| 1. |
- Clark, Andrew G., et al.
(author)
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Evolution of genes and genomes on the Drosophila phylogeny
- 2007
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 450:7167, s. 203-218
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Journal article (peer-reviewed)abstract
- Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.
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| 2. |
- Wang, Zhaoming, et al.
(author)
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Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33
- 2014
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:24, s. 6616-6633
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Journal article (peer-reviewed)abstract
- Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
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| 3. |
- Fang, Jun, et al.
(author)
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Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148
- 2017
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Journal article (peer-reviewed)abstract
- Genome wide association studies (GWAS) have mapped multiple independent cancer susceptibility loci to chr5p15.33. Here, we show that fine-mapping of pancreatic and testicular cancer GWAS within one of these loci (Region 2 in CLPTM1L) focuses the signal to nine highly correlated SNPs. Of these, rs36115365-C associated with increased pancreatic and testicular but decreased lung cancer and melanoma risk, and exhibited preferred protein-binding and enhanced regulatory activity. Transcriptional gene silencing of this regulatory element repressed TERT expression in an allele-specific manner. Proteomic analysis identifies allele-preferred binding of Zinc finger protein 148 (ZNF148) to rs36115365-C, further supported by binding of purified recombinant ZNF148. Knockdown of ZNF148 results in reduced TERT expression, telomerase activity and telomere length. Our results indicate that the association with chr5p15.33-Region 2 may be explained by rs36115365, a variant influencing TERT expression via ZNF148 in a manner consistent with elevated TERT in carriers of the C allele.
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| 4. |
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| 5. |
- Hartung, Kerstin, et al.
(author)
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Diagnosing topographic forcing in an atmospheric dataset : The case of the North American Cordillera
- 2020
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In: Quarterly Journal of the Royal Meteorological Society. - : Wiley. - 0035-9009 .- 1477-870X. ; 146:726, s. 314-326
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Journal article (peer-reviewed)abstract
- It is well known from modelling studies that surface topography influences the large-scale atmospheric circulation and that several model biases are associated with incorrect representation of topography. The textbook explanation of topographic effects on large-scale circulation appeals to the theoretical relationship between surface forcing and vortex stretching along trajectories in single-layer models. The goal of this study is to design and use a simple diagnostic of the large-scale forcing on the atmosphere when air is passing over topography, directly from atmospheric fields, based on this theoretical relationship. The study examines the interaction of the atmosphere with the North American Cordillera and samples the flow by means of trajectories during Northern Hemisphere winter. We detect a signal of topographic forcing in the atmospheric dataset, which, although much less distinct than in the theoretical relationship, nevertheless exhibits a number of expected properties. Namely, the signal increases with latitude, is usually stronger upslope than downslope, and is enhanced if the flow is more orthogonal to the mountain ridge, for example during periods of positive Pacific-North American index (PNA). Furthermore, a connection is found between an enhanced signal of topographic forcing downslope of the North American Cordillera and periods of more frequent downstream European blocking.
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| 6. |
- Hoskins, Brian, et al.
(author)
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The detailed dynamics of the June–August Hadley Cell
- 2020
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In: Quarterly Journal of the Royal Meteorological Society. - : John Wiley & Sons. - 1477-870X .- 0035-9009. ; 146:727, s. 557-575
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Journal article (peer-reviewed)abstract
- The seminal theory for the Hadley Cells has demonstrated that their existence is necessary for the reduction of tropical temperature gradients to a value such that the implied zonal winds are realisable. At the heart of the theory is the notion of angular momentum conservation in the upper branch of the Hadley Cells. Eddy mixing associated with extra‐tropical systems is invoked to give continuity at the edge of the Hadley Cell and to reduce the subtropical jet by a factor of 3 or more to those observed. In this paper a detailed view is presented of the dynamics of the June–August Hadley Cell, as given by ERA data for the period 1981–2010, with an emphasis on the dynamics of the upper branch. The steady and transient northward fluxes of angular momentum have a very similar structure, both having a maximum on the equator and a reversal in sign near 12°S, with the transient flux merging into that associated with eddies on the winter sub‐tropical jet. In the northward absolute vorticity flux, the Coriolis torque is balanced by both the steady and transient fluxes. The overturning circulations that average to give the Hadley Cell are confined to specific longitudinal regions, as are the steady and transient momentum fluxes. In these regions, both intra‐seasonal and synoptic variations are important. The dominant contributor to the Hadley Cell is from the Indian Ocean and W Pacific regions, and the maxima in OLR variability and meridional wind in these regions have a characteristic structure associated with the Westward‐moving Mixed Rossby‐Gravity wave. Much of the upper tropospheric motion into the winter hemisphere occurs in filaments of air from the summer equatorial region. These filaments can reach the winter sub‐tropical jet, leading to the strengthening of it and of the eddies on it, implying strong tropical‐extratropical interaction.
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| 7. |
- Klein, Alison P., et al.
(author)
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Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer
- 2018
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In: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 9
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Journal article (peer-reviewed)abstract
- In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 x 10(-8)). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PAN-DoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 (NOC2L, P = 8.36 x 10(-14)), rs2941471 at 8q21.11 (HNF4G, P = 6.60 x 10(-10)), rs4795218 at 17q12 (HNF1B, P = 1.32 x 10(-8)), and rs1517037 at 18q21.32 (GRP, P = 3.28 x 10(-8)). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene.
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| 8. |
- Rockström, Johan, et al.
(author)
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Climate change : The necessary, the possible and the desirable Earth League climate statement on the implications for climate policy from the 5th IPCC Assessment
- 2014
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In: Earth’s Future. - 2328-4277. ; 2:12, s. 606-611
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Journal article (peer-reviewed)abstract
- The development of human civilisations has occurred at a time of stable climate. This climate stability is now threatened by human activity. The rising global climate risk occurs at a decisive moment for world development. World nations are currently discussing a global development agenda consequent to the Millennium Development Goals (MDGs), which ends in 2015. It is increasingly possible to envisage a world where absolute poverty is largely eradicated within one generation and where ambitious goals on universal access and equal opportunities for dignified lives are adopted. These grand aspirations for a world population approaching or even exceeding nine billion in 2050 is threatened by substantial global environmental risks and by rising inequality. Research shows that development gains, in both rich and poor nations, can be undermined by social, economic and ecological problems caused by human-induced global environmental change. Climate risks, and associated changes in marine and terrestrial ecosystems that regulate the resilience of the climate system, are at the forefront of these global risks. We, as citizens with a strong engagement in Earth system science and socio-ecological dynamics, share the vision of a more equitable and prosperous future for the world, yet we also see threats to this future from shifts in climate and environmental processes. Without collaborative action now, our shared Earth system may not be able to sustainably support a large proportion of humanity in the decades ahead.
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| 9. |
- Roy, Sushmita, et al.
(author)
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Identification of functional elements and regulatory circuits by Drosophila modENCODE.
- 2010
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In: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 330:6012, s. 1787-1797
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Journal article (peer-reviewed)abstract
- To gain insight into how genomic information is translated into cellular and developmental programs, the Drosophila model organism Encyclopedia of DNA Elements (modENCODE) project is comprehensively mapping transcripts, histone modifications, chromosomal proteins, transcription factors, replication proteins and intermediates, and nucleosome properties across a developmental time course and in multiple cell lines. We have generated more than 700 data sets and discovered protein-coding, noncoding, RNA regulatory, replication, and chromatin elements, more than tripling the annotated portion of the Drosophila genome. Correlated activity patterns of these elements reveal a functional regulatory network, which predicts putative new functions for genes, reveals stage- and tissue-specific regulators, and enables gene-expression prediction. Our results provide a foundation for directed experimental and computational studies in Drosophila and related species and also a model for systematic data integration toward comprehensive genomic and functional annotation.
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| 10. |
- Zhang, Mingfeng, et al.
(author)
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Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21
- 2016
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In: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:41, s. 66328-66343
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Journal article (peer-reviewed)abstract
- Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10(-15)), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10(-9)) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10(-8)). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 (NR5A2), chr8q24.21 (MYC) and chr5p15.33 (CLPTM1L-TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal (n = 10) and tumor (n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10(-8)). This finding was validated in a second set of paired (n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10(-4)-2.0x10(-3)). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.
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