Biomedical subjects

Huaiyu Mi

Publications and source records attributed to Huaiyu Mi.

8 recordsLinked to original sources

PubMed2007

Ontology annotation: mapping genomic regions to biological function.

With numerous whole genomes now in hand, and experimental data about genes and biological pathways on the increase, a systems approach to biological research is becoming essential. Ontologies provide a formal representation of knowledge that is amenable to computational as well as human analysis, an obvious underpinning of systems biology. Mapping function to gene products in the genome consists of two, somewhat intertwined enterprises: ontology building and ontology annotation. Ontology building is the formal representation of a domain of knowledge; ontology annotation is association of specific genomic regions (which we refer to simply as 'genes', including genes and their regulatory elements and products such as proteins and functional RNAs) to parts of the ontology. We consider two complementary representations of gene function: the Gene Ontology (GO) and pathway ontologies. GO represents function from the gene's eye view, in relation to a large and growing context of biological knowledge at all levels. Pathway ontologies represent function from the point of view of biochemical reactions and interactions, which are ordered into networks and causal cascades. The more mature GO provides an example of ontology annotation: how conclusions from the scientific literature and from evolutionary relationships are converted into formal statements about gene function. Annotations are made using a variety of different types of evidence, which can be used to estimate the relative reliability of different annotations.

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PubMed2006

PANTHER version 6: protein sequence and function evolution data with expanded representation of biological pathways.

PANTHER is a freely available, comprehensive software system for relating protein sequence evolution to the evolution of specific protein functions and biological roles. Since 2005, there have been three main improvements to PANTHER. First, the sequences used to create evolutionary trees are carefully selected to provide coverage of phylogenetic as well as functional information. Second, PANTHER is now a member of the InterPro Consortium, and the PANTHER hidden markov Models (HMMs) are distributed as part of InterProScan. Third, we have dramatically expanded the number of pathways associated with subfamilies in PANTHER. Pathways provide a detailed, structured representation of protein function in the context of biological reaction networks. PANTHER pathways were generated using the emerging Systems Biology Markup Language (SBML) standard using pathway network editing software called CellDesigner. The pathway collection currently contains approximately 1500 reactions in 130 pathways, curated by expert biologists with authorship attribution. The curation environment is designed to be easy to use, and the number of pathways is growing steadily. Because the reaction participants are linked to subfamilies and corresponding HMMs, reactions can be inferred across numerous different organisms. The HMMs can be downloaded by FTP, and tools for analyzing data in the context of pathways and function ontologies are available at http://www.pantherdb.org.

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PubMed2006

Applications for protein sequence-function evolution data: mRNA/protein expression analysis and coding SNP scoring tools.

The vast amount of protein sequence data now available, together with accumulating experimental knowledge of protein function, enables modeling of protein sequence and function evolution. The PANTHER database was designed to model evolutionary sequence-function relationships on a large scale. There are a number of applications for these data, and we have implemented web services that address three of them. The first is a protein classification service. Proteins can be classified, using only their amino acid sequences, to evolutionary groups at both the family and subfamily levels. Specific subfamilies, and often families, are further classified when possible according to their functions, including molecular function and the biological processes and pathways they participate in. The second application, then, is an expression data analysis service, where functional classification information can help find biological patterns in the data obtained from genome-wide experiments. The third application is a coding single-nucleotide polymorphism scoring service. In this case, information about evolutionarily related proteins is used to assess the likelihood of a deleterious effect on protein function arising from a single substitution at a specific amino acid position in the protein. All three web services are available at http://www.pantherdb.org/tools.

Amino Acid Substitution↗

PubMed2005

The PANTHER database of protein families, subfamilies, functions and pathways.

PANTHER is a large collection of protein families that have been subdivided into functionally related subfamilies, using human expertise. These subfamilies model the divergence of specific functions within protein families, allowing more accurate association with function (ontology terms and pathways), as well as inference of amino acids important for functional specificity. Hidden Markov models (HMMs) are built for each family and subfamily for classifying additional protein sequences. The latest version, 5.0, contains 6683 protein families, divided into 31,705 subfamilies, covering approximately 90% of mammalian protein-coding genes. PANTHER 5.0 includes a number of significant improvements over previous versions, most notably (i) representation of pathways (primarily signaling pathways) and association with subfamilies and individual protein sequences; (ii) an improved methodology for defining the PANTHER families and subfamilies, and for building the HMMs; (iii) resources for scoring sequences against PANTHER HMMs both over the web and locally; and (iv) a number of new web resources to facilitate analysis of large gene lists, including data generated from high-throughput expression experiments. Efforts are underway to add PANTHER to the InterPro suite of databases, and to make PANTHER consistent with the PIRSF database. PANTHER is now publicly available without restriction at http://panther.appliedbiosystems.com.

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PubMed2003

PANTHER: a browsable database of gene products organized by biological function, using curated protein family and subfamily classification.

The PANTHER database was designed for high-throughput analysis of protein sequences. One of the key features is a simplified ontology of protein function, which allows browsing of the database by biological functions. Biologist curators have associated the ontology terms with groups of protein sequences rather than individual sequences. Statistical models (Hidden Markov Models, or HMMs) are built from each of these groups. The advantage of this approach is that new sequences can be automatically classified as they become available. To ensure accurate functional classification, HMMs are constructed not only for families, but also for functionally distinct subfamilies. Multiple sequence alignments and phylogenetic trees, including curator-assigned information, are available for each family. The current version of the PANTHER database includes training sequences from all organisms in the GenBank non-redundant protein database, and the HMMs have been used to classify gene products across the entire genomes of human, and Drosophila melanogaster. The ontology terms and protein families and subfamilies, as well as Drosophila gene c;assifications, can be browsed and searched for free. Due to outstanding contractual obligations, access to human gene classifications and to protein family trees and multiple sequence alignments will temporarily require a nominal registration fee. PANTHER is publicly available on the web at http://panther.celera.com.

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PubMed2003

Assessment of genome-wide protein function classification for Drosophila melanogaster.

The functional classification of genes on a genome-wide scale is now in its infancy, and we make a first attempt to assess existing methods and identify sources of error. To this end, we compared two independent efforts for associating proteins with functions, one implemented by FlyBase and the other by PANTHER at Celera Genomics. Both methods make inferences based on sequence similarity and the available experimental evidence. However, they differ considerably in methodology and process. Overall, assuming that the systematic error across the two methods is relatively small, we find the protein-to-function association error rate of both the FlyBase and PANTHER methods to be <2%. The primary source of error for both methods appears to be simple human error. Although homology-based inference can certainly cause errors in annotation, our analysis indicates that the frequency of such errors is relatively small compared with the number of correct inferences. Moreover, these homology errors can be minimized by careful tree-based inference, such as that implemented in PANTHER. Often, functional associations are made by one method and not the other, indicating that one of the greatest challenges lies in improving the completeness of available ontology associations.

Animals↗

PubMed2003

PANTHER: a library of protein families and subfamilies indexed by function.

In the genomic era, one of the fundamental goals is to characterize the function of proteins on a large scale. We describe a method, PANTHER, for relating protein sequence relationships to function relationships in a robust and accurate way. PANTHER is composed of two main components: the PANTHER library (PANTHER/LIB) and the PANTHER index (PANTHER/X). PANTHER/LIB is a collection of "books," each representing a protein family as a multiple sequence alignment, a Hidden Markov Model (HMM), and a family tree. Functional divergence within the family is represented by dividing the tree into subtrees based on shared function, and by subtree HMMs. PANTHER/X is an abbreviated ontology for summarizing and navigating molecular functions and biological processes associated with the families and subfamilies. We apply PANTHER to three areas of active research. First, we report the size and sequence diversity of the families and subfamilies, characterizing the relationship between sequence divergence and functional divergence across a wide range of protein families. Second, we use the PANTHER/X ontology to give a high-level representation of gene function across the human and mouse genomes. Third, we use the family HMMs to rank missense single nucleotide polymorphisms (SNPs), on a database-wide scale, according to their likelihood of affecting protein function.

Algorithms↗

PubMed2002

Distribution of rSlo Ca2+-activated K+ channels in rat astrocyte perivascular endfeet.

Evidence that Ca(2+)-activated K(+) (K(Ca)) channels play a role in cell volume changes and K(+) homeostasis led to a prediction that astrocytes would have K(Ca) channels near blood vessels in order to maintain K(+) homeostasis. Consistent with this thinking the present study demonstrates that rSlo K(Ca) channels are in glial cells of the adult rat central nervous system (CNS) and highly localized to specializations of astrocytes associated with the brain vasculature. Using confocal and thin-section electron microscopic immunolabeling methods the distribution of rSlo was examined in adult rat brain. Strong rSlo immunolabeling was present around the vasculature of most brain regions. Examination of dye-filled hippocampal astrocytes revealed rSlo immunolabeling polarized in astrocytic endfeet. Ultrastructural analysis confirmed that the rSlo staining was concentrated in astrocytic endfeet ensheathing capillaries as well as abutting the pia mater. Immunostaining within the endfeet was predominantly distributed at the plasma membrane directly adjacent to either the vascular basal lamina or the pial surface. The distribution of the aquaporin-4 (AQP-4) water channel was also examined using dye-filled hippocampal astrocytes. In confirmation of earlier reports, intense AQP-4 immunolabeling was generally observed at the perimeter of blood vessels, and coincided with perivascular endfeet and rSlo labeling. We propose that rSlo K(Ca) channels, with their sensitivity to membrane depolarization and intracellular calcium, play a role in the K(+) modulation of cerebral blood flow. Additional knowledge of the molecular and cellular machinery present at perivascular endfeet may provide insight into the structural and functional molecular elements responsible for the neuronal activity-dependent regulation of cerebral blood flow.

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