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Single-nucleotide evolutionary constraint scores highlight disease-causing mutations

Nature Methods volume 7, pages 250–251 (2010)Cite this article

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Identifying disease-causing genetic variants in individual human genomes is a major challenge, even in protein-coding exons (the 'exome'). Analysis of nucleotide-level sequence conservation may help address this challenge, on the assumption that purifying selection 'constrains' evolutionary divergence at phenotypically important nucleotides. In contrast to functional classifiers (for example, nonsynonymous mutations), constraint scores are quantitative and applicable to any genomic position1. However, it remains unclear if constraint scores can facilitate causal variant discovery, as statistical power is estimated to be marginal at the single-nucleotide level given current genome alignments1,2.

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Figure 1: RS scores inversely correlate with DAF of single-nucleotide variants in eight HapMap exomes.
Figure 2: Constraint scores enrich for disease-causing genes.

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Acknowledgements

G.M.C. is grateful for support from a Merck, Jane Coffin Childs Memorial Fund postdoctoral fellowship. D.L.G. is supported by a Lucille P. Markey Biomedical Research Stanford Graduate Fellowship. S.B.N. is supported by the Agency for Science, Technology and Research, Singapore. This work was also supported by grants from the US National Institutes of Health: U01 HL66682 (D.A.N.), 5R01HL094976-02 (D.A.N. and J.S.), 5R01HD048895 (M.J.B.) and 1R21HG004749-01 (J.S.).

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Authors and Affiliations

  1. Department of Genome Sciences, University of Washington, Seattle, Washington, USA

    Gregory M Cooper, Sarah B Ng, Michael J Bamshad, Jay Shendure & Deborah A Nickerson

  2. Department of Genetics Stanford University, Stanford, California, USA

    David L Goode & Arend Sidow

  3. Department of Pathology, Stanford University, Stanford, California, USA

    Arend Sidow

  4. Department of Pediatrics, University of Washington, Seattle, Washington, USA

    Michael J Bamshad

Authors
  1. Gregory M Cooper
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  2. David L Goode
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  3. Sarah B Ng
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  4. Arend Sidow
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  5. Michael J Bamshad
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  6. Jay Shendure
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  7. Deborah A Nickerson
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Correspondence to Gregory M Cooper.

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Cooper, G., Goode, D., Ng, S. et al. Single-nucleotide evolutionary constraint scores highlight disease-causing mutations. Nat Methods 7, 250–251 (2010). https://doi.org/10.1038/nmeth0410-250

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