The alignment between the boundaries of protein domains and the boundaries of exons could provide... more The alignment between the boundaries of protein domains and the boundaries of exons could provide evidence for the evolution of proteins via domain shuffling, but literature in the field has so far struggled to conclusively show this. Here, on larger data sets than previously possible, we do finally show that this phenomenon is indisputably found widely across the eukaryotic tree. In contrast, the alignment between exons and the boundaries of intrinsically disordered regions of proteins is not a general property of eukaryotes. Most interesting of all is the discovery that domain–exon alignment is much more common in recently evolved protein sequences than older ones.
A major bottleneck in our understanding of the molecular underpinnings of life is the assignment ... more A major bottleneck in our understanding of the molecular underpinnings of life is the assignment of function to proteins. While molecular experiments provide the most reliable annotation of proteins, their relatively low throughput and restricted purview have led to an increasing role for computational function prediction. However, assessing methods for protein function prediction and tracking progress in the field remain challenging. We conducted the second critical assessment of functional annotation (CAFA), a timed challenge to assess computational methods that automatically assign protein function. We evaluated 126 methods from 56 research groups for their ability to predict biological functions using Gene Ontology and gene-disease associations using Human Phenotype Ontology on a set of 3681 proteins from 18 species. CAFA2 featured expanded analysis compared with CAFA1, with regards to data set size, variety, and assessment metrics. To review progress in the field, the analysis ...
Transdifferentiation, the process of converting from one cell type to another without going throu... more Transdifferentiation, the process of converting from one cell type to another without going through a pluripotent state, has great promise for regenerative medicine. The identification of key transcription factors for reprogramming is currently limited by the cost of exhaustive experimental testing of plausible sets of factors, an approach that is inefficient and unscalable. Here we present a predictive system (Mogrify) that combines gene expression data with regulatory network information to predict the reprogramming factors necessary to induce cell conversion. We have applied Mogrify to 173 human cell types and 134 tissues, defining an atlas of cellular reprogramming. Mogrify correctly predicts the transcription factors used in known transdifferentiations. Furthermore, we validated two new transdifferentiations predicted by Mogrify. We provide a practical and efficient mechanism for systematically implementing novel cell conversions, facilitating the generalization of reprogrammin...
The alignment between the boundaries of protein domains and the boundaries of exons could provide... more The alignment between the boundaries of protein domains and the boundaries of exons could provide evidence for the evolution of proteins via domain shuffling, but literature in the field has so far struggled to conclusively show this. Here, on larger data sets than previously possible, we do finally show that this phenomenon is indisputably found widely across the eukaryotic tree. In contrast, the alignment between exons and the boundaries of intrinsically disordered regions of proteins is not a general property of eukaryotes. Most interesting of all is the discovery that domain–exon alignment is much more common in recently evolved protein sequences than older ones.
A major bottleneck in our understanding of the molecular underpinnings of life is the assignment ... more A major bottleneck in our understanding of the molecular underpinnings of life is the assignment of function to proteins. While molecular experiments provide the most reliable annotation of proteins, their relatively low throughput and restricted purview have led to an increasing role for computational function prediction. However, assessing methods for protein function prediction and tracking progress in the field remain challenging. We conducted the second critical assessment of functional annotation (CAFA), a timed challenge to assess computational methods that automatically assign protein function. We evaluated 126 methods from 56 research groups for their ability to predict biological functions using Gene Ontology and gene-disease associations using Human Phenotype Ontology on a set of 3681 proteins from 18 species. CAFA2 featured expanded analysis compared with CAFA1, with regards to data set size, variety, and assessment metrics. To review progress in the field, the analysis ...
Transdifferentiation, the process of converting from one cell type to another without going throu... more Transdifferentiation, the process of converting from one cell type to another without going through a pluripotent state, has great promise for regenerative medicine. The identification of key transcription factors for reprogramming is currently limited by the cost of exhaustive experimental testing of plausible sets of factors, an approach that is inefficient and unscalable. Here we present a predictive system (Mogrify) that combines gene expression data with regulatory network information to predict the reprogramming factors necessary to induce cell conversion. We have applied Mogrify to 173 human cell types and 134 tissues, defining an atlas of cellular reprogramming. Mogrify correctly predicts the transcription factors used in known transdifferentiations. Furthermore, we validated two new transdifferentiations predicted by Mogrify. We provide a practical and efficient mechanism for systematically implementing novel cell conversions, facilitating the generalization of reprogrammin...
Proceedings of the National Academy of Sciences of the United States of America, Jan 31, 2015
The most diverse marine ecosystems, coral reefs, depend upon a functional symbiosis between a cni... more The most diverse marine ecosystems, coral reefs, depend upon a functional symbiosis between a cnidarian animal host (the coral) and intracellular photosynthetic dinoflagellate algae. The molecular and cellular mechanisms underlying this endosymbiosis are not well understood, in part because of the difficulties of experimental work with corals. The small sea anemone Aiptasia provides a tractable laboratory model for investigating these mechanisms. Here we report on the assembly and analysis of the Aiptasia genome, which will provide a foundation for future studies and has revealed several features that may be key to understanding the evolution and function of the endosymbiosis. These features include genomic rearrangements and taxonomically restricted genes that may be functionally related to the symbiosis, aspects of host dependence on alga-derived nutrients, a novel and expanded cnidarian-specific family of putative pattern-recognition receptors that might be involved in the animal...
We have discovered that positions of splice junctions in genes are constrained by the tolerance f... more We have discovered that positions of splice junctions in genes are constrained by the tolerance for disorder-promoting amino acids in the translated protein region. It is known that efficient splicing requires nucleotide bias at the splice junction; the preferred usage produces a distribution of amino acids that is disorder-promoting. We observe that efficiency of splicing, as seen in the amino-acid distribution, is not compromised to accommodate globular structure. Thus we infer that it is the positions of splice junctions in the gene that must be under constraint by the local protein environment. Examining exonic splicing enhancers found near the splice junction in the gene, reveals that these (short DNA motifs) are more prevalent in exons that encode disordered protein regions than exons encoding structured regions. Thus we also conclude that local protein features constrain efficient splicing more in structure than in disorder.
Genome3D (http://www.genome3d.eu) is a collaborative resource that provides predicted domain anno... more Genome3D (http://www.genome3d.eu) is a collaborative resource that provides predicted domain annotations and structural models for key sequences. Since introducing Genome3D in a previous NAR paper, we have substantially extended and improved the resource. We have annotated representatives from Pfam families to improve coverage of diverse sequences and added a fast sequence search to the website to allow users to find Genome3D-annotated sequences similar to their own. We have improved and extended the Genome3D data, enlarging the source data set from three model organisms to 10, and adding VIVACE, a resource new to Genome3D. We have analysed and updated Genome3D's SCOP/CATH mapping. Finally, we have improved the superposition tools, which now give users a more powerful interface for investigating similarities and differences between structural models.
The InterPro database (http://www.ebi.ac.uk/interpro/) is a freely available resource that can be... more The InterPro database (http://www.ebi.ac.uk/interpro/) is a freely available resource that can be used to classify sequences into protein families and to predict the presence of important domains and sites. Central to the InterPro database are predictive models, known as signatures, from a range of different protein family databases that have different biological focuses and use different methodological approaches to classify protein families and domains. InterPro integrates these signatures, capitalizing on the respective strengths of the individual databases, to produce a powerful protein classification resource. Here, we report on the status of InterPro as it enters its 15th year of operation, and give an overview of new developments with the database and its associated Web interfaces and software. In particular, the new domain architecture search tool is described and the process of mapping of Gene Ontology terms to InterPro is outlined. We also discuss the challenges faced by t...
yThe members of the FANTOM Consortium are provided in the supplementary file, Supplementary Mater... more yThe members of the FANTOM Consortium are provided in the supplementary file, Supplementary Material online.
We present the Proteome Quality Index (PQI; http:// pqi-list.org), a much-needed resource for use... more We present the Proteome Quality Index (PQI; http:// pqi-list.org), a much-needed resource for users of bacterial and eukaryotic proteomes. Completely sequenced genomes for which there is an available set of protein sequences (the proteome) are given a oneto five-star rating supported by 11 different metrics of quality. The database indexes over 3000 proteomes at the time of writing and is provided via a website for browsing, filtering and downloading. Previous to this work, there was no systematic way to account for the large variability in quality of the thousands of proteomes, and this is likely to have profoundly influenced the outcome of many published studies, in particular large-scale comparative analyses. The lack of a measure of proteome quality is likely due to the difficulty in producing one, a problem that we have approached by integrating multiple metrics. The continued development and improvement of the index will require the contribution of additional metrics by us and...
We have discovered that positions of splice junc-tions in genes are constrained by the tolerance ... more We have discovered that positions of splice junc-tions in genes are constrained by the tolerance for disorder-promoting amino acids in the translated protein region. It is known that efficient splicing re-quires nucleotide bias at the splice junction; the preferred usage produces a distribution of amino acids that is disorder-promoting. We observe that ef-ficiency of splicing, as seen in the amino-acid distri-bution, is not compromised to accommodate globu-lar structure. Thus we infer that it is the positions of splice junctions in the gene that must be under con-straint by the local protein environment. Examining exonic splicing enhancers found near the splice junc-tion in the gene, reveals that these (short DNA motifs) are more prevalent in exons that encode disordered protein regions than exons encoding structured re-gions. Thus we also conclude that local protein fea-tures constrain efficient splicing more in structure than in disorder.
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