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Biomedical subjects

W James Kent

Publications and source records attributed to W James Kent.

At least 19 recordsLinked to original sources
PubMed2006

The ENCODE Project at UC Santa Cruz.

The goal of the Encyclopedia Of DNA Elements (ENCODE) Project is to identify all functional elements in the human genome. The pilot phase is for comparison of existing methods and for the development of new methods to rigorously analyze a defined 1% of the human genome sequence. Experimental datasets are focused on the origin of replication, DNase I hypersensitivity, chromatin immunoprecipitation, promoter function, gene structure, pseudogenes, non-protein-coding RNAs, transcribed RNAs, multiple sequence alignment and evolutionarily constrained elements. The ENCODE project at UCSC website (http://genome.ucsc.edu/ENCODE) is the primary portal for the sequence-based data produced as part of the ENCODE project. In the pilot phase of the project, over 30 labs provided experimental results for a total of 56 browser tracks supported by 385 database tables. The site provides researchers with a number of tools that allow them to visualize and analyze the data as well as download data for local analyses. This paper describes the portal to the data, highlights the data that has been made available, and presents the tools that have been developed within the ENCODE project. Access to the data and types of interactive analysis that are possible are illustrated through supplemental examples.

Base Sequence↗
PubMed2006

Variation resources at UC Santa Cruz.

The variation resources within the University of California Santa Cruz Genome Browser include polymorphism data drawn from public collections and analyses of these data, along with their display in the context of other genomic annotations. Primary data from dbSNP is included for many organisms, with added information including genomic alleles and orthologous alleles for closely related organisms. Display filtering and coloring is available by variant type, functional class or other annotations. Annotation of potential errors is highlighted and a genomic alignment of the variant's flanking sequence is displayed. HapMap allele frequencies and linkage disequilibrium (LD) are available for each HapMap population, along with non-human primate alleles. The browsing and analysis tools, downloadable data files and links to documentation and other information can be found at http://genome.ucsc.edu/.

Alleles↗
PubMed2006

Reconstructing contiguous regions of an ancestral genome.

This article analyzes mammalian genome rearrangements at higher resolution than has been published to date. We identify 3171 intervals, covering approximately 92% of the human genome, within which we find no rearrangements larger than 50 kilobases (kb) in the lineages leading to human, mouse, rat, and dog from their most recent common ancestor. Combining intervals that are adjacent in all contemporary species produces 1338 segments that may contain large insertions or deletions but that are free of chromosome fissions or fusions as well as inversions or translocations >50 kb in length. We describe a new method for predicting the ancestral order and orientation of those intervals from their observed adjacencies in modern species. We combine the results from this method with data from chromosome painting experiments to produce a map of an early mammalian genome that accounts for 96.8% of the available human genome sequence data. The precision is further increased by mapping inversions as small as 31 bp. Analysis of the predicted evolutionary breakpoints in the human lineage confirms certain published observations but disagrees with others. Although only a few mammalian genomes are currently sequenced to high precision, our theoretical analyses and computer simulations indicate that our results are reasonably accurate and that they will become highly accurate in the foreseeable future. Our methods were developed as part of a project to reconstruct the genome sequence of the last ancestor of human, dogs, and most other placental mammals.

Algorithms↗
PubMed2006

A distal enhancer and an ultraconserved exon are derived from a novel retroposon.

Hundreds of highly conserved distal cis-regulatory elements have been characterized so far in vertebrate genomes. Many thousands more are predicted on the basis of comparative genomics. However, in stark contrast to the genes that they regulate, in invertebrates virtually none of these regions can be traced by using sequence similarity, leaving their evolutionary origins obscure. Here we show that a class of conserved, primarily non-coding regions in tetrapods originated from a previously unknown short interspersed repetitive element (SINE) retroposon family that was active in the Sarcopterygii (lobe-finned fishes and terrestrial vertebrates) in the Silurian period at least 410 million years ago (ref. 4), and seems to be recently active in the 'living fossil' Indonesian coelacanth, Latimeria menadoensis. Using a mouse enhancer assay we show that one copy, 0.5 million bases from the neuro-developmental gene ISL1, is an enhancer that recapitulates multiple aspects of Isl1 expression patterns. Several other copies represent new, possibly regulatory, alternatively spliced exons in the middle of pre-existing Sarcopterygian genes. One of these, a more than 200-base-pair ultraconserved region, 100% identical in mammals, and 80% identical to the coelacanth SINE, contains a 31-amino-acid-residue alternatively spliced exon of the messenger RNA processing gene PCBP2 (ref. 6). These add to a growing list of examples in which relics of transposable elements have acquired a function that serves their host, a process termed 'exaptation', and provide an origin for at least some of the many highly conserved vertebrate-specific genomic sequences.

Animals↗
PubMed2006

The UCSC Known Genes.

The University of California Santa Cruz (UCSC) Known Genes dataset is constructed by a fully automated process, based on protein data from Swiss-Prot/TrEMBL (UniProt) and the associated mRNA data from Genbank. The detailed steps of this process are described. Extensive cross-references from this dataset to other genomic and proteomic data were constructed. For each known gene, a details page is provided containing rich information about the gene, together with extensive links to other relevant genomic, proteomic and pathway data. As of July 2005, the UCSC Known Genes are available for human, mouse and rat genomes. The Known Genes serves as a foundation to support several key programs: the Genome Browser, Proteome Browser, Gene Sorter and Table Browser offered at the UCSC website. All the associated data files and program source code are also available. They can be accessed at http://genome.ucsc.edu. The genomic coverage of UCSC Known Genes, RefSeq, Ensembl Genes, H-Invitational and CCDS is analyzed. Although UCSC Known Genes offers the highest genomic and CDS coverage among major human and mouse gene sets, more detailed analysis suggests all of them could be further improved.

Base Sequence↗
PubMed2006

Piloting the zebrafish genome browser.

This correspondence is a primer for the zebrafish research community on zebrafish tracks available in the UCSC Genome Browser at http://genome.ucsc.edu based on Sanger's Zv4 assembly. A primary capability of this facility is comparative informatics between humans (as well as many other model organisms) and zebrafish. The zebrafish genome sequencing project has played important roles in mutant mapping and cloning, and comparative genomic research projects. This easy-to-use genome browser aims to display and download useful genome sequence information for zebrafish mutant mapping and cloning projects. Its user-friendly interface expedites annotation of the zebrafish genome sequence.

Animals↗
PubMed2005

Galaxy: a platform for interactive large-scale genome analysis.

Accessing and analyzing the exponentially expanding genomic sequence and functional data pose a challenge for biomedical researchers. Here we describe an interactive system, Galaxy, that combines the power of existing genome annotation databases with a simple Web portal to enable users to search remote resources, combine data from independent queries, and visualize the results. The heart of Galaxy is a flexible history system that stores the queries from each user; performs operations such as intersections, unions, and subtractions; and links to other computational tools. Galaxy can be accessed at http://g2.bx.psu.edu.

Biological Evolution↗
PubMed2005

Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes.

We have conducted a comprehensive search for conserved elements in vertebrate genomes, using genome-wide multiple alignments of five vertebrate species (human, mouse, rat, chicken, and Fugu rubripes). Parallel searches have been performed with multiple alignments of four insect species (three species of Drosophila and Anopheles gambiae), two species of Caenorhabditis, and seven species of Saccharomyces. Conserved elements were identified with a computer program called phastCons, which is based on a two-state phylogenetic hidden Markov model (phylo-HMM). PhastCons works by fitting a phylo-HMM to the data by maximum likelihood, subject to constraints designed to calibrate the model across species groups, and then predicting conserved elements based on this model. The predicted elements cover roughly 3%-8% of the human genome (depending on the details of the calibration procedure) and substantially higher fractions of the more compact Drosophila melanogaster (37%-53%), Caenorhabditis elegans (18%-37%), and Saccharaomyces cerevisiae (47%-68%) genomes. From yeasts to vertebrates, in order of increasing genome size and general biological complexity, increasing fractions of conserved bases are found to lie outside of the exons of known protein-coding genes. In all groups, the most highly conserved elements (HCEs), by log-odds score, are hundreds or thousands of bases long. These elements share certain properties with ultraconserved elements, but they tend to be longer and less perfectly conserved, and they overlap genes of somewhat different functional categories. In vertebrates, HCEs are associated with the 3' UTRs of regulatory genes, stable gene deserts, and megabase-sized regions rich in moderately conserved noncoding sequences. Noncoding HCEs also show strong statistical evidence of an enrichment for RNA secondary structure.

3' Untranslated Regions↗
PubMed2005

The UCSC Proteome Browser.

The University of California Santa Cruz (UCSC) Proteome Browser provides a wealth of protein information presented in graphical images and with links to other protein-related Internet sites. The Proteome Browser is tightly integrated with the UCSC Genome Browser. For the first time, Genome Browser users have both the genome and proteome worlds at their fingertips simultaneously. The Proteome Browser displays tracks of protein and genomic sequences, exon structure, polarity, hydrophobicity, locations of cysteine and glycosylation potential, Superfamily domains and amino acids that deviate from normal abundance. Histograms show genome-wide distribution of protein properties, including isoelectric point, molecular weight, number of exons, InterPro domains and cysteine locations, together with specific property values of the selected protein. The Proteome Browser also provides links to gene annotations in the Genome Browser, the Known Genes details page and the Gene Sorter; domain information from Superfamily, InterPro and Pfam; three-dimensional structures at the Protein Data Bank and ModBase; and pathway data at KEGG, BioCarta/CGAP and BioCyc. As of August 2004, the Proteome Browser is available for human, mouse and rat proteomes. The browser may be accessed from any Known Genes details page of the Genome Browser at http://genome.ucsc.edu. A user's guide is also available on this website.

California↗
PubMed2005

Assessing computational tools for the discovery of transcription factor binding sites.

The prediction of regulatory elements is a problem where computational methods offer great hope. Over the past few years, numerous tools have become available for this task. The purpose of the current assessment is twofold: to provide some guidance to users regarding the accuracy of currently available tools in various settings, and to provide a benchmark of data sets for assessing future tools.

Amino Acid Motifs↗
PubMed2004

Environmentally induced foregut remodeling by PHA-4/FoxA and DAF-12/NHR.

Growth and development of the Caenorhabditis elegans foregut (pharynx) depends on coordinated gene expression, mediated by pharynx defective (PHA)-4/FoxA in combination with additional, largely unidentified transcription factors. Here, we used whole genome analysis to establish clusters of genes expressed in different pharyngeal cell types. We created an expectation maximization algorithm to identify cis-regulatory elements that activate expression within the pharyngeal gene clusters. One of these elements mediates the response to environmental conditions within pharyngeal muscles and is recognized by the nuclear hormone receptor (NHR) DAF-12. Our data suggest that PHA-4 and DAF-12 endow the pharynx with transcriptional plasticity to respond to diverse developmental and physiological cues. Our combination of bioinformatics and in vivo analysis has provided a powerful means for genome-wide investigation of transcriptional control.

Animals↗
PubMed2004

Over 20% of human transcripts might form sense-antisense pairs.

The major challenge to identifying natural sense- antisense (SA) transcripts from public databases is how to determine the correct orientation for an expressed sequence, especially an expressed sequence tag sequence. In this study, we established a set of very stringent criteria to identify the correct orientation of each human transcript. We used these orientation-reliable transcripts to create 26 741 transcription clusters in the human genome. Our analysis shows that 22% (5880) of the human transcription clusters form SA pairs, higher than any previous estimates. Our orientation-specific RT-PCR results along with the comparison of experimental data from previous studies confirm that our SA data set is reliable. This study not only demonstrates that our criteria for the prediction of SA transcripts are efficient, but also provides additional convincing data to support the view that antisense transcription is quite pervasive in the human genome. In-depth analyses show that SA transcripts have some significant differences compared with other types of transcripts, with regard to chromosomal distribution and Gene Ontology-annotated categories of physiological roles, functions and spatial localizations of gene products.

Base Pairing↗
PubMed2004

Ultraconserved elements in the human genome.

There are 481 segments longer than 200 base pairs (bp) that are absolutely conserved (100% identity with no insertions or deletions) between orthologous regions of the human, rat, and mouse genomes. Nearly all of these segments are also conserved in the chicken and dog genomes, with an average of 95 and 99% identity, respectively. Many are also significantly conserved in fish. These ultraconserved elements of the human genome are most often located either overlapping exons in genes involved in RNA processing or in introns or nearby genes involved in the regulation of transcription and development. Along with more than 5000 sequences of over 100 bp that are absolutely conserved among the three sequenced mammals, these represent a class of genetic elements whose functions and evolutionary origins are yet to be determined, but which are more highly conserved between these species than are proteins and appear to be essential for the ontogeny of mammals and other vertebrates.

Alternative Splicing↗
PubMed2004

Hotspots of mammalian chromosomal evolution.

BACKGROUND: Chromosomal evolution is thought to occur through a random process of breakage and rearrangement that leads to karyotype differences and disruption of gene order. With the availability of both the human and mouse genomic sequences, detailed analysis of the sequence properties underlying these breakpoints is now possible. RESULTS: We report an abundance of primate-specific segmental duplications at the breakpoints of syntenic blocks in the human genome. Using conservative criteria, we find that 25% (122/461) of all breakpoints contain > or = 10 kb of duplicated sequence. This association is highly significant (p < 0.0001) when compared to a simulated random-breakage model. The significance is robust under a variety of parameters, multiple sets of conserved synteny data, and for orthologous breakpoints between and within chromosomes. A comparison of mouse lineage-specific breakpoints since the divergence of rat and mouse showed a similar association with regions associated with segmental duplications in the primate genome. CONCLUSION: These results indicate that segmental duplications are associated with syntenic rearrangements, even when pericentromeric and subtelomeric regions are excluded. However, segmental duplications are not necessarily the cause of the rearrangements. Rather, our analysis supports a nonrandom model of chromosomal evolution that implicates specific regions within the mammalian genome as having been predisposed to both recurrent small-scale duplication and large-scale evolutionary rearrangements.

Animals↗
PubMed2004

The UCSC Table Browser data retrieval tool.

The University of California Santa Cruz (UCSC) Table Browser (http://genome.ucsc.edu/cgi-bin/hgText) provides text-based access to a large collection of genome assemblies and annotation data stored in the Genome Browser Database. A flexible alternative to the graphical-based Genome Browser, this tool offers an enhanced level of query support that includes restrictions based on field values, free-form SQL queries and combined queries on multiple tables. Output can be filtered to restrict the fields and lines returned, and may be organized into one of several formats, including a simple tab- delimited file that can be loaded into a spreadsheet or database as well as advanced formats that may be uploaded into the Genome Browser as custom annotation tracks. The Table Browser User's Guide located on the UCSC website provides instructions and detailed examples for constructing queries and configuring output.

Animals↗
PubMed2004

Aligning multiple genomic sequences with the threaded blockset aligner.

We define a "threaded blockset," which is a novel generalization of the classic notion of a multiple alignment. A new computer program called TBA (for "threaded blockset aligner") builds a threaded blockset under the assumption that all matching segments occur in the same order and orientation in the given sequences; inversions and duplications are not addressed. TBA is designed to be appropriate for aligning many, but by no means all, megabase-sized regions of multiple mammalian genomes. The output of TBA can be projected onto any genome chosen as a reference, thus guaranteeing that different projections present consistent predictions of which genomic positions are orthologous. This capability is illustrated using a new visualization tool to view TBA-generated alignments of vertebrate Hox clusters from both the mammalian and fish perspectives. Experimental evaluation of alignment quality, using a program that simulates evolutionary change in genomic sequences, indicates that TBA is more accurate than earlier programs. To perform the dynamic-programming alignment step, TBA runs a stand-alone program called MULTIZ, which can be used to align highly rearranged or incompletely sequenced genomes. We describe our use of MULTIZ to produce the whole-genome multiple alignments at the Santa Cruz Genome Browser.

Animals↗
PubMed2003

Evolution's cauldron: duplication, deletion, and rearrangement in the mouse and human genomes.

This study examines genomic duplications, deletions, and rearrangements that have happened at scales ranging from a single base to complete chromosomes by comparing the mouse and human genomes. From whole-genome sequence alignments, 344 large (>100-kb) blocks of conserved synteny are evident, but these are further fragmented by smaller-scale evolutionary events. Excluding transposon insertions, on average in each megabase of genomic alignment we observe two inversions, 17 duplications (five tandem or nearly tandem), seven transpositions, and 200 deletions of 100 bases or more. This includes 160 inversions and 75 duplications or transpositions of length >100 kb. The frequencies of these smaller events are not substantially higher in finished portions in the assembly. Many of the smaller transpositions are processed pseudogenes; we define a "syntenic" subset of the alignments that excludes these and other small-scale transpositions. These alignments provide evidence that approximately 2% of the genes in the human/mouse common ancestor have been deleted or partially deleted in the mouse. There also appears to be slightly less nontransposon-induced genome duplication in the mouse than in the human lineage. Although some of the events we detect are possibly due to misassemblies or missing data in the current genome sequence or to the limitations of our methods, most are likely to represent genuine evolutionary events. To make these observations, we developed new alignment techniques that can handle large gaps in a robust fashion and discriminate between orthologous and paralogous alignments.

Animals↗