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

Daniel M. Jordan, Stephan G. Frangakis, Christelle Golzio, Christopher A. Cassa, Joanne Kurtzberg, Erica Ellen Davis, Shamil R. Sunyaev, Elias Nicholas Katsanis

Research output: Contribution to journalArticlepeer-review

75 Scopus citations


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 patients2. 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 genes3,4 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 pathogenicity5,6.

Original languageEnglish (US)
Pages (from-to)225-229
Number of pages5
Issue number7564
StatePublished - Aug 13 2015

ASJC Scopus subject areas

  • General


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