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Genetic analysis of genome-wide variation in human gene expression

Abstract

Natural variation in gene expression is extensive in humans and other organisms, and variation in the baseline expression level of many genes has a heritable component. To localize the genetic determinants of these quantitative traits (expression phenotypes) in humans, we used microarrays to measure gene expression levels and performed genome-wide linkage analysis for expression levels of 3,554 genes in 14 large families. For approximately 1,000 expression phenotypes, there was significant evidence of linkage to specific chromosomal regions. Both cis- and trans-acting loci regulate variation in the expression levels of genes, although most act in trans. Many gene expression phenotypes are influenced by several genetic determinants. Furthermore, we found hotspots of transcriptional regulation where significant evidence of linkage for several expression phenotypes (up to 31) coincides, and expression levels of many genes that share the same regulatory region are significantly correlated. The combination of microarray techniques for phenotyping and linkage analysis for quantitative traits allows the genetic mapping of determinants that contribute to variation in human gene expression.

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Figure 1: Genome scans for ten expression phenotypes.
Figure 2: Master transcriptional regulators.
Figure 3: Regression of expression phenotype of LOC64167 and HSD17B12 on nearby SNPs.

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References

  1. Oleksiak, M. F., Churchill, G. A. & Crawford, D. L. Variation in gene expression within and among natural populations. Nature Genet. 32, 261–266 (2002)

    Article  CAS  Google Scholar 

  2. Brem, R. B., Yvert, G., Clinton, R. & Kruglyak, L. Genetic dissection of transcriptional regulation in budding yeast. Science 296, 752–755 (2002)

    Article  ADS  CAS  Google Scholar 

  3. Yvert, G. et al. Trans-acting regulatory variation in Saccharomyces cerevisiae and the role of transcription factors. Nature Genet. 3, 57–64 (2003)

    Article  Google Scholar 

  4. Yan, H., Yuan, W., Velculescu, V. E., Vogelstein, B. & Kinzler, K. W. Allelic variation in human gene expression. Science 297, 1143 (2002)

    Article  ADS  CAS  Google Scholar 

  5. Schadt, E. E. et al. Genetics of gene expression surveyed in maize, mouse and man. Nature 422, 297–302 (2003)

    Article  ADS  CAS  Google Scholar 

  6. Cheung, V. G. et al. Natural variation in human gene expression assessed in lymphoblastoid cells. Nature Genet. 33, 422–425 (2003)

    Article  CAS  Google Scholar 

  7. Cheung, V. G. & Spielman, R. S. The genetics of variation in gene expression. Nature Genet. 32, 522–525 (2002)

    Article  CAS  Google Scholar 

  8. Cheung, V. G. et al. Genetics of quantitative variation in human gene expression. Cold Spring Harb. Symp. Quant. Biol. 68, 403–407 (2003)

    Article  CAS  Google Scholar 

  9. Dausset, J. et al. Centre d'etude du polymorphisme humain (CEPH): collaborative genetic mapping of the human genome. Genomics 6, 575–577 (1990)

    Article  CAS  Google Scholar 

  10. Matise, T. C. et al. A 3.9-centimorgan-resolution human single-nucleotide polymorphism linkage map and screening set. Am. J. Hum. Genet. 73, 271–284 (2003)

    Article  CAS  Google Scholar 

  11. S.A.G.E. Statistical Analysis for Genetic Epidemiology. (Statistical Solutions Ltd, Cork, Ireland, 2003)

  12. Haseman, J. K. & Elston, R. C. The investigation of linkage between a quantitative trait and a marker locus. Behav. Genet. 2, 3–19 (1972)

    Article  CAS  Google Scholar 

  13. Lander, E. & Kruglyak, L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nature Genet. 11, 241–247 (1995)

    Article  CAS  Google Scholar 

  14. Nobrega, M., Ovcharenko, I., Afzal, V. & Rubin, E. Scanning human gene deserts for long-range enhancers. Science 302, 413 (2003)

    Article  CAS  Google Scholar 

  15. Lettice, L. A. et al. Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly. Proc. Natl Acad. Sci. USA 99, 7548–7553 (2002)

    Article  ADS  CAS  Google Scholar 

  16. Cohen, B. A., Mitra, R. D., Hughes, J. D. & Church, G. M. A computational analysis of whole-genome expression data reveals chromosomal domains of gene expression. Nature Genet. 26, 183–186 (2000)

    Article  CAS  Google Scholar 

  17. Caron, H. et al. The human transcriptome map: clustering of highly expressed genes in chromosomal domains. Science 291, 1289–1292 (2001)

    Article  ADS  CAS  Google Scholar 

  18. Spellman, P. T. & Rubin, G. M. Evidence for large domains of similarly expressed genes in the Drosophila genome. J. Biol. 1, 5 (2002)

    Article  Google Scholar 

  19. Abecasis, G. R., Cardon, L. R. & Cookson, W. O. A general test of association for quantitative traits in nuclear families. Am. J. Hum. Genet. 66, 279–292 (2000)

    Article  CAS  Google Scholar 

  20. McKenzie, C. A. et al. Trans-ethnic fine mapping of a quantitative trait locus for circulating angiotensin I-converting enzyme (ACE). Hum. Mol. Genet. 10, 1077–1084 (2001)

    Article  CAS  Google Scholar 

  21. Abecasis, G. R., Cherny, S. S., Cookson, W. O. & Cardon, L. R. Merlin-rapid analysis of dense genetic maps using sparse gene flow trees. Nature Genet. 30, 97–101 (2002)

    Article  CAS  Google Scholar 

  22. Shete, S., Jacobs, K. B. & Elston, R. C. Adding further power to the Haseman and Elston method for detecting linkage in larger sibships: weighting sums and differences. Hum. Hered. 55, 79–85 (2003)

    Article  Google Scholar 

Download references

Acknowledgements

We thank T. Matise and W. Ewens for discussions and advice, and J. Burdick for technical help. Some analyses for this paper were carried out by using the program package S.A.G.E., which is supported by a grant from the National Center for Research Resources. This work is supported by grants from the National Institutes of Health (to R.S.S. and V.G.C.) and the W.W. Smith Endowed Chair (to V.G.C.).

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Correspondence to Richard S. Spielman or Vivian G. Cheung.

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Morley, M., Molony, C., Weber, T. et al. Genetic analysis of genome-wide variation in human gene expression. Nature 430, 743–747 (2004). https://doi.org/10.1038/nature02797

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