Biomedical subjects

Daryl J Thomas

Publications and source records attributed to Daryl J Thomas.

6 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↗

PubMed2005

Conserved noncoding sequences are selectively constrained and not mutation cold spots.

Noncoding genetic variants are likely to influence human biology and disease, but recognizing functional noncoding variants is difficult. Approximately 3% of noncoding sequence is conserved among distantly related mammals, suggesting that these evolutionarily conserved noncoding regions (CNCs) are selectively constrained and contain functional variation. However, CNCs could also merely represent regions with lower local mutation rates. Here we address this issue and show that CNCs are selectively constrained in humans by analyzing HapMap genotype data. Specifically, new (derived) alleles of SNPs within CNCs are rarer than new alleles in nonconserved regions (P = 3 x 10(-18)), indicating that evolutionary pressure has suppressed CNC-derived allele frequencies. Intronic CNCs and CNCs near genes show greater allele frequency shifts, with magnitudes comparable to those for missense variants. Thus, conserved noncoding variants are more likely to be functional. Allele frequency distributions highlight selectively constrained genomic regions that should be intensively surveyed for functionally important variation.

Conserved Sequence↗

PubMed2005

LS-SNP: large-scale annotation of coding non-synonymous SNPs based on multiple information sources.

MOTIVATION: The NCBI dbSNP database lists over 9 million single nucleotide polymorphisms (SNPs) in the human genome, but currently contains limited annotation information. SNPs that result in amino acid residue changes (nsSNPs) are of critical importance in variation between individuals, including disease and drug sensitivity. RESULTS: We have developed LS-SNP, a genomic scale software pipeline to annotate nsSNPs. LS-SNP comprehensively maps nsSNPs onto protein sequences, functional pathways and comparative protein structure models, and predicts positions where nsSNPs destabilize proteins, interfere with the formation of domain-domain interfaces, have an effect on protein-ligand binding or severely impact human health. It currently annotates 28,043 validated SNPs that produce amino acid residue substitutions in human proteins from the SwissProt/TrEMBL database. Annotations can be viewed via a web interface either in the context of a genomic region or by selecting sets of SNPs, genes, proteins or pathways. These results are useful for identifying candidate functional SNPs within a gene, haplotype or pathway and in probing molecular mechanisms responsible for functional impacts of nsSNPs. AVAILABILITY: http://www.salilab.org/LS-SNP CONTACT: rachelk@salilab.org SUPPLEMENTARY INFORMATION: http://salilab.org/LS-SNP/supp-info.pdf.

Algorithms↗

PubMed2005

Genomic regions exhibiting positive selection identified from dense genotype data.

The allele frequency spectrum of polymorphisms in DNA sequences can be used to test for signatures of natural selection that depart from the expected frequency spectrum under the neutral theory. We observed a significant (P = 0.001) correlation between the Tajima's D test statistic in full resequencing data and Tajima's D in a dense, genome-wide data set of genotyped polymorphisms for a set of 179 genes. Based on this, we used a sliding window analysis of Tajima's D across the human genome to identify regions putatively subject to strong, recent, selective sweeps. This survey identified seven Contiguous Regions of Tajima's D Reduction (CRTRs) in an African-descent population (AD), 23 in a European-descent population (ED), and 29 in a Chinese-descent population (XD). Only four CRTRs overlapped between populations: three between ED and XD and one between AD and ED. Full resequencing of eight genes within six CRTRs demonstrated frequency spectra inconsistent with neutral expectations for at least one gene within each CRTR. Identification of the functional polymorphism (and/or haplotype) responsible for the selective sweeps within each CRTR may provide interesting insights into the strongest selective pressures experienced by the human genome over recent evolutionary history.

Black or African American↗

PubMed2005

Sequence features in regions of weak and strong linkage disequilibrium.

We use genotype data generated by the International HapMap Project to dissect the relationship between sequence features and the degree of linkage disequilibrium in the genome. We show that variation in linkage disequilibrium is broadly similar across populations and examine sequence landscape in regions of strong and weak disequilibrium. Linkage disequilibrium is generally low within approximately 15 Mb of the telomeres of each chromosome and noticeably elevated in large, duplicated regions of the genome as well as within approximately 5 Mb of centromeres and other heterochromatic regions. At a broad scale (100-1000 kb resolution), our results show that regions of strong linkage disequilibrium are typically GC poor and have reduced polymorphism. In addition, these regions are enriched for LINE repeats, but have fewer SINE, DNA, and simple repeats than the rest of the genome. At a fine scale, we examine the sequence composition of "hotspots" for the rapid breakdown of linkage disequilibrium and show that they are enriched in SINEs, in simple repeats, and in sequences that are conserved between species. Regions of high and low linkage disequilibrium (the top and bottom quartiles of the genome) have a higher density of genes and coding bases than the rest of the genome. Closer examination of the data shows that whereas some types of genes (including genes involved in immune response and sensory perception) are typically located in regions of low linkage disequilibrium, other genes (including those involved in DNA and RNA metabolism, response to DNA damage, and the cell cycle) are preferentially located in regions of strong linkage disequilibrium. Our results provide a detailed analysis of the relationship between sequence features and linkage disequilibrium and suggest an evolutionary justification for the heterogeneity in linkage disequilibrium in the genome.

Base Composition↗