6619–6621 (1985)

    Article  ADS  CAS  Google Scholar 

  18. Shawlot, W. & Behringer, R. R. Requirement for Lim1 in head-organizer function. Nature 374, 425–430 (1995)

    Article  ADS  CAS  Google Scholar 

  19. Probst, F. J. et al. Correction of deafness in shaker-2 mice by an unconventional myosin in a BAC transgene. Science 280, 1444–1447 (1998)

    Article  ADS  CAS  Google Scholar 

  20. Nehls, M., Pfeifer, D., Schorpp, M., Hedrich, H. & Boehm, T. New member of the winged-helix protein family disrupted in mouse and rat nude mutations. Nature 372, 103–107 (1994)

    Article  ADS  CAS  Google Scholar 

  21. Nusslein-Volhard, C., Wieschaus, E. & Kluding, H. Mutations affecting the pattern of the larval cuticle in Drosophila melanogaster I. Zygotic loci on the second chromosome. Rouxs Arch. Dev. Biol. 193, 267–282 (1984)

    Article  CAS  Google Scholar 

  22. Peters, L. L. et al. Anion exchanger 1 (band 3) is required to prevent erythrocyte membrane surface loss but not to form the membrane skeleton. Cell 86, 917–927 (1996)

    Article  CAS  Google Scholar 

  23. Southgate, C. D., Chishti, A. H., Mitchell, B., Yi, S. J. & Palek, J. Targeted disruption of the murine erthyroid band 3 gene results in spherocytosis and severe haemolytic anaemia despite a normal membrane skeleton. Nature Genet. 14, 227–230 (1996)

    Article  CAS  Google Scholar 

  24. Jarolim, P. et al. Mutations of conserved arginines in the membrane domain of erythroid band 3 lead to a decrease in membrane-associated band 3 and to the phenotype of hereditary spherocytosis. Blood 85, 634–640 (1995)

    CAS  PubMed  Google Scholar 

  25. Karet, F. E. et al. Mutations in the chloride-bicarbonate exchanger gene AE1 cause autosomal dominant but not autosomal recessive distal renal tubular acidosis. Proc. Natl Acad. Sci. USA 95, 6337–6342 (1998)

    Article  ADS  CAS  Google Scholar 

  26. Bruce, L. J. et al. Familial distal renal tubular acidosis is associated with mutations in the red cell anion exchanger (band 3, AE1) gene. J. Clin. Invest. 100, 1693–1707 (1997)

    Article  CAS  Google Scholar 

  27. The FANTOM Consortium and the RIKEN Genome Exploration Research Group Phase I & II Team. Analysis of the mouse transcriptome based on functional annotation of 60,770 full-length cDNAs. Nature 420, 563–573 (2002)

    Article  Google Scholar 

  28. Behringer, R. R. (ed.) Mouse knockout and mutation database. BioMedNet 〈http://research.bmn.com/mkmd〉 (2003)

  29. Kile, B. T., Mason-Garrison, C. & Justice, M. J. Sex and strain-related differences in the peripheral blood cell values of inbred mouse strains. Mamm. Genome 14, 81–85 (2003)

    Article  Google Scholar 

  30. Noveroske, J. N. et al. Quaking is essential for blood vessel development. Genesis 32, 218–230 (2002)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank C. Viator, C. Dinh, S. Moncrief, A. Zalud, J. Maffucci, C. Mason-Garrison, K. Firozi, M. Alviento, C. Hubbard, B. Hasson and M. Scantlin for technical assistance, and J. Zhong and M. Patterson for database support. We also thank L. Peters for the gift of Slc4a1 knockout mice. Y. Furuta, H. Bellen, S. Lovell, S. Watowich and H. Gilbert are thanked for critical reading of this manuscript. This work was supported by NIH grants to M.J.J. and A.B. K.E.H. was supported by an NIH-NRSA grant. B.T.K. is a Fellow of the Leukemia Research Foundation.

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Correspondence to Monica J. Justice.

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The authors declare that they have no competing financial interests.

Supplementary information

41586_2003_BFnature01865_MOESM1_ESM.xls

Supplementary Table 1: A complete list of mutations isolated throughout the genome, a short phenotype description, and map location if known. (XLS 27 kb)

Supplementary Table 2: Breeding and embryo dissection data for all lethal mutations on chromosome 11 (XLS 16 kb)

Supplementary Table 3: Breeding and penetrance data on all viable mutations on chromosome 11 (XLS 10 kb)

Supplementary Table 4: Complementation testing ofl11Jus1 – 47, summarizing data from 2,760 crosses. (XLS 25 kb)

Supplementary Table 5: Complementation testing of postnatal l11Jus51-55 and l11Jus57. (XLS 9 kb)

Supplementary Figure 1: Abnormalities in some of the late postnatal lethals. (PPT 270 kb)

41586_2003_BFnature01865_MOESM7_ESM.ppt

Supplementary Figure 2: Additional photos of l11Jus3, l11Jus27, and three mutations classified as having neural tube defects: l11Jus8, l11Jus15, and l11Jus39. (PPT 5756 kb)

Supplementary Figure 3: Testis histology of some of the infertile mutations (JPG 37 kb)

Supplementary Movie: Neurological dystonia in l11Jus57. (MOV 326 kb)

Supplementary Information: Phenotyping (DOC 31 kb)

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Kile, B., Hentges, K., Clark, A. et al. Functional genetic analysis of mouse chromosome 11. Nature 425, 81–86 (2003). https://doi.org/10.1038/nature01865

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