Comprehensive detection of genes causing a phenotype using phenotype sequencing and pathway analysis.
Discovering all the genetic causes of a phenotype is an important goal in functional genomics. We combine an experimental design for detecting independent genetic causes of a phenotype with a high-throughput sequencing analysis that maximizes sensitivity for comprehensively identifying them. Testing...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2014-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3935835?pdf=render |
| _version_ | 1818534185550217216 |
|---|---|
| author | Marc Harper Luisa Gronenberg James Liao Christopher Lee |
| author_facet | Marc Harper Luisa Gronenberg James Liao Christopher Lee |
| author_sort | Marc Harper |
| collection | DOAJ |
| description | Discovering all the genetic causes of a phenotype is an important goal in functional genomics. We combine an experimental design for detecting independent genetic causes of a phenotype with a high-throughput sequencing analysis that maximizes sensitivity for comprehensively identifying them. Testing this approach on a set of 24 mutant strains generated for a metabolic phenotype with many known genetic causes, we show that this pathway-based phenotype sequencing analysis greatly improves sensitivity of detection compared with previous methods, and reveals a wide range of pathways that can cause this phenotype. We demonstrate our approach on a metabolic re-engineering phenotype, the PEP/OAA metabolic node in E. coli, which is crucial to a substantial number of metabolic pathways and under renewed interest for biofuel research. Out of 2157 mutations in these strains, pathway-phenoseq discriminated just five gene groups (12 genes) as statistically significant causes of the phenotype. Experimentally, these five gene groups, and the next two high-scoring pathway-phenoseq groups, either have a clear connection to the PEP metabolite level or offer an alternative path of producing oxaloacetate (OAA), and thus clearly explain the phenotype. These high-scoring gene groups also show strong evidence of positive selection pressure, compared with strictly neutral selection in the rest of the genome. |
| first_indexed | 2024-12-11T18:08:26Z |
| format | Article |
| id | doaj.art-f22759206ca84326a08fa92f25130c7c |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-11T18:08:26Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-f22759206ca84326a08fa92f25130c7c2022-12-22T00:55:38ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0192e8807210.1371/journal.pone.0088072Comprehensive detection of genes causing a phenotype using phenotype sequencing and pathway analysis.Marc HarperLuisa GronenbergJames LiaoChristopher LeeDiscovering all the genetic causes of a phenotype is an important goal in functional genomics. We combine an experimental design for detecting independent genetic causes of a phenotype with a high-throughput sequencing analysis that maximizes sensitivity for comprehensively identifying them. Testing this approach on a set of 24 mutant strains generated for a metabolic phenotype with many known genetic causes, we show that this pathway-based phenotype sequencing analysis greatly improves sensitivity of detection compared with previous methods, and reveals a wide range of pathways that can cause this phenotype. We demonstrate our approach on a metabolic re-engineering phenotype, the PEP/OAA metabolic node in E. coli, which is crucial to a substantial number of metabolic pathways and under renewed interest for biofuel research. Out of 2157 mutations in these strains, pathway-phenoseq discriminated just five gene groups (12 genes) as statistically significant causes of the phenotype. Experimentally, these five gene groups, and the next two high-scoring pathway-phenoseq groups, either have a clear connection to the PEP metabolite level or offer an alternative path of producing oxaloacetate (OAA), and thus clearly explain the phenotype. These high-scoring gene groups also show strong evidence of positive selection pressure, compared with strictly neutral selection in the rest of the genome.http://europepmc.org/articles/PMC3935835?pdf=render |
| spellingShingle | Marc Harper Luisa Gronenberg James Liao Christopher Lee Comprehensive detection of genes causing a phenotype using phenotype sequencing and pathway analysis. PLoS ONE |
| title | Comprehensive detection of genes causing a phenotype using phenotype sequencing and pathway analysis. |
| title_full | Comprehensive detection of genes causing a phenotype using phenotype sequencing and pathway analysis. |
| title_fullStr | Comprehensive detection of genes causing a phenotype using phenotype sequencing and pathway analysis. |
| title_full_unstemmed | Comprehensive detection of genes causing a phenotype using phenotype sequencing and pathway analysis. |
| title_short | Comprehensive detection of genes causing a phenotype using phenotype sequencing and pathway analysis. |
| title_sort | comprehensive detection of genes causing a phenotype using phenotype sequencing and pathway analysis |
| url | http://europepmc.org/articles/PMC3935835?pdf=render |
| work_keys_str_mv | AT marcharper comprehensivedetectionofgenescausingaphenotypeusingphenotypesequencingandpathwayanalysis AT luisagronenberg comprehensivedetectionofgenescausingaphenotypeusingphenotypesequencingandpathwayanalysis AT jamesliao comprehensivedetectionofgenescausingaphenotypeusingphenotypesequencingandpathwayanalysis AT christopherlee comprehensivedetectionofgenescausingaphenotypeusingphenotypesequencingandpathwayanalysis |