37 research outputs found
Organised Genome Dynamics in the Escherichia coli Species Results in Highly Diverse Adaptive Paths
The Escherichia coli species represents one of the best-studied model organisms, but also encompasses a variety of commensal and pathogenic strains that diversify by high rates of genetic change. We uniformly (re-) annotated the genomes of 20 commensal and pathogenic E. coli strains and one strain of E. fergusonii (the closest E. coli related species), including seven that we sequenced to completion. Within the ∼18,000 families of orthologous genes, we found ∼2,000 common to all strains. Although recombination rates are much higher than mutation rates, we show, both theoretically and using phylogenetic inference, that this does not obscure the phylogenetic signal, which places the B2 phylogenetic group and one group D strain at the basal position. Based on this phylogeny, we inferred past evolutionary events of gain and loss of genes, identifying functional classes under opposite selection pressures. We found an important adaptive role for metabolism diversification within group B2 and Shigella strains, but identified few or no extraintestinal virulence-specific genes, which could render difficult the development of a vaccine against extraintestinal infections. Genome flux in E. coli is confined to a small number of conserved positions in the chromosome, which most often are not associated with integrases or tRNA genes. Core genes flanking some of these regions show higher rates of recombination, suggesting that a gene, once acquired by a strain, spreads within the species by homologous recombination at the flanking genes. Finally, the genome's long-scale structure of recombination indicates lower recombination rates, but not higher mutation rates, at the terminus of replication. The ensuing effect of background selection and biased gene conversion may thus explain why this region is A+T-rich and shows high sequence divergence but low sequence polymorphism. Overall, despite a very high gene flow, genes co-exist in an organised genome
The Influence of Number and Timing of Pregnancies on Breast Cancer Risk for Women With BRCA1 or BRCA2 Mutations
International audienceBACKGROUND:Full-term pregnancy (FTP) is associated with a reduced breast cancer (BC) risk over time, but women are at increased BC risk in the immediate years following an FTP. No large prospective studies, however, have examined whether the number and timing of pregnancies are associated with BC risk for BRCA1 and BRCA2 mutation carriers.METHODS:Using weighted and time-varying Cox proportional hazards models, we investigated whether reproductive events are associated with BC risk for mutation carriers using a retrospective cohort (5707 BRCA1 and 3525 BRCA2 mutation carriers) and a prospective cohort (2276 BRCA1 and 1610 BRCA2 mutation carriers), separately for each cohort and the combined prospective and retrospective cohort.RESULTS:For BRCA1 mutation carriers, there was no overall association with parity compared with nulliparity (combined hazard ratio [HRc] = 0.99, 95% confidence interval [CI] = 0.83 to 1.18). Relative to being uniparous, an increased number of FTPs was associated with decreased BC risk (HRc = 0.79, 95% CI = 0.69 to 0.91; HRc = 0.70, 95% CI = 0.59 to 0.82; HRc = 0.50, 95% CI = 0.40 to 0.63, for 2, 3, and ≥4 FTPs, respectively, P trend < .0001) and increasing duration of breastfeeding was associated with decreased BC risk (combined cohort P trend = .0003). Relative to being nulliparous, uniparous BRCA1 mutation carriers were at increased BC risk in the prospective analysis (prospective hazard ration [HRp] = 1.69, 95% CI = 1.09 to 2.62). For BRCA2 mutation carriers, being parous was associated with a 30% increase in BC risk (HRc = 1.33, 95% CI = 1.05 to 1.69), and there was no apparent decrease in risk associated with multiparity except for having at least 4 FTPs vs. 1 FTP (HRc = 0.72, 95% CI = 0.54 to 0.98).CONCLUSIONS:These findings suggest differential associations with parity between BRCA1 and BRCA2 mutation carriers with higher risk for uniparous BRCA1 carriers and parous BRCA2 carriers
Identification of a BRCA2-Specific modifier locus at 6p24 related to breast cancer risk
Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer
Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk
BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat
An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers
Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe
The Influence of Number and Timing of Pregnancies on Breast Cancer Risk for Women With BRCA1 or BRCA2 Mutations
Background: Full-term pregnancy (FTP) is associated with a reduced breast cancer (BC) risk over time, but women are at
increased BC risk in the immediate years following an FTP. No large prospective studies, however, have examined whether
the number and timing of pregnancies are associated with BC risk for BRCA1 and BRCA2 mutation carriers.
Methods: Using weighted and time-varying Cox proportional hazards models, we investigated whether reproductive events
are associated with BC risk for mutation carriers using a retrospective cohort (5707 BRCA1 and 3525 BRCA2 mutation carriers)
and a prospective cohort (2276 BRCA1 and 1610 BRCA2 mutation carriers), separately for each cohort and the combined prospective and retrospective cohort.
Results: For BRCA1 mutation carriers, there was no overall association with parity compared with nulliparity (combined
hazard ratio [HRc] ¼ 0.99, 95% confidence interval [CI] ¼ 0.83 to 1.18). Relative to being uniparous, an increased number of FTPs was associated with decreased BC risk (HRc¼ 0.79, 95% CI ¼ 0.69 to 0.91; HRc¼ 0.70, 95% CI ¼ 0.59 to 0.82; HRc¼ 0.50, 95%
CI ¼ 0.40 to 0.63, for 2, 3, and 4 FTPs, respectively, Ptrend < .0001) and increasing duration of breastfeeding was associated
with decreased BC risk (combined cohort Ptrend ¼ .0003). Relative to being nulliparous, uniparous BRCA1 mutation carriers
were at increased BC risk in the prospective analysis (prospective hazard ration [HRp] ¼ 1.69, 95% CI ¼ 1.09 to 2.62). For BRCA2
mutation carriers, being parous was associated with a 30% increase in BC risk (HRc ¼ 1.33, 95% CI ¼ 1.05 to 1.69), and there
was no apparent decrease in risk associated with multiparity except for having at least 4 FTPs vs. 1 FTP (HRc¼ 0.72, 95%
CI ¼ 0.54 to 0.98).
Conclusions: These findings suggest differential associations with parity between BRCA1 and BRCA2 mutation carriers with
higher risk for uniparous BRCA1 carriers and parous BRCA2 carriers
Taking into account protective works in land-use planning for mountain torrential floods: state of the art of the present French practices
International audienceIn 1995, a law stated a common regulatory natural risk zoning for French municipalities through a land-use planning procedure called Risk Prevention Plan (PPR). In mountain valleys and especially within torrential watersheds, considering protective structures in those plans is an actual concern. Those protections do have an effect on phenomena and modify hazard and risk levels. This paper gives an overview on how torrential protective works are taken into account in present risk prevention plans. To carry out this study, 53 recent risk prevention plans over 11 French mountain departments were selected and analyzed through a common analysis grid. Torrential protection works are taken into account in more than one third of analyzed plans. Protections mostly considered are dikes, bank protections, check-dams and sediment traps. Modalities of integration of these structures vary from one plan to another, influencing both hazard and regulatory zoning. Results also show a wide range of practices between departments and even inside them. Conclusions brought out enhance knowledge about actual practices which were not sufficiently known so far. Findings and new additional recommendations will be included in a future PPR methodological guide exclusively suited for torrential context, which is currently still missing
Taking into account protective works in land-use planning for mountain torrential floods: state of the art of the present French practices
International audienceIn 1995, a law stated a common regulatory natural risk zoning for French municipalities through a land-use planning procedure called Risk Prevention Plan (PPR). In mountain valleys and especially within torrential watersheds, considering protective structures in those plans is an actual concern. Those protections do have an effect on phenomena and modify hazard and risk levels. This paper gives an overview on how torrential protective works are taken into account in present risk prevention plans. To carry out this study, 53 recent risk prevention plans over 11 French mountain departments were selected and analyzed through a common analysis grid. Torrential protection works are taken into account in more than one third of analyzed plans. Protections mostly considered are dikes, bank protections, check-dams and sediment traps. Modalities of integration of these structures vary from one plan to another, influencing both hazard and regulatory zoning. Results also show a wide range of practices between departments and even inside them. Conclusions brought out enhance knowledge about actual practices which were not sufficiently known so far. Findings and new additional recommendations will be included in a future PPR methodological guide exclusively suited for torrential context, which is currently still missing
Structure of a d(TGGGGT) quadruplex crystallized in the presence of Li(+) ions.
International audienc
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RadCalNet: A Radiometric Calibration Network for Earth Observing Imagers Operating in the Visible to Shortwave Infrared Spectral Range
Vicarious calibration approaches using in situ measurements saw first use in the early 1980s and have since improved to keep pace with the evolution of the radiometric requirements of the sensors that are being calibrated. The advantage of in situ measurements for vicarious calibration is that they can be carried out with traceable and quantifiable accuracy, making them ideal for interconsistency studies of on-orbit sensors. The recent development of automated sites to collect the in situ data has led to an increase in the available number of datasets for sensor calibration. The current work describes the Radiometric Calibration Network (RadCalNet) that is an effort to provide automated surface and atmosphere in situ data as part of a network including multiple sites for the purpose of optical imager radiometric calibration in the visible to shortwave infrared spectral range. The key goals of RadCalNet are to standardize protocols for collecting data, process to top-of-atmosphere reflectance, and provide uncertainty budgets for automated sites traceable to the international system of units. RadCalNet is the result of efforts by the RadCalNet Working Group under the umbrella of the Committee on Earth Observation Satellites (CEOS) Working Group on Calibration and Validation (WGCV) and the Infrared Visible Optical Sensors (IVOS). Four radiometric calibration instrumented sites located in the USA, France, China, and Namibia are presented here that were used as initial sites for prototyping and demonstrating RadCalNet. All four sites rely on collection of data for assessing the surface reflectance as well as atmospheric data over that site. The data are converted to top-of-atmosphere reflectance within RadCalNet and provided through a web portal to allow users to either radiometrically calibrate or verify the calibration of their sensors of interest. Top-of-atmosphere reflectance data with associated uncertainties are available at 10 nm intervals over the 400 nm to 1000 nm spectral range at 30 min intervals for a nadir-viewing geometry. An example is shown demonstrating how top-of-atmosphere data from RadCalNet can be used to determine the interconsistency between two sensors.European Space Agency Technology and Research Programme [4000110704]; European Space Agency Earthnet Programme [CCN5 4000110704]; Metrology for Earth Observation and Climate project (MetEOC-2) within the EMRP programme [ENV55 532]; EURAMET; European Union's FP7 programme; European Union's H2020 programme; European Space Agency Technology and Research Programme through the ACTION project; UK Government's Department for Business, Energy and Industrial Strategy (BEIS) through the UK's National Measurement System programmes; Bureau of International Co-operation Chinese Academy of SciencesChinese Academy of Sciences [181811KYSB20160040]; NASANational Aeronautics & Space Administration (NASA) [NNX14AE20G, NNX15AM86G, NNX16AL25G]; USGSUnited States Geological Survey [G14AC00371]; MetEOC-3 project under the EMPIR programme [16ENV03]Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]