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Identification of cis-suppression of human disease mutations by comparative genomics.

Publication ,  Journal Article
Jordan, DM; Frangakis, SG; Golzio, C; Cassa, CA; Kurtzberg, J; Task Force for Neonatal Genomics, ; Davis, EE; Sunyaev, SR; Katsanis, N
Published in: Nature
August 13, 2015

Patterns of amino acid conservation have served as a tool for understanding protein evolution. The same principles have also found broad application in human genomics, driven by the need to interpret the pathogenic potential of variants in patients. Here we performed a systematic comparative genomics analysis of human disease-causing missense variants. We found that an appreciable fraction of disease-causing alleles are fixed in the genomes of other species, suggesting a role for genomic context. We developed a model of genetic interactions that predicts most of these to be simple pairwise compensations. Functional testing of this model on two known human disease genes revealed discrete cis amino acid residues that, although benign on their own, could rescue the human mutations in vivo. This approach was also applied to ab initio gene discovery to support the identification of a de novo disease driver in BTG2 that is subject to protective cis-modification in more than 50 species. Finally, on the basis of our data and models, we developed a computational tool to predict candidate residues subject to compensation. Taken together, our data highlight the importance of cis-genomic context as a contributor to protein evolution; they provide an insight into the complexity of allele effect on phenotype; and they are likely to assist methods for predicting allele pathogenicity.

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Published In

Nature

DOI

EISSN

1476-4687

Publication Date

August 13, 2015

Volume

524

Issue

7564

Start / End Page

225 / 229

Location

England

Related Subject Headings

  • Tumor Suppressor Proteins
  • Suppression, Genetic
  • Sequence Alignment
  • Proteins
  • Phenotype
  • Mutation, Missense
  • Microtubule-Associated Proteins
  • Microcephaly
  • Immediate-Early Proteins
  • Humans
 

Citation

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Jordan, D. M., Frangakis, S. G., Golzio, C., Cassa, C. A., Kurtzberg, J., Task Force for Neonatal Genomics, ., … Katsanis, N. (2015). Identification of cis-suppression of human disease mutations by comparative genomics. Nature, 524(7564), 225–229. https://doi.org/10.1038/nature14497
Jordan, Daniel M., Stephan G. Frangakis, Christelle Golzio, Christopher A. Cassa, Joanne Kurtzberg, Joanne Task Force for Neonatal Genomics, Erica E. Davis, Shamil R. Sunyaev, and Nicholas Katsanis. “Identification of cis-suppression of human disease mutations by comparative genomics.Nature 524, no. 7564 (August 13, 2015): 225–29. https://doi.org/10.1038/nature14497.
Jordan DM, Frangakis SG, Golzio C, Cassa CA, Kurtzberg J, Task Force for Neonatal Genomics, et al. Identification of cis-suppression of human disease mutations by comparative genomics. Nature. 2015 Aug 13;524(7564):225–9.
Jordan, Daniel M., et al. “Identification of cis-suppression of human disease mutations by comparative genomics.Nature, vol. 524, no. 7564, Aug. 2015, pp. 225–29. Pubmed, doi:10.1038/nature14497.
Jordan DM, Frangakis SG, Golzio C, Cassa CA, Kurtzberg J, Task Force for Neonatal Genomics, Davis EE, Sunyaev SR, Katsanis N. Identification of cis-suppression of human disease mutations by comparative genomics. Nature. 2015 Aug 13;524(7564):225–229.
Journal cover image

Published In

Nature

DOI

EISSN

1476-4687

Publication Date

August 13, 2015

Volume

524

Issue

7564

Start / End Page

225 / 229

Location

England

Related Subject Headings

  • Tumor Suppressor Proteins
  • Suppression, Genetic
  • Sequence Alignment
  • Proteins
  • Phenotype
  • Mutation, Missense
  • Microtubule-Associated Proteins
  • Microcephaly
  • Immediate-Early Proteins
  • Humans