Detection of regulatory variation in mouse genes (original) (raw)

Nature Genetics volume 32, pages 432–437 (2002)Cite this article

Abstract

Functional polymorphism in genes can be classified as coding variation, altering the amino-acid sequence of the encoded protein, or regulatory variation, affecting the level or pattern of expression of the gene. Coding variation can be recognized directly from DNA sequence, and consequently its frequency and characteristics have been extensively described. By contrast, virtually nothing is known about the extent to which gene regulation varies in populations. Yet it is likely that regulatory variants are important in modulating gene function: alterations in gene regulation have been proposed to influence disease susceptibility and to have been the primary substrate for the evolution of species1. Here, we report a systematic study to assess the extent of _cis_-acting regulatory variation in 69 genes across four inbred mouse strains. We find that at least four of these genes show allelic differences in expression level of 1.5-fold or greater, and that some of these differences are tissue specific. The results show that the impact of regulatory variants can be detected at a significant frequency in a genomic survey and suggest that such variation may have important consequences for organismal phenotype and evolution. The results indicate that larger-scale surveys in both mouse and human could identify a substantial number of genes with common regulatory variation.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 12 print issues and online access

$209.00 per year

only $17.42 per issue

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. King, M.C. & Wilson, A.C. Evolution at two levels in humans and chimpanzees. Science 188, 107–116 (1975).
    CAS Google Scholar
  2. Cargill, M. et al. Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nat. Genet. 22, 231–238 (1999).
    Article CAS Google Scholar
  3. Cambien, F. et al. Sequence diversity in 36 candidate genes for cardiovascular disorders. Am. J. Hum. Genet. 65, 183–191 (1999).
    Article CAS Google Scholar
  4. Li, W.H. & Sadler, L.A. Low nucleotide diversity in man. Genetics 129, 513–523 (1991).
    CAS PubMed PubMed Central Google Scholar
  5. Halushka, M.K. et al. Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis. Nat. Genet. 22, 239–247 (1999).
    Article CAS Google Scholar
  6. Singer-Sam, J. Quantitation of specific transcripts by RT–PCR SNuPE assay. PCR Methods Appl. 3, S48–S50 (1994).
    Article CAS Google Scholar
  7. Szabo, P.E. & Mann, J.R. Allele-specific expression and total expression levels of imprinted genes during early mouse development: implications for imprinting mechanisms. Genes Dev. 9, 3097–3108 (1995).
    Article CAS Google Scholar
  8. Lindblad-Toh, K. et al. Large-scale discovery and genotyping of single-nucleotide polymorphisms in the mouse. Nat. Genet. 24, 381–386 (2000).
    Article CAS Google Scholar
  9. Syvanen, A.C., Aalto-Setala, K., Harju, L., Kontula, K. & Soderlund, H. A primer-guided nucleotide incorporation assay in the genotyping of apolipoprotein E. Genomics 8, 684–692 (1990).
    Article CAS Google Scholar
  10. Kobayashi, M. et al. Fluorescence-based DNA minisequence analysis for detection of known single-base changes in genomic DNA. Mol. Cell. Probes 9, 175–182 (1995).
    Article CAS Google Scholar
  11. Pastinen, T., Kurg, A., Metspalu, A., Peltonen, L. & Syvanen, A.C. Minisequencing: a specific tool for DNA analysis and diagnostics on oligonucleotide arrays. Genome Res. 7, 606–614 (1997).
    Article CAS Google Scholar
  12. Chen, X., Zehnbauer, B., Gnirke, A. & Kwok, P.Y. Fluorescence energy transfer detection as a homogeneous DNA diagnostic method. Proc. Natl Acad. Sci. USA 94, 10756–10761 (1997).
    Article CAS Google Scholar
  13. Landegren, U., Nilsson, M. & Kwok, P.Y. Reading bits of genetic information: methods for single-nucleotide polymorphism analysis. Genome Res. 8, 769–776 (1998).
    Article CAS Google Scholar
  14. Kennedy, B.P. et al. A natural disruption of the secretory group II phospholipase A2 gene in inbred mouse strains. J. Biol. Chem. 270, 22378–22385 (1995).
    Article CAS Google Scholar
  15. Lander, E.S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).
    Article CAS Google Scholar
  16. Bosma, P.J. et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. N. Engl. J. Med. 333, 1171–1175 (1995).
    Article CAS Google Scholar
  17. Monaghan, G., Ryan, M., Seddon, R., Hume, R. & Burchell, B. Genetic variation in bilirubin UPD-glucuronosyltransferase gene promoter and Gilbert's syndrome. Lancet 347, 578–581 (1996).
    Article CAS Google Scholar
  18. Grosveld, F., van Assendelft, G.B., Greaves, D.R. & Kollias, G. Position-independent, high-level expression of the human β-globin gene in transgenic mice. Cell 51, 975–985 (1987).
    Article CAS Google Scholar
  19. Dillon, N., Trimborn, T., Strouboulis, J., Fraser, P. & Grosveld, F. The effect of distance on long-range chromatin interactions. Mol. Cell 1, 131–139 (1997).
    Article CAS Google Scholar
  20. Li, Q., Harju, S. & Peterson, K.R. Locus control regions: coming of age at a decade plus. Trends Genet. 15, 403–408 (1999).
    Article Google Scholar
  21. Rave-Harel, N. et al. The molecular basis of partial penetrance of splicing mutations in cystic fibrosis. Am. J. Hum. Genet. 60, 87–94 (1997).
    CAS PubMed PubMed Central Google Scholar
  22. Quandt, K., Frech, K., Karas, H., Wingender, E. & Werner, T. MatInd and MatInspector: new fast and versatile tools for detection of consensus matches in nucleotide sequence data. Nucleic Acids Res. 23, 4878–4884 (1995).
    Article CAS Google Scholar
  23. Grabe, N. AliBaba2: context specific identification of transcription factor binding sites. In Silico Biol. 2, S1–S15 (2002).
    PubMed Google Scholar

Download references

Acknowledgements

We thank J. Platko, A. Rachupka, R. Prill and D. Richter for cDNA sequencing; E. Winchester and K. Lindblad-Toh for assistance in identification of appropriate SNPs to assay; Y.M. Lim and P. Sklar for help with initial SBE assays; M. Daly for gel analysis software and discussions; J. Rioux and E.J. Kulbokas for aiding genomic DNA sequencing; and D. Reich, G. Acton, K. Hong, A. Gimelbrant and A. Chess for discussions. This work was supported in part by a fellowship of the Damon Runyon Cancer Research Foundation (to C.R.C.) and by grants from the US National Institutes of Health (to E.S.L.). J.N.H. is a recipient of a Howard Hughes Medical Institute Postdoctoral Fellowship for Physicians.

Author information

Authors and Affiliations

  1. Whitehead Institute and MIT Center for Genome Research, Nine Cambridge Center, Cambridge, 02142, Massachusetts, USA
    Christopher R. Cowles, Joel N. Hirschhorn, David Altshuler & Eric S. Lander
  2. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA
    Joel N. Hirschhorn & David Altshuler
  3. Divisions of Genetics and Endocrinology, Children's Hospital, Boston, Massachusetts, USA
    Joel N. Hirschhorn
  4. Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts, USA
    David Altshuler
  5. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
    Eric S. Lander

Authors

  1. Christopher R. Cowles
    You can also search for this author inPubMed Google Scholar
  2. Joel N. Hirschhorn
    You can also search for this author inPubMed Google Scholar
  3. David Altshuler
    You can also search for this author inPubMed Google Scholar
  4. Eric S. Lander
    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence toEric S. Lander.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

About this article

Cite this article

Cowles, C., Hirschhorn, J., Altshuler, D. et al. Detection of regulatory variation in mouse genes.Nat Genet 32, 432–437 (2002). https://doi.org/10.1038/ng992

Download citation

This article is cited by