Limits...
OrthoList: a compendium of C. elegans genes with human orthologs.

Shaye DD, Greenwald I - PLoS ONE (2011)

Bottom Line: We performed a meta-analysis of results from four orthology prediction programs and generated a compendium, "OrthoList", containing 7,663 C. elegans protein-coding genes.We compiled Ortholist by InterPro domains and Gene Ontology annotation, making it easy to identify C. elegans orthologs of human disease genes for potential functional analysis.Moreover, we find that OrthoList provides a useful basis for annotating orthology and reveals more C. elegans orthologs of human genes in various functional groups, such as transcription factors, than previously described.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute, Columbia University, College of Physicians and Surgeons, New York, New York, United States of America. ds451@columbia.edu

ABSTRACT

Background: C. elegans is an important model for genetic studies relevant to human biology and disease. We sought to assess the orthology between C. elegans and human genes to understand better the relationship between their genomes and to generate a compelling list of candidates to streamline RNAi-based screens in this model.

Results: We performed a meta-analysis of results from four orthology prediction programs and generated a compendium, "OrthoList", containing 7,663 C. elegans protein-coding genes. Various assessments indicate that OrthoList has extensive coverage with low false-positive and false-negative rates. Part of this evaluation examined the conservation of components of the receptor tyrosine kinase, Notch, Wnt, TGF-ß and insulin signaling pathways, and led us to update compendia of conserved C. elegans kinases, nuclear hormone receptors, F-box proteins, and transcription factors. Comparison with two published genome-wide RNAi screens indicated that virtually all of the conserved hits would have been obtained had just the OrthoList set (∼38% of the genome) been targeted. We compiled Ortholist by InterPro domains and Gene Ontology annotation, making it easy to identify C. elegans orthologs of human disease genes for potential functional analysis.

Conclusions: We anticipate that OrthoList will be of considerable utility to C. elegans researchers for streamlining RNAi screens, by focusing on genes with apparent human orthologs, thus reducing screening effort by ∼60%. Moreover, we find that OrthoList provides a useful basis for annotating orthology and reveals more C. elegans orthologs of human genes in various functional groups, such as transcription factors, than previously described.

Show MeSH
OrthoList coverage of conserved signaling pathways.Genes in bold are found by at least one orthology-predicting program, and thus included in OrthoList. The source data for this figure can be found in Table S5. A) RTK/Ras/MAPK pathway (reviewed in [34]). Note that ras-1 and ras-2 have not been defined functionally, although they are highly conserved. B) Notch pathway (reviewed in reviewed in [32]). C) TGF-ß pathway (reviewed in [33]). We note that tag-68, was only defined by conservation and no phenotype has been associated with its loss. D) Wnt pathway (reviewed in [30]). Note that our analysis was restricted to the conserved, canonical Wnt pathway. E) Insulin pathway. We specifically highlight the six insulins (daf-28, ins-1, ins-4, ins-6, ins-7 and ins-8), out of forty, that have been found (by overexpression, biochemical methods, RNAi or by existence of a semi-dominant allele) to be functional (reviewed in [31]).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3102077&req=5

pone-0020085-g003: OrthoList coverage of conserved signaling pathways.Genes in bold are found by at least one orthology-predicting program, and thus included in OrthoList. The source data for this figure can be found in Table S5. A) RTK/Ras/MAPK pathway (reviewed in [34]). Note that ras-1 and ras-2 have not been defined functionally, although they are highly conserved. B) Notch pathway (reviewed in reviewed in [32]). C) TGF-ß pathway (reviewed in [33]). We note that tag-68, was only defined by conservation and no phenotype has been associated with its loss. D) Wnt pathway (reviewed in [30]). Note that our analysis was restricted to the conserved, canonical Wnt pathway. E) Insulin pathway. We specifically highlight the six insulins (daf-28, ins-1, ins-4, ins-6, ins-7 and ins-8), out of forty, that have been found (by overexpression, biochemical methods, RNAi or by existence of a semi-dominant allele) to be functional (reviewed in [31]).

Mentions: To evaluate further the utility and completeness of OrthoList we asked which components of known conserved signaling pathways are found in this list. To this end, we looked for members of the Receptor Tyrosine Kinase (RTK)/Ras/Mitogen-Activated Protein Kinase (MAPK), Notch, Wingless (Wnt), Transforming Growth Factor Beta (TGF-ß) and Insulin pathways (reviewed in [30]–[34]). We found that for these known conserved pathways most of their core components, particularly those involved in signal transduction, are found in the OrthoList (see Figure 3 and Table S5). Thus, we believe that an RNAi library based on this list should reduce the function of these pathways, and by extension of other conserved pathways, at one or more steps. In addition, for each pathway, there are interesting observations regarding the nature and extent of the conservation between C. elegans and humans.


OrthoList: a compendium of C. elegans genes with human orthologs.

Shaye DD, Greenwald I - PLoS ONE (2011)

OrthoList coverage of conserved signaling pathways.Genes in bold are found by at least one orthology-predicting program, and thus included in OrthoList. The source data for this figure can be found in Table S5. A) RTK/Ras/MAPK pathway (reviewed in [34]). Note that ras-1 and ras-2 have not been defined functionally, although they are highly conserved. B) Notch pathway (reviewed in reviewed in [32]). C) TGF-ß pathway (reviewed in [33]). We note that tag-68, was only defined by conservation and no phenotype has been associated with its loss. D) Wnt pathway (reviewed in [30]). Note that our analysis was restricted to the conserved, canonical Wnt pathway. E) Insulin pathway. We specifically highlight the six insulins (daf-28, ins-1, ins-4, ins-6, ins-7 and ins-8), out of forty, that have been found (by overexpression, biochemical methods, RNAi or by existence of a semi-dominant allele) to be functional (reviewed in [31]).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3102077&req=5

pone-0020085-g003: OrthoList coverage of conserved signaling pathways.Genes in bold are found by at least one orthology-predicting program, and thus included in OrthoList. The source data for this figure can be found in Table S5. A) RTK/Ras/MAPK pathway (reviewed in [34]). Note that ras-1 and ras-2 have not been defined functionally, although they are highly conserved. B) Notch pathway (reviewed in reviewed in [32]). C) TGF-ß pathway (reviewed in [33]). We note that tag-68, was only defined by conservation and no phenotype has been associated with its loss. D) Wnt pathway (reviewed in [30]). Note that our analysis was restricted to the conserved, canonical Wnt pathway. E) Insulin pathway. We specifically highlight the six insulins (daf-28, ins-1, ins-4, ins-6, ins-7 and ins-8), out of forty, that have been found (by overexpression, biochemical methods, RNAi or by existence of a semi-dominant allele) to be functional (reviewed in [31]).
Mentions: To evaluate further the utility and completeness of OrthoList we asked which components of known conserved signaling pathways are found in this list. To this end, we looked for members of the Receptor Tyrosine Kinase (RTK)/Ras/Mitogen-Activated Protein Kinase (MAPK), Notch, Wingless (Wnt), Transforming Growth Factor Beta (TGF-ß) and Insulin pathways (reviewed in [30]–[34]). We found that for these known conserved pathways most of their core components, particularly those involved in signal transduction, are found in the OrthoList (see Figure 3 and Table S5). Thus, we believe that an RNAi library based on this list should reduce the function of these pathways, and by extension of other conserved pathways, at one or more steps. In addition, for each pathway, there are interesting observations regarding the nature and extent of the conservation between C. elegans and humans.

Bottom Line: We performed a meta-analysis of results from four orthology prediction programs and generated a compendium, "OrthoList", containing 7,663 C. elegans protein-coding genes.We compiled Ortholist by InterPro domains and Gene Ontology annotation, making it easy to identify C. elegans orthologs of human disease genes for potential functional analysis.Moreover, we find that OrthoList provides a useful basis for annotating orthology and reveals more C. elegans orthologs of human genes in various functional groups, such as transcription factors, than previously described.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute, Columbia University, College of Physicians and Surgeons, New York, New York, United States of America. ds451@columbia.edu

ABSTRACT

Background: C. elegans is an important model for genetic studies relevant to human biology and disease. We sought to assess the orthology between C. elegans and human genes to understand better the relationship between their genomes and to generate a compelling list of candidates to streamline RNAi-based screens in this model.

Results: We performed a meta-analysis of results from four orthology prediction programs and generated a compendium, "OrthoList", containing 7,663 C. elegans protein-coding genes. Various assessments indicate that OrthoList has extensive coverage with low false-positive and false-negative rates. Part of this evaluation examined the conservation of components of the receptor tyrosine kinase, Notch, Wnt, TGF-ß and insulin signaling pathways, and led us to update compendia of conserved C. elegans kinases, nuclear hormone receptors, F-box proteins, and transcription factors. Comparison with two published genome-wide RNAi screens indicated that virtually all of the conserved hits would have been obtained had just the OrthoList set (∼38% of the genome) been targeted. We compiled Ortholist by InterPro domains and Gene Ontology annotation, making it easy to identify C. elegans orthologs of human disease genes for potential functional analysis.

Conclusions: We anticipate that OrthoList will be of considerable utility to C. elegans researchers for streamlining RNAi screens, by focusing on genes with apparent human orthologs, thus reducing screening effort by ∼60%. Moreover, we find that OrthoList provides a useful basis for annotating orthology and reveals more C. elegans orthologs of human genes in various functional groups, such as transcription factors, than previously described.

Show MeSH