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Human-mouse genome comparisons to locate regulatory sites

Nature Genetics volume 26, pages 225–228 (2000)Cite this article

Abstract

Elucidating the human transcriptional regulatory network1 is a challenge of the post-genomic era. Technical progress so far is impressive, including detailed understanding of regulatory mechanisms for at least a few genes in multicellular organisms2,3,4, rapid and precise localization of regulatory regions within extensive regions of DNA by means of cross-species comparison5,6,7, and de novo determination of transcription-factor binding specificities from large-scale yeast expression data8. Here we address two problems involved in extending these results to the human genome: first, it has been unclear how many model organism genomes will be needed to delineate most regulatory regions; and second, the discovery of transcription-factor binding sites (response elements) from expression data has not yet been generalized from single-celled organisms to multicellular organisms. We found that 98% (74/75) of experimentally defined sequence-specific binding sites of skeletal-muscle-specific transcription factors are confined to the 19% of human sequences that are most conserved in the orthologous rodent sequences. Also we found that in using this restriction, the binding specificities of all three major muscle-specific transcription factors (MYF, SRF and MEF2) can be computationally identified.

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Figure 1: Probability of alignment for the sequences flanking the 5′ end of the first exon of natriuretic propeptide (NPPA).
Figure 2: Conservation of genomic sequence between humans and rodents for alignments where lengthRodent/lengthHuman ≥0.5.
Figure 3: Three patterns identified in the 5′ flanking sequences of genes selectively expressed in skeletal muscle.

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Acknowledgements

We thank our colleagues at SmithKline Beecham and the Wadsworth Center for input, and the Computational Molecular Biology Core at the Wadsworth Center and I. Auger for assistance. This work was supported by grants from the NIH to J.W.F. (NHGRI R01 HG00981-03) and C.E.L. (NHGRI R01 HG01257).

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Author notes

  1. Wyeth W. Wasserman

    Present address: Center for Genomics Research, Karolinska Institutet, Stockholm, Sweden

Authors and Affiliations

  1. Bioinformatics Group, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, USA

    Wyeth W. Wasserman & James W. Fickett

  2. New York State Department of Health, Wadsworth Center, Empire State Plaza, PO Box 509, Albany, New York, USA

    Michael Palumbo, William Thompson & Charles E. Lawrence

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  1. Wyeth W. Wasserman
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  2. Michael Palumbo
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  5. Charles E. Lawrence
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Correspondence to Charles E. Lawrence.

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Wasserman, W., Palumbo, M., Thompson, W. et al. Human-mouse genome comparisons to locate regulatory sites. Nat Genet 26, 225–228 (2000). https://doi.org/10.1038/79965

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