Identifying pathogenicity of human variants via paralog-based yeast complementation.
To better understand the health implications of personal genomes, we now face a largely unmet challenge to identify functional variants within disease-associated genes. Functional variants can be identified by trans-species complementation, e.g., by failure to rescue a yeast strain bearing a mutatio...
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| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2017-05-01
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| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1006779 |
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| _version_ | 1849430735464693760 |
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| author | Fan Yang Song Sun Guihong Tan Michael Costanzo David E Hill Marc Vidal Brenda J Andrews Charles Boone Frederick P Roth |
| author_facet | Fan Yang Song Sun Guihong Tan Michael Costanzo David E Hill Marc Vidal Brenda J Andrews Charles Boone Frederick P Roth |
| author_sort | Fan Yang |
| collection | DOAJ |
| description | To better understand the health implications of personal genomes, we now face a largely unmet challenge to identify functional variants within disease-associated genes. Functional variants can be identified by trans-species complementation, e.g., by failure to rescue a yeast strain bearing a mutation in an orthologous human gene. Although orthologous complementation assays are powerful predictors of pathogenic variation, they are available for only a few percent of human disease genes. Here we systematically examine the question of whether complementation assays based on paralogy relationships can expand the number of human disease genes with functional variant detection assays. We tested over 1,000 paralogous human-yeast gene pairs for complementation, yielding 34 complementation relationships, of which 33 (97%) were novel. We found that paralog-based assays identified disease variants with success on par with that of orthology-based assays. Combining all homology-based assay results, we found that complementation can often identify pathogenic variants outside the homologous sequence region, presumably because of global effects on protein folding or stability. Within our search space, paralogy-based complementation more than doubled the number of human disease genes with a yeast-based complementation assay for disease variation. |
| format | Article |
| id | doaj-art-2f29d2a8d69541efa935142b9503e2ee |
| institution | Kabale University |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2017-05-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-2f29d2a8d69541efa935142b9503e2ee2025-08-20T03:27:52ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042017-05-01135e100677910.1371/journal.pgen.1006779Identifying pathogenicity of human variants via paralog-based yeast complementation.Fan YangSong SunGuihong TanMichael CostanzoDavid E HillMarc VidalBrenda J AndrewsCharles BooneFrederick P RothTo better understand the health implications of personal genomes, we now face a largely unmet challenge to identify functional variants within disease-associated genes. Functional variants can be identified by trans-species complementation, e.g., by failure to rescue a yeast strain bearing a mutation in an orthologous human gene. Although orthologous complementation assays are powerful predictors of pathogenic variation, they are available for only a few percent of human disease genes. Here we systematically examine the question of whether complementation assays based on paralogy relationships can expand the number of human disease genes with functional variant detection assays. We tested over 1,000 paralogous human-yeast gene pairs for complementation, yielding 34 complementation relationships, of which 33 (97%) were novel. We found that paralog-based assays identified disease variants with success on par with that of orthology-based assays. Combining all homology-based assay results, we found that complementation can often identify pathogenic variants outside the homologous sequence region, presumably because of global effects on protein folding or stability. Within our search space, paralogy-based complementation more than doubled the number of human disease genes with a yeast-based complementation assay for disease variation.https://doi.org/10.1371/journal.pgen.1006779 |
| spellingShingle | Fan Yang Song Sun Guihong Tan Michael Costanzo David E Hill Marc Vidal Brenda J Andrews Charles Boone Frederick P Roth Identifying pathogenicity of human variants via paralog-based yeast complementation. PLoS Genetics |
| title | Identifying pathogenicity of human variants via paralog-based yeast complementation. |
| title_full | Identifying pathogenicity of human variants via paralog-based yeast complementation. |
| title_fullStr | Identifying pathogenicity of human variants via paralog-based yeast complementation. |
| title_full_unstemmed | Identifying pathogenicity of human variants via paralog-based yeast complementation. |
| title_short | Identifying pathogenicity of human variants via paralog-based yeast complementation. |
| title_sort | identifying pathogenicity of human variants via paralog based yeast complementation |
| url | https://doi.org/10.1371/journal.pgen.1006779 |
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