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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.

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OrthoList coverage of hits from genome-wide RNAi screens.Venn diagrams analyzing hits obtained from RNAi screens examining (A) cell division [43] and (B) endocytic/secretory trafficking [44]. For each screen the overlap between OrthoList and the orthologous subset of hits is shown (percentage refers to how well covered by OrthoList this conserved subset is). Orthology assignments for hits missing from OrthoList (shown above overlap) and those found in OrthoList that were not called homologs in the original publications (shown below overlap) were confirmed by TreeFam and/or RBH (see Materials and Methods). Source data for these diagrams can be found in Tables S6 and S8.
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pone-0020085-g004: OrthoList coverage of hits from genome-wide RNAi screens.Venn diagrams analyzing hits obtained from RNAi screens examining (A) cell division [43] and (B) endocytic/secretory trafficking [44]. For each screen the overlap between OrthoList and the orthologous subset of hits is shown (percentage refers to how well covered by OrthoList this conserved subset is). Orthology assignments for hits missing from OrthoList (shown above overlap) and those found in OrthoList that were not called homologs in the original publications (shown below overlap) were confirmed by TreeFam and/or RBH (see Materials and Methods). Source data for these diagrams can be found in Tables S6 and S8.

Mentions: In the cell division screen, Sönnichsen et al. used an injectable RNAi library targeting 19,075 genes and found that 661 affect the first two rounds of cell division during C. elegans embryogenesis [43]. Updating the list of hits (see Materials and Methods) shows that only 652 of these still exist in the most recent genome release (see Table S6A). To get a sense of what the results would be if only the genes from OrthoList had been used for the screen, we wanted to know how many of the hits with human homologs are in our compendium. Sönnichsen et al. suggested that 575 of their hits had human homologs (see [43] and Materials and Methods). However, our analysis, by RBH and TreeFam, suggests that at least 17 hits previously thought to have human homologs do not do so by these criteria (see Table S6D), while 14 hits previously not thought to have homologs actually do (see Table S6E). Thus, the actual number of hits from this screen with human orthologs is 572, of which 565 are in the OrthoList (see Figure 4A and Tables S6B, C). Therefore, had the cell division screen been done against just the OrthoList set, ∼99%, of the conserved hits would have been recovered performing only ∼40% of the injections, representing a significant savings in time and effort.


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

Shaye DD, Greenwald I - PLoS ONE (2011)

OrthoList coverage of hits from genome-wide RNAi screens.Venn diagrams analyzing hits obtained from RNAi screens examining (A) cell division [43] and (B) endocytic/secretory trafficking [44]. For each screen the overlap between OrthoList and the orthologous subset of hits is shown (percentage refers to how well covered by OrthoList this conserved subset is). Orthology assignments for hits missing from OrthoList (shown above overlap) and those found in OrthoList that were not called homologs in the original publications (shown below overlap) were confirmed by TreeFam and/or RBH (see Materials and Methods). Source data for these diagrams can be found in Tables S6 and S8.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3102077&req=5

pone-0020085-g004: OrthoList coverage of hits from genome-wide RNAi screens.Venn diagrams analyzing hits obtained from RNAi screens examining (A) cell division [43] and (B) endocytic/secretory trafficking [44]. For each screen the overlap between OrthoList and the orthologous subset of hits is shown (percentage refers to how well covered by OrthoList this conserved subset is). Orthology assignments for hits missing from OrthoList (shown above overlap) and those found in OrthoList that were not called homologs in the original publications (shown below overlap) were confirmed by TreeFam and/or RBH (see Materials and Methods). Source data for these diagrams can be found in Tables S6 and S8.
Mentions: In the cell division screen, Sönnichsen et al. used an injectable RNAi library targeting 19,075 genes and found that 661 affect the first two rounds of cell division during C. elegans embryogenesis [43]. Updating the list of hits (see Materials and Methods) shows that only 652 of these still exist in the most recent genome release (see Table S6A). To get a sense of what the results would be if only the genes from OrthoList had been used for the screen, we wanted to know how many of the hits with human homologs are in our compendium. Sönnichsen et al. suggested that 575 of their hits had human homologs (see [43] and Materials and Methods). However, our analysis, by RBH and TreeFam, suggests that at least 17 hits previously thought to have human homologs do not do so by these criteria (see Table S6D), while 14 hits previously not thought to have homologs actually do (see Table S6E). Thus, the actual number of hits from this screen with human orthologs is 572, of which 565 are in the OrthoList (see Figure 4A and Tables S6B, C). Therefore, had the cell division screen been done against just the OrthoList set, ∼99%, of the conserved hits would have been recovered performing only ∼40% of the injections, representing a significant savings in time and effort.

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.

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