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Sökning: WFRF:(Torrents David)

  • Resultat 1-10 av 11
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1.
  • Rheinbay, Esther, et al. (författare)
  • Analyses of non-coding somatic drivers in 2,658 cancer whole genomes
  • 2020
  • Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 578:7793, s. 102-111
  • Tidskriftsartikel (refereegranskat)abstract
    • The discovery of drivers of cancer has traditionally focused on protein-coding genes(1-4). Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium(5) of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers(6,7), raise doubts about others and identify novel candidates, including point mutations in the 5' region of TP53, in the 3' untranslated regions of NFKBIZ and TOB1, focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available.
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2.
  • Hillier, Ladeana W, et al. (författare)
  • Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution
  • 2004
  • Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 432:7018, s. 695-716
  • Tidskriftsartikel (refereegranskat)abstract
    • We present here a draft genome sequence of the red jungle fowl, Gallus gallus. Because the chicken is a modern descendant of the dinosaurs and the first non-mammalian amniote to have its genome sequenced, the draft sequence of its genome--composed of approximately one billion base pairs of sequence and an estimated 20,000-23,000 genes--provides a new perspective on vertebrate genome evolution, while also improving the annotation of mammalian genomes. For example, the evolutionary distance between chicken and human provides high specificity in detecting functional elements, both non-coding and coding. Notably, many conserved non-coding sequences are far from genes and cannot be assigned to defined functional classes. In coding regions the evolutionary dynamics of protein domains and orthologous groups illustrate processes that distinguish the lineages leading to birds and mammals. The distinctive properties of avian microchromosomes, together with the inferred patterns of conserved synteny, provide additional insights into vertebrate chromosome architecture.
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4.
  • Mikkelsen, Tarjei, et al. (författare)
  • Initial sequence of the chimpanzee genome and comparison with the human genome
  • 2005
  • Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 437:7055, s. 69-87
  • Tidskriftsartikel (refereegranskat)abstract
    • Here we present a draft genome sequence of the common chimpanzee (Pan troglodytes). Through comparison with the human genome, we have generated a largely complete catalogue of the genetic differences that have accumulated since the human and chimpanzee species diverged from our common ancestor, constituting approximately thirty-five million single-nucleotide changes, five million insertion/deletion events, and various chromosomal rearrangements. We use this catalogue to explore the magnitude and regional variation of mutational forces shaping these two genomes, and the strength of positive and negative selection acting on their genes. In particular, we find that the patterns of evolution in human and chimpanzee protein-coding genes are highly correlated and dominated by the fixation of neutral and slightly deleterious alleles. We also use the chimpanzee genome as an outgroup to investigate human population genetics and identify signatures of selective sweeps in recent human evolution.
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5.
  • Crona, Mikael, 1981-, et al. (författare)
  • Subunit and small-molecule interaction of ribonucleotide reductases via surface plasmon resonance biosensor analyses
  • 2010
  • Ingår i: Protein Engineering Design & Selection. - : Oxford University Press. - 1741-0126 .- 1741-0134. ; 23:8, s. 633-641
  • Tidskriftsartikel (refereegranskat)abstract
    • Ribonucleotide reductase (RNR) synthesizes deoxyribonucleotides for DNA replication and repair and is controlled by sophisticated allosteric regulation involving differential affinity of nucleotides for regulatory sites. We have developed a robust and sensitive method for coupling biotinylated RNRs to surface plasmon resonance streptavidin biosensor chips via a 30.5 Å linker. In comprehensive studies on three RNRs effector nucleotides strengthened holoenzyme interactions, whereas substrate had no effect on subunit interactions. The RNRs differed in their response to the negative allosteric effector dATP that binds to an ATP-cone domain. A tight RNR complex was formed in Escherichia coli class Ia RNR with a functional ATP cone. No strengthening of subunit interactions was observed in the class Ib RNR from the human pathogen Bacillus anthracis that lacks the ATP cone. A moderate strengthening was seen in the atypical Aeromonas hydrophila phage 1 class Ia RNR that has a split catalytic subunit and a non-functional ATP cone with remnant dATP-mediated regulatory features. We also successfully immobilized a functional catalytic NrdA subunit of the E.coli enzyme, facilitating study of nucleotide interactions. Our surface plasmon resonance methodology has the potential to provide biological insight into nucleotide-mediated regulation of any RNR, and can be used for high-throughput screening of potential RNR inhibitors
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8.
  • Miguel-Escalada, Irene, et al. (författare)
  • Human pancreatic islet three-dimensional chromatin architecture provides insights into the genetics of type 2 diabetes
  • 2019
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036. ; 51:7, s. 1137-1148
  • Tidskriftsartikel (refereegranskat)abstract
    • Genetic studies promise to provide insight into the molecular mechanisms underlying type 2 diabetes (T2D). Variants associated with T2D are often located in tissue-specific enhancer clusters or super-enhancers. So far, such domains have been defined through clustering of enhancers in linear genome maps rather than in three-dimensional (3D) space. Furthermore, their target genes are often unknown. We have created promoter capture Hi-C maps in human pancreatic islets. This linked diabetes-associated enhancers to their target genes, often located hundreds of kilobases away. It also revealed >1,300 groups of islet enhancers, super-enhancers and active promoters that form 3D hubs, some of which show coordinated glucose-dependent activity. We demonstrate that genetic variation in hubs impacts insulin secretion heritability, and show that hub annotations can be used for polygenic scores that predict T2D risk driven by islet regulatory variants. Human islet 3D chromatin architecture, therefore, provides a framework for interpretation of T2D genome-wide association study (GWAS) signals.
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9.
  • Nord, David, et al. (författare)
  • A functional homing endonuclease in the Bacillus anthracis nrdE group I intron
  • 2007
  • Ingår i: Journal of Bacteriology. - 0021-9193 .- 1098-5530. ; 189:14, s. 5293-5301
  • Tidskriftsartikel (refereegranskat)abstract
    • The essential Bacillus anthracis nrdE gene carries a self-splicing group I intron with a putative homing endonuclease belonging to the GIY-YIG family. Here, we show that the nrdE pre-mRNA is spliced and that the homing endonuclease cleaves an intronless nrdE gene 5 nucleotides (nt) upstream of the intron insertion site, producing 2-nt 3' extensions. We also show that the sequence required for efficient cleavage spans at least 4 bp upstream and 31 bp downstream of the cleaved coding strand. The position of the recognition sequence in relation to the cleavage position is as expected for a GIY-YIG homing endonuclease. Interestingly, nrdE genes from several other Bacillaceae were also susceptible to cleavage, with those of Bacillus cereus, Staphylococcus epidermidis (nrdE1), B. anthracis, and Bacillus thuringiensis serovar konkukian being better substrates than those of Bacillus subtilis, Bacillus lichenformis, and S. epidermidis (nrdE2). On the other hand, nrdE genes from Lactococcus lactis, Escherichia coli, Salmonella enterica serovar Typhimurium, and Corynebacterium ammoniagenes were not cleaved. Intervening sequences (IVSs) residing in protein-coding genes are often found in enzymes involved in DNA metabolism, and the ribonucleotide reductase nrdE gene is a frequent target for self-splicing IVSs. A comparison of nrdE genes from seven gram-positive low-G + C bacteria, two bacteriophages, and Nocardia farcinica showed five different insertion sites for self-splicing IVSs within the coding region of the nrdE gene.
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10.
  • Thorley, Jack, et al. (författare)
  • No task specialization among helpers in Damaraland mole-rats
  • 2018
  • Ingår i: Animal Behaviour. - : Elsevier. - 0003-3472 .- 1095-8282. ; 143, s. 9-24
  • Tidskriftsartikel (refereegranskat)abstract
    • The specialization of individuals in specific behavioural tasks is often attributed either to irreversible differences in development, which generate functionally divergent cooperative phenotypes, or to agerelated changes in the relative frequency with which individuals perform different cooperative activities; both of which are common in many insect caste systems. However, contrasts in cooperative behaviour can take other forms and, to date, few studies of cooperative behaviour in vertebrates have explored the effects of age, adult phenotype and early development on individual differences in cooperative behaviour in sufficient detail to discriminate between these alternatives. Here, we used multinomial models to quantify the extent of behavioural specialization within nonreproductive Damaraland mole-rats, Fukomys damarensis, at different ages. We showed that, although there were large differences between individuals in their contribution to cooperative activities, there was no evidence of individual specialization in cooperative activities that resembled the differences found in insect societies with distinct castes where individual contributions to different activities are negatively related to each other. Instead, individual differences in helping behaviour appeared to be the result of age-related changes in the extent to which individuals committed to all forms of helping. A similar pattern is observed in cooperatively breeding meerkats, Suricata suricatta, and there is no unequivocal evidence of caste differentiation in any cooperative vertebrate. The multinomial models we employed offer a powerful heuristic tool to explore task specialization and developmental divergence across social taxa and provide an analytical approach that may be useful in exploring the distribution of different forms of helping behaviour in other cooperative species. (C) 2018 The Authors. Published by Elsevier Ltd on behalf of The Association for the Study of Animal Behaviour.
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  • Resultat 1-10 av 11
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