Biomedical subjects

Terrence S Furey

Publications and source records attributed to Terrence S Furey.

14 recordsLinked to original sources

PubMed2006

Genomic sweeping for hypermethylated genes.

MOTIVATION: Genes silenced by the aberrent methylation of nearby CpG islands can contribute to the onset or progression of cancer and represent potential biomarkers for diagnosis and prognosis. Relatively few have thus far been validated as hypermethylated in cancer among over 14,000 candidates with promoter region CpG islands. A descriptive set of genes known to be unmethylated in cancer does not exist. This lack of a negative set and a large number of candidates necessitated the development of a new approach to identify novel genes hypermethylated in cancer. RESULTS: We developed a general method, cluster_boost, that in an imbalanced data setting predicts new minority class members given limited known samples and a large set of unlabeled samples. Synthetic datasets modeled after the hypermethylated genes data show that cluster_boost can successfully identify minority samples within unlabeled data. Using genome sequence features, cluster_boost predicted candidate hypermethylated genes among 14,000 genes of unknown status. In primary ovarian cancers, we determined the methylation status for 15 genes with different levels of support for being hypermethlyated. Results indicate cluster_boost can accurately identify novel genes hypermethylated in cancer. AVAILABILITY: Software and datasets are freely available at http://labs.genome.duke.edu/FureyLab/cluster_boost.php. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Algorithms↗

PubMed2006

Genome-wide sequence and functional analysis of early replicating DNA in normal human fibroblasts.

BACKGROUND: The replication of mammalian genomic DNA during the S phase is a highly coordinated process that occurs in a programmed manner. Recent studies have begun to elucidate the pattern of replication timing on a genomic scale. Using a combination of experimental and computational techniques, we identified a genome-wide set of the earliest replicating sequences. This was accomplished by first creating a cosmid library containing DNA enriched in sequences that replicate early in the S phase of normal human fibroblasts. Clone ends were then sequenced and aligned to the human genome. RESULTS: By clustering adjacent or overlapping early replicating clones, we identified 1759 "islands" averaging 100 kb in length, allowing us to perform the most detailed analysis to date of DNA characteristics and genes contained within early replicating DNA. Islands are enriched in open chromatin, transcription related elements, and Alu repetitive elements, with an underrepresentation of LINE elements. In addition, we found a paucity of LTR retroposons, DNA transposon sequences, and an enrichment in all classes of tandem repeats, except for dinucleotides. CONCLUSION: An analysis of genes associated with islands revealed that nearly half of all genes in the WNT family, and a number of genes in the base excision repair pathway, including four of ten DNA glycosylases, were associated with island sequences. Also, we found an overrepresentation of members of apoptosis-associated genes in very early replicating sequences from both fibroblast and lymphoblastoid cells. These data suggest that there is a temporal pattern of replication for some functionally related genes.

Cell Proliferation↗

PubMed2006

Evidence of influence of genomic DNA sequence on human X chromosome inactivation.

A significant number of human X-linked genes escape X chromosome inactivation and are thus expressed from both the active and inactive X chromosomes. The basis for escape from inactivation and the potential role of the X chromosome primary DNA sequence in determining a gene's X inactivation status is unclear. Using a combination of the X chromosome sequence and a comprehensive X inactivation profile of more than 600 genes, two independent yet complementary approaches were used to systematically investigate the relationship between X inactivation and DNA sequence features. First, statistical analyses revealed that a number of repeat features, including long interspersed nuclear element (LINE) and mammalian-wide interspersed repeat repetitive elements, are significantly enriched in regions surrounding transcription start sites of genes that are subject to inactivation, while Alu repetitive elements and short motifs containing ACG/CGT are significantly enriched in those that escape inactivation. Second, linear support vector machine classifiers constructed using primary DNA sequence features were used to correctly predict the X inactivation status for >80% of all X-linked genes. We further identified a small set of features that are important for accurate classification, among which LINE-1 and LINE-2 content show the greatest individual discriminatory power. Finally, as few as 12 features can be used for accurate support vector machine classification. Taken together, these results suggest that features of the underlying primary DNA sequence of the human X chromosome may influence the spreading and/or maintenance of X inactivation.

Base Sequence↗

PubMed2006

Comparison of human (and other) genome browsers.

The sequence of the human genome provides a scaffold on which numerous annotations, such the locations of genes, can be laid. Genome browsers have been created to allow the simultaneous display of multiple annotations within a graphical interface. In addition, they provide the ability to search for markers and sequences, to extract annotations for specific regions or for the whole genome and to act as a central starting point for genomic research. This review describes the basic functionality of genome browsers and compares three of them: the University of California Santa Cruz (UCSC) Genome Browser, the Ensembl Genome Browser and the NCBI MapViewer.

Animals↗

PubMed2004

The structure and evolution of centromeric transition regions within the human genome.

An understanding of how centromeric transition regions are organized is a critical aspect of chromosome structure and function; however, the sequence context of these regions has been difficult to resolve on the basis of the draft genome sequence. We present a detailed analysis of the structure and assembly of all human pericentromeric regions (5 megabases). Most chromosome arms (35 out of 43) show a gradient of dwindling transcriptional diversity accompanied by an increasing number of interchromosomal duplications in proximity to the centromere. At least 30% of the centromeric transition region structure originates from euchromatic gene-containing segments of DNA that were duplicatively transposed towards pericentromeric regions at a rate of six-seven events per million years during primate evolution. This process has led to the formation of a minimum of 28 new transcripts by exon exaptation and exon shuffling, many of which are primarily expressed in the testis. The distribution of these duplicated segments is nonrandom among pericentromeric regions, suggesting that some regions have served as preferential acceptors of euchromatic DNA.

Animals↗

PubMed2004

The DNA sequence and biology of human chromosome 19.

Chromosome 19 has the highest gene density of all human chromosomes, more than double the genome-wide average. The large clustered gene families, corresponding high G + C content, CpG islands and density of repetitive DNA indicate a chromosome rich in biological and evolutionary significance. Here we describe 55.8 million base pairs of highly accurate finished sequence representing 99.9% of the euchromatin portion of the chromosome. Manual curation of gene loci reveals 1,461 protein-coding genes and 321 pseudogenes. Among these are genes directly implicated in mendelian disorders, including familial hypercholesterolaemia and insulin-resistant diabetes. Nearly one-quarter of these genes belong to tandemly arranged families, encompassing more than 25% of the chromosome. Comparative analyses show a fascinating picture of conservation and divergence, revealing large blocks of gene orthology with rodents, scattered regions with more recent gene family expansions and deletions, and segments of coding and non-coding conservation with the distant fish species Takifugu.

Alternative Splicing↗

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

Comparative recombination rates in the rat, mouse, and human genomes.

Levels of recombination vary among species, among chromosomes within species, and among regions within chromosomes in mammals. This heterogeneity may affect levels of diversity, efficiency of selection, and genome composition, as well as have practical consequences for the genetic mapping of traits. We compared the genetic maps to the genome sequence assemblies of rat, mouse, and human to estimate local recombination rates across these genomes. Humans have greater overall levels of recombination, as well as greater variance. In rat and mouse, the size of the chromosome and proximity to telomere have less effect on local recombination rate than in human. At the chromosome level, rat and mouse X chromosomes have the lowest recombination rates, whereas human chromosome X does not show the same pattern. In all species, local recombination rate is significantly correlated with several sequence variables, including GC%, CpG density, repetitive elements, and the neutral mutation rate, with some pronounced differences between species. Recombination rate in one species is not strongly correlated with the rate in another, when comparing homologous syntenic blocks of the genome. This comparative approach provides additional insight into the causes and consequences of genomic heterogeneity in recombination.

Animals↗

PubMed2004

Analysis of human mRNAs with the reference genome sequence reveals potential errors, polymorphisms, and RNA editing.

The NCBI Reference Sequence (RefSeq) project and the NIH Mammalian Gene Collection (MGC) together define a set of approximately 30,000 nonredundant human mRNA sequences with identified coding regions representing 17,000 distinct loci. These high-quality mRNA sequences allow for the identification of transcribed regions in the human genome sequence, and many researchers accept them as the correct representation of each defined gene sequence. Computational comparison of these mRNA sequences and the recently published essentially finished human genome sequence reveals several thousand undocumented nonsynonymous substitution and frame shift discrepancies between the two resources. Additional analysis is undertaken to verify that the euchromatic human genome is sufficiently complete--containing nearly the whole mRNA collection, thus allowing for a comprehensive analysis to be undertaken. Many of the discrepancies will prove to be genuine polymorphisms in the human population, somatic cell genomic variants, or examples of RNA editing. It is observed that the genome sequence variant has significant additional support from other mRNAs and ESTs, almost four times more often than does the mRNA variant, suggesting that the genome sequence is more accurate. In approximately 15% of these cases, there is substantial support for both variants, suggestive of an undocumented polymorphism. An initial screening against a 24-individual genomic DNA diversity panel verified 60% of a small set of potential single nucleotide polymorphisms from which successful results could be obtained. We also find statistical evidence that a few of these discrepancies are due to RNA editing. Overall, these results suggest that the mRNA collections may contain a substantial number of errors. For current and future mRNA collections, it may be prudent to fully reconcile each genome sequence discrepancy, classifying each as a polymorphism, site of RNA editing or somatic cell variation, or genome sequence error.

Computational Biology↗

PubMed2003

The DNA sequence of human chromosome 7.

Human chromosome 7 has historically received prominent attention in the human genetics community, primarily related to the search for the cystic fibrosis gene and the frequent cytogenetic changes associated with various forms of cancer. Here we present more than 153 million base pairs representing 99.4% of the euchromatic sequence of chromosome 7, the first metacentric chromosome completed so far. The sequence has excellent concordance with previously established physical and genetic maps, and it exhibits an unusual amount of segmentally duplicated sequence (8.2%), with marked differences between the two arms. Our initial analyses have identified 1,150 protein-coding genes, 605 of which have been confirmed by complementary DNA sequences, and an additional 941 pseudogenes. Of genes confirmed by transcript sequences, some are polymorphic for mutations that disrupt the reading frame.

Animals↗

PubMed2003

Integration of the cytogenetic map with the draft human genome sequence.

Chemically staining metaphase chromosomes resulting in an alternating dark and light banding pattern provide a tool by which abnormalities in chromosomes from diseased cells can be identified. The localization of these aberrations to a chromosomal region provides clues as to which gene or genes may contribute to a particular disease. With the sequencing of the human genome, it became critical to determine the positions of these cytogenetic bands within the sequence in order to take advantage of vast amount of information now anchored to the sequence, especially the locations of genes. The molecular basis of cytogenetic bands is not well understood, therefore their positions cannot be determined solely based on sequence information. We developed a dynamic programming algorithm that employs results from approximately 9500 fluorescence in situ hybridization experiments to approximate the locations of the 850 high-resolution bands in the June 2002 version of the draft human genome sequence. These band predictions support previously identified correlations between band stain intensity and certain structural characteristics of chromosomes, namely GC content, repeat structure content, CpG island density, gene density and degree of condensation.

Algorithms↗

PubMed2003

Covariation in frequencies of substitution, deletion, transposition, and recombination during eutherian evolution.

Six measures of evolutionary change in the human genome were studied, three derived from the aligned human and mouse genomes in conjunction with the Mouse Genome Sequencing Consortium, consisting of (1) nucleotide substitution per fourfold degenerate site in coding regions, (2) nucleotide substitution per site in relics of transposable elements active only before the human-mouse speciation, and (3) the nonaligning fraction of human DNA that is nonrepetitive or in ancestral repeats; and three derived from human genome data alone, consisting of (4) SNP density, (5) frequency of insertion of transposable elements, and (6) rate of recombination. Features 1 and 2 are measures of nucleotide substitutions at two classes of "neutral" sites, whereas 4 is a measure of recent mutations. Feature 3 is a measure dominated by deletions in mouse, whereas 5 represents insertions in human. It was found that all six vary significantly in megabase-sized regions genome-wide, and many vary together. This indicates that some regions of a genome change slowly by all processes that alter DNA, and others change faster. Regional variation in all processes is correlated with, but not completely accounted for, by GC content in human and the difference between GC content in human and mouse.

Animals↗

PubMed2002

Initial sequencing and comparative analysis of the mouse genome.

The sequence of the mouse genome is a key informational tool for understanding the contents of the human genome and a key experimental tool for biomedical research. Here, we report the results of an international collaboration to produce a high-quality draft sequence of the mouse genome. We also present an initial comparative analysis of the mouse and human genomes, describing some of the insights that can be gleaned from the two sequences. We discuss topics including the analysis of the evolutionary forces shaping the size, structure and sequence of the genomes; the conservation of large-scale synteny across most of the genomes; the much lower extent of sequence orthology covering less than half of the genomes; the proportions of the genomes under selection; the number of protein-coding genes; the expansion of gene families related to reproduction and immunity; the evolution of proteins; and the identification of intraspecies polymorphism.

Animals↗

PubMed2002

The human genome browser at UCSC.

As vertebrate genome sequences near completion and research refocuses to their analysis, the issue of effective genome annotation display becomes critical. A mature web tool for rapid and reliable display of any requested portion of the genome at any scale, together with several dozen aligned annotation tracks, is provided at http://genome.ucsc.edu. This browser displays assembly contigs and gaps, mRNA and expressed sequence tag alignments, multiple gene predictions, cross-species homologies, single nucleotide polymorphisms, sequence-tagged sites, radiation hybrid data, transposon repeats, and more as a stack of coregistered tracks. Text and sequence-based searches provide quick and precise access to any region of specific interest. Secondary links from individual features lead to sequence details and supplementary off-site databases. One-half of the annotation tracks are computed at the University of California, Santa Cruz from publicly available sequence data; collaborators worldwide provide the rest. Users can stably add their own custom tracks to the browser for educational or research purposes. The conceptual and technical framework of the browser, its underlying MYSQL database, and overall use are described. The web site currently serves over 50,000 pages per day to over 3000 different users.

California↗