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Träfflista för sökning "WFRF:(Clamp Michele) "

Sökning: WFRF:(Clamp Michele)

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1.
  • Birney, Ewan, et al. (författare)
  • Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project
  • 2007
  • Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 447:7146, s. 799-816
  • Tidskriftsartikel (refereegranskat)abstract
    • We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.
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2.
  • Clamp, Michele, et al. (författare)
  • Distinguishing protein-coding and noncoding genes in the human genome
  • 2007
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - 0027-8424 .- 1091-6490. ; 104:49, s. 19428-19433
  • Tidskriftsartikel (refereegranskat)abstract
    • Although the Human Genome Project was completed 4 years ago, the catalog of human protein-coding genes remains a matter of controversy. Current catalogs list a total of ≈24,500 putative protein-coding genes. It is broadly suspected that a large fraction of these entries are functionally meaningless ORFs present by chance in RNA transcripts, because they show no evidence of evolutionary conservation with mouse or dog. However, there is currently no scientific justification for excluding ORFs simply because they fail to show evolutionary conservation: the alternative hypothesis is that most of these ORFs are actually valid human genes that reflect gene innovation in the primate lineage or gene loss in the other lineages. Here, we reject this hypothesis by carefully analyzing the nonconserved ORFs—specifically, their properties in other primates. We show that the vast majority of these ORFs are random occurrences. The analysis yields, as a by-product, a major revision of the current human catalogs, cutting the number of protein-coding genes to ≈20,500. Specifically, it suggests that nonconserved ORFs should be added to the human gene catalog only if there is clear evidence of an encoded protein. It also provides a principled methodology for evaluating future proposed additions to the human gene catalog. Finally, the results indicate that there has been relatively little true innovation in mammalian protein-coding genes.
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3.
  • Garber, Manuel, et al. (författare)
  • Identifying novel constrained elements by exploiting biased substitution patterns
  • 2009
  • Ingår i: Bioinformatics. - 1367-4803 .- 1367-4811. ; 25:12, s. I54-I62
  • Tidskriftsartikel (refereegranskat)abstract
    • Motivation: Comparing the genomes from closely related species provides a powerful tool to identify functional elements in a reference genome. Many methods have been developed to identify conserved sequences across species; however, existing methods only model conservation as a decrease in the rate of mutation and have ignored selection acting on the pattern of mutations. Results: We present a new approach that takes advantage of deeply sequenced clades to identify evolutionary selection by uncovering not only signatures of rate-based conservation but also substitution patterns characteristic of sequence undergoing natural selection. We describe a new statistical method for modeling biased nucleotide substitutions, a learning algorithm for inferring site-specific substitution biases directly from sequence alignments and a hidden Markov model for detecting constrained elements characterized by biased substitutions. We show that the new approach can identify significantly more degenerate constrained sequences than rate-based methods. Applying it to the ENCODE regions, we identify as much as 10.2% of these regions are under selection.
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5.
  • Lindblad-Toh, Kerstin, et al. (författare)
  • A high-resolution map of human evolutionary constraint using 29 mammals
  • 2011
  • Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 478:7370, s. 476-482
  • Tidskriftsartikel (refereegranskat)abstract
    • The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering similar to 4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for similar to 60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate-and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease.
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6.
  • Lindblad-Toh, Kerstin, et al. (författare)
  • Genome sequence, comparative analysis and haplotype structure of the domestic dog.
  • 2005
  • Ingår i: Nature. - 1476-4687. ; 438:7069, s. 803-19
  • Tidskriftsartikel (refereegranskat)abstract
    • Here we report a high-quality draft genome sequence of the domestic dog (Canis familiaris), together with a dense map of single nucleotide polymorphisms (SNPs) across breeds. The dog is of particular interest because it provides important evolutionary information and because existing breeds show great phenotypic diversity for morphological, physiological and behavioural traits. We use sequence comparison with the primate and rodent lineages to shed light on the structure and evolution of genomes and genes. Notably, the majority of the most highly conserved non-coding sequences in mammalian genomes are clustered near a small subset of genes with important roles in development. Analysis of SNPs reveals long-range haplotypes across the entire dog genome, and defines the nature of genetic diversity within and across breeds. The current SNP map now makes it possible for genome-wide association studies to identify genes responsible for diseases and traits, with important consequences for human and companion animal health.
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7.
  • Lowe, Craig B, et al. (författare)
  • Three periods of regulatory innovation during vertebrate evolution
  • 2011
  • Ingår i: Science. - 0036-8075 .- 1095-9203. ; 333:6045, s. 1019-1024
  • Tidskriftsartikel (refereegranskat)abstract
    • The gain, loss, and modification of gene regulatory elements may underlie a substantial proportion of phenotypic changes on animal lineages. To investigate the gain of regulatory elements throughout vertebrate evolution, we identified genome-wide sets of putative regulatory regions for five vertebrates, including humans. These putative regulatory regions are conserved nonexonic elements (CNEEs), which are evolutionarily conserved yet do not overlap any coding or noncoding mature transcript. We then inferred the branch on which each CNEE came under selective constraint. Our analysis identified three extended periods in the evolution of gene regulatory elements. Early vertebrate evolution was characterized by regulatory gains near transcription factors and developmental genes, but this trend was replaced by innovations near extracellular signaling genes, and then innovations near posttranslational protein modifiers.
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8.
  • Margulies, Elliott H, et al. (författare)
  • Analyses of deep mammalian sequence alignments and constraint predictions for 1% of the human genome
  • 2007
  • Ingår i: Genome Research. - 1088-9051 .- 1549-5469. ; 17:6, s. 760-774
  • Tidskriftsartikel (refereegranskat)abstract
    • A key component of the ongoing ENCODE project involves rigorous comparative sequence analyses for the initially targeted 1% of the human genome. Here, we present orthologous sequence generation, alignment, and evolutionary constraint analyses of 23 mammalian species for all ENCODE targets. Alignments were generated using four different methods; comparisons of these methods reveal large-scale consistency but substantial differences in terms of small genomic rearrangements, sensitivity (sequence coverage), and specificity (alignment accuracy). We describe the quantitative and qualitative trade-offs concomitant with alignment method choice and the levels of technical error that need to be accounted for in applications that require multisequence alignments. Using the generated alignments, we identified constrained regions using three different methods. While the different constraint-detecting methods are in general agreement, there are important discrepancies relating to both the underlying alignments and the specific algorithms. However, by integrating the results across the alignments and constraint-detecting methods, we produced constraint annotations that were found to be robust based on multiple independent measures. Analyses of these annotations illustrate that most classes of experimentally annotated functional elements are enriched for constrained sequences; however, large portions of each class (with the exception of protein-coding sequences) do not overlap constrained regions. The latter elements might not be under primary sequence constraint, might not be constrained across all mammals, or might have expendable molecular functions. Conversely, 40% of the constrained sequences do not overlap any of the functional elements that have been experimentally identified. Together, these findings demonstrate and quantify how many genomic functional elements await basic molecular characterization.
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9.
  • Mikkelsen, Tarjei S, et al. (författare)
  • Genome of the marsupial Monodelphis domestica reveals innovation in non-coding sequences
  • 2007
  • Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 447:7141, s. 167-177
  • Tidskriftsartikel (refereegranskat)abstract
    • We report a high-quality draft of the genome sequence of the grey, short-tailed opossum (Monodelphis domestica). As the first metatherian ('marsupial') species to be sequenced, the opossum provides a unique perspective on the organization and evolution of mammalian genomes. Distinctive features of the opossum chromosomes provide support for recent theories about genome evolution and function, including a strong influence of biased gene conversion on nucleotide sequence composition, and a relationship between chromosomal characteristics and X chromosome inactivation. Comparison of opossum and eutherian genomes also reveals a sharp difference in evolutionary innovation between protein-coding and non-coding functional elements. True innovation in protein-coding genes seems to be relatively rare, with lineage-specific differences being largely due to diversification and rapid turnover in gene families involved in environmental interactions. In contrast, about 20% of eutherian conserved non-coding elements (CNEs) are recent inventions that postdate the divergence of Eutheria and Metatheria. A substantial proportion of these eutherian-specific CNEs arose from sequence inserted by transposable elements, pointing to transposons as a major creative force in the evolution of mammalian gene regulation.
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10.
  • Pontius, Joan U, et al. (författare)
  • Initial sequence and comparative analysis of the cat genome
  • 2007
  • Ingår i: Genome Research. - 1088-9051 .- 1549-5469. ; 17:11, s. 1675-1689
  • Tidskriftsartikel (refereegranskat)abstract
    • The genome sequence (1.9-fold coverage) of an inbred Abyssinian domestic cat was assembled, mapped, and annotated with a comparative approach that involved cross-reference to annotated genome assemblies of six mammals (human, chimpanzee, mouse, rat, dog, and cow). The results resolved chromosomal positions for 663,480 contigs, 20,285 putative feline gene orthologs, and 133,499 conserved sequence blocks (CSBs). Additional annotated features include repetitive elements, endogenous retroviral sequences, nuclear mitochondrial (numt) sequences, micro-RNAs, and evolutionary breakpoints that suggest historic balancing of translocation and inversion incidences in distinct mammalian lineages. Large numbers of single nucleotide polymorphisms (SNPs), deletion insertion polymorphisms (DIPs), and short tandem repeats (STRs), suitable for linkage or association studies were characterized in the context of long stretches of chromosome homozygosity. In spite of the light coverage capturing approximately 65% of euchromatin sequence from the cat genome, these comparative insights shed new light on the tempo and mode of gene/genome evolution in mammals, promise several research applications for the cat, and also illustrate that a comparative approach using more deeply covered mammals provides an informative, preliminary annotation of a light (1.9-fold) coverage mammal genome sequence.
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