title: Identification of cis-suppression of human disease mutations by comparative genomics.
abstract: 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.
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Jordan
authors.affiliation: Center for Human Disease Modeling, Duke University, Durham, North Carolina 27701, USA.
authors.forename: Stephan G
authors.initials: SG
authors.lastname: Frangakis
authors.affiliation: Center for Human Disease Modeling, Duke University, Durham, North Carolina 27701, USA.
authors.forename: Christelle
authors.initials: C
authors.lastname: Golzio
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Cassa
authors.affiliation: Department of Pediatrics, Division of Pediatric Blood and Marrow Transplantation, Duke University, Durham, North Carolina 27710, USA.
authors.forename: Joanne
authors.initials: J
authors.lastname: Kurtzberg
authors.affiliation: Center for Human Disease Modeling, Duke University, Durham, North Carolina 27701, USA.
authors.forename: Erica E
authors.initials: EE
authors.lastname: Davis
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Shamil R
authors.initials: SR
authors.lastname: Sunyaev
authors.affiliation: Center for Human Disease Modeling, Duke University, Durham, North Carolina 27701, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000483:Alleles; D000818:Animals; D004194:Disease / Q000235:genetics*; D019143:Evolution, Molecular; D015894:Genome, Human / Q000235:genetics; D023281:Genomics; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics; D008831:Microcephaly / Q000235:genetics; D008869:Microtubule-Associated Proteins; D020125:Mutation, Missense / Q000235:genetics*; D010641:Phenotype; D011506:Proteins / Q000235:genetics; D016415:Sequence Alignment; D013489:Suppression, Genetic / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C429655:BBS4 protein, human; D017874:Immediate-Early Proteins; D008869:Microtubule-Associated Proteins; D011506:Proteins; C532826:RPGRIP1L protein, human; D025521:Tumor Suppressor Proteins; C070114:BTG2 protein, human