| 1. |
- Romagnoni, A, et al.
(author)
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Comparative performances of machine learning methods for classifying Crohn Disease patients using genome-wide genotyping data
- 2019
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 10351-
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Journal article (peer-reviewed)abstract
- Crohn Disease (CD) is a complex genetic disorder for which more than 140 genes have been identified using genome wide association studies (GWAS). However, the genetic architecture of the trait remains largely unknown. The recent development of machine learning (ML) approaches incited us to apply them to classify healthy and diseased people according to their genomic information. The Immunochip dataset containing 18,227 CD patients and 34,050 healthy controls enrolled and genotyped by the international Inflammatory Bowel Disease genetic consortium (IIBDGC) has been re-analyzed using a set of ML methods: penalized logistic regression (LR), gradient boosted trees (GBT) and artificial neural networks (NN). The main score used to compare the methods was the Area Under the ROC Curve (AUC) statistics. The impact of quality control (QC), imputing and coding methods on LR results showed that QC methods and imputation of missing genotypes may artificially increase the scores. At the opposite, neither the patient/control ratio nor marker preselection or coding strategies significantly affected the results. LR methods, including Lasso, Ridge and ElasticNet provided similar results with a maximum AUC of 0.80. GBT methods like XGBoost, LightGBM and CatBoost, together with dense NN with one or more hidden layers, provided similar AUC values, suggesting limited epistatic effects in the genetic architecture of the trait. ML methods detected near all the genetic variants previously identified by GWAS among the best predictors plus additional predictors with lower effects. The robustness and complementarity of the different methods are also studied. Compared to LR, non-linear models such as GBT or NN may provide robust complementary approaches to identify and classify genetic markers.
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| 2. |
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| 3. |
- Nolte, I. M., et al.
(author)
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Genetic loci associated with heart rate variability and their effects on cardiac disease risk
- 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
- Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74 < r(g) < -0.55) and blood pressure (-0.35 < r(g) < -0.20). These findings provide clinically relevant biological insight into heritable variation in vagal heart rhythm regulation, with a key role for genetic variants (GNG11, RGS6) that influence G-protein heterotrimer action in GIRK-channel induced pacemaker membrane hyperpolarization.
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| 4. |
- Clark, DW, et al.
(author)
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Associations of autozygosity with a broad range of human phenotypes
- 2019
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4957-
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Journal article (peer-reviewed)abstract
- In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.
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| 5. |
- Speliotes, Elizabeth K., et al.
(author)
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Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
- 2010
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 937-948
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Journal article (peer-reviewed)abstract
- Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
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| 6. |
- Momozawa, Y, et al.
(author)
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IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes
- 2018
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1, s. 2427-
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Journal article (peer-reviewed)abstract
- GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach.
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| 9. |
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| 10. |
- Lindblad-Toh, Kerstin, et al.
(author)
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Genome sequence, comparative analysis and haplotype structure of the domestic dog.
- 2005
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 438:7069, s. 803-19
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Journal article (peer-reviewed)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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| 11. |
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| 12. |
- Ayala, Ana I., et al.
(author)
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Analysis of summer heat budget of lakes under a changing climate across a geographic gradient
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Other publication (other academic/artistic)abstract
- Warming surface water temperature is the most direct consequence of climate change in lakes and therefore, predicting the heat exchange at the air-water interface is important to understand how atmospheric forcing will affect lake temperature and thermal structure. Here, we forced a one-dimensional hydrodynamic lake model with outputs from four different climate models under three future greenhouse gas emission scenarios from 1976 to 2099. To investigate the changes in summer (June to August or December to February in the northern or southern hemisphere, respectively) net surface heat flux and the individual flux components for 47 lakes with varying in size and geographic location were analysed. The results show that in the most extreme case (RCP 8.5) summer lake surface temperature is projected to increase by 4.72±0.70 °C by the end of the 21st century, due to increasing absorption of solar radiation (17.40±8.81 W m-2) and of long-wave radiation (33.01±5.44 W m-2). The increased lake surface temperature, also lead to higher heat losses to the atmosphere by outgoing long-wave radiation (27.54±4.07 W m-2) and by latent heat flux (25.10±7.37 W m-2), while a lower heat loss by sensible heat flux is projected (-3.20±1.94 W m-2). Altogether, the net heat balance and thus the accumulation of heat in the lakes over summer remains almost unchanged. However, a shift in the contributions of the individuals heat fluxes is projected, with the latent heat flux gaining relative importance.
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| 13. |
- Ayala, Ana I., et al.
(author)
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Climate Change Impacts on Surface Heat Fluxes in a Deep Monomictic Lake
- 2023
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In: Journal of Geophysical Research - Atmospheres. - 2169-897X .- 2169-8996. ; 128:11
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Journal article (peer-reviewed)abstract
- Turbulent and radiative energy exchanges between lakes and the atmosphere play an importantrole in determining the process of lake-mixing and stratification, including how lakes respond to climate andto climate change. Here we used a one-dimensional hydrodynamic lake model to assess seasonal impacts ofclimate change on individual surface heat flux components in Lough Feeagh, Ireland, a deep, monomictic lake.We drove the lake model with an ensemble of outputs from four climate models under three future greenhousegas scenarios from 1976 to 2099. In these experiments, the results showed significant increases in the radiativebudget that were largely counteracted by significant increases in the turbulent fluxes. The combined change inthe individual surface heat fluxes led to a change in the total surface heat flux that was small, but sufficient tolead to significant changes in the volume-weighted average lake temperature. The largest projected changes intotal surface heat fluxes were in spring and autumn. Both spring heating and autumnal cooling significantlydecreased under future climate conditions, while changes to total surface heat fluxes in winter and summerwere an order of magnitude lower. This led to counter-intuitive results that, in a warming world, there wouldbe less heat not more entering Lough Feeagh during the springtime, and little change in net heating over thesummer or winter compared to natural climate conditions, projected increases in the volume-weighted averagelake temperature were found to be largely due to reduced heat loss during autumn.
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| 14. |
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| 15. |
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| 16. |
- Cleynen, Isabelle, et al.
(author)
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Inherited determinants of Crohn's disease and ulcerative colitis phenotypes : a genetic association study
- 2016
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In: The Lancet. - New York, USA : Elsevier. - 0140-6736 .- 1474-547X. ; 387:10014, s. 156-167
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Journal article (peer-reviewed)abstract
- Background: Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases.Methods This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34,819 patients (19,713 with Crohn's disease, 14,683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype-phenotype associations across 156,154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile.Findings: After quality control, the primary analysis included 29,838 patients (16,902 with Crohn's disease, 12,597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for inflammatory bowel disease showed strong association with disease subphenotype (p=1·65 × 10(-78)), even after exclusion of NOD2, MHC, and 3p21 (p=9·23 × 10(-18)). Predictive models based on the genetic risk score strongly distinguished colonic from ileal Crohn's disease. Our genetic risk score could also identify a small number of patients with discrepant genetic risk profiles who were significantly more likely to have a revised diagnosis after follow-up (p=6·8 × 10(-4)).Interpretation: Our data support a continuum of disorders within inflammatory bowel disease, much better explained by three groups (ileal Crohn's disease, colonic Crohn's disease, and ulcerative colitis) than by Crohn's disease and ulcerative colitis as currently defined. Disease location is an intrinsic aspect of a patient's disease, in part genetically determined, and the major driver to changes in disease behaviour over time.Funding: International Inflammatory Bowel Disease Genetics Consortium members funding sources (see Acknowledgments for full list).
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| 17. |
- Goyette, Philippe, et al.
(author)
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High-density mapping of the MHC identifies a shared role for HLA-DRB1*01 : 03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis
- 2015
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In: Nature Genetics. - New York, USA : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 47:2, s. 172-179
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Journal article (peer-reviewed)abstract
- Genome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn's disease and ulcerative colitis have shown strong evidence of association to the major histocompatibility complex (MHC). This region encodes a large number of immunological candidates, including the antigen-presenting classical human leukocyte antigen (HLA) molecules. Studies in IBD have indicated that multiple independent associations exist at HLA and non-HLA genes, but they have lacked the statistical power to define the architecture of association and causal alleles. To address this, we performed high-density SNP typing of the MHC in >32,000 individuals with IBD, implicating multiple HLA alleles, with a primary role for HLA-DRB1*01:03 in both Crohn's disease and ulcerative colitis. Noteworthy differences were observed between these diseases, including a predominant role for class II HLA variants and heterozygous advantage observed in ulcerative colitis, suggesting an important role of the adaptive immune response in the colonic environment in the pathogenesis of IBD.
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| 18. |
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| 19. |
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| 20. |
- McGovern, Dermot P B, et al.
(author)
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Genome-wide association identifies multiple ulcerative colitis susceptibility loci
- 2010
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:4, s. 332-337
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Journal article (peer-reviewed)abstract
- Ulcerative colitis is a chronic, relapsing inflammatory condition of the gastrointestinal tract with a complex genetic and environmental etiology. In an effort to identify genetic variation underlying ulcerative colitis risk, we present two distinct genome-wide association studies of ulcerative colitis and their joint analysis with a previously published scan, comprising, in aggregate, 2,693 individuals with ulcerative colitis and 6,791 control subjects. Fifty-nine SNPs from 14 independent loci attained an association significance of P < 10(-5). Seven of these loci exceeded genome-wide significance (P < 5 x 10(-8)). After testing an independent cohort of 2,009 cases of ulcerative colitis and 1,580 controls, we identified 13 loci that were significantly associated with ulcerative colitis (P < 5 x 10(-8)), including the immunoglobulin receptor gene FCGR2A, 5p15, 2p16 and ORMDL3 (orosomucoid1-like 3). We confirmed association with 14 previously identified ulcerative colitis susceptibility loci, and an analysis of acknowledged Crohn's disease loci showed that roughly half of the known Crohn's disease associations are shared with ulcerative colitis. These data implicate approximately 30 loci in ulcerative colitis, thereby providing insight into disease pathogenesis.
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| 21. |
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| 22. |
- Mesman, Jorrit P., 1993-
(author)
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Assessing future effects on lake ecosystem resilience using data analysis and dynamic modelling : Modelling the effects of extreme weather events and climate warming on lakes
- 2021
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Doctoral thesis (other academic/artistic)abstract
- Extreme weather events can have short-term and long-term effects on lake thermal structure, nutrient dynamics, and community composition. Moreover, changes in lake variables induced by global climate change may influence the response and recovery of lake ecosystems to extreme weather events. The linkage between extreme weather and lakes includes interactions between physics and biology, and long-term and short-term dynamics, which are not yet well understood. Process-based modelling is used in this thesis to further explore this topic, and to assess how lake responses to extreme weather events may change under the influence of climate warming.Lake-internal feedback mechanisms were shown to potentially cause sudden shifts in climate-induced transitions in lake mixing regimes, with a role for extreme weather events to induce such shifts. Additionally, one-dimensional physical lake models performed well in reproducing trends in lake variables during storms and heatwaves in a study covering multiple locations and models. However, extreme weather events still presented periods of increased model uncertainty, which should be taken into account. A software package was developed to promote the use of ensemble lake modelling, which is one way to include uncertainty in model forecasting efforts. This could be particularly helpful in periods of extreme weather. With tools and theory now in place, a coupled physical-biogeochemical model was then used to assess what are the most important drivers of how lake phytoplankton responds to storms, and how this response might change with climate warming. Storm intensity, thermal structure, nutrients, and light all affected the phytoplankton concentration after storms. Moderate wind speeds had increasing effects compared to high wind speeds, but a sufficiently deep mixed layer reduced the response to wind strongly. Higher nutrients and light promoted increasing effects of wind, and higher temperatures promoted decreasing effects. The response of phytoplankton to storms did not change markedly between present-day and future-climate scenarios.This thesis furthers our understanding of the processes involved in extreme events acting on lakes. A more complete understanding is necessary to develop more reliable models and anticipate future conditions. Furthermore, modelling was shown to be a viable approach to study these events and validation data and tools were provided to increase the reliability of this method. In these times of increasing environmental pressures and changing extreme weather patterns, more insight into future effects of extreme events is much needed.
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| 23. |
- Mesman, Jorrit P., 1993-, et al.
(author)
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Drivers of phytoplankton responses to summer wind events in a stratified lake : a modelling study
- 2022
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In: Limnology and Oceanography. - : John Wiley & Sons. - 0024-3590 .- 1939-5590. ; 67:4, s. 856-873
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Journal article (peer-reviewed)abstract
- Extreme wind events affect lake phytoplankton amongst others by deepening the mixed layer and increasing internal nutrient loading. Both increases and decreases of phytoplankton biomass after storms have been observed, but the precise mechanisms driving these responses remain poorly understood or quantified. In this study, we coupled a one-dimensional physical model to a biogeochemical model to investigate the factors regulating short-term phytoplankton responses to summer storms, now and under expected warmer future conditions. We simulated physical, chemical and biological dynamics in Lake Erken, Sweden, and found that wind storms could increase or decrease the phytoplankton concentration one week after the storm, depending on antecedent lake physical and chemical conditions. Storms had little effect on phytoplankton biomass if the mixed layer was deep prior to storm exposure. Higher incoming shortwave radiation and hypolimnetic nutrient concentration boosted growth, whereas higher surface water temperatures decreased phytoplankton concentration after storms. Medium-intensity wind speeds resulted in more phytoplankton biomass after storms than high-intensity wind. Simulations under a future climate scenario did not show marked differences in the way wind affects phytoplankton growth following storms. Our study shows that storm impacts on lake phytoplankton are complex and likely to vary as a function of local environmental conditions.
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| 24. |
- Mesman, Jorrit P., 1993-, et al.
(author)
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Performance of one-dimensional hydrodynamic lake models during short-term extreme weather events
- 2020
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In: Environmental Modelling & Software. - : Elsevier BV. - 1364-8152 .- 1873-6726. ; 133
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Journal article (peer-reviewed)abstract
- Numerical lake models are useful tools to study hydrodynamics in lakes, and are increasingly applied to extreme weather events. However, little is known about the accuracy of such models during these short-term events. We used high-frequency data from three lakes to test the performance of three one-dimensional (1D) hydrodynamic models (Simstrat, GOTM, GLM) during storms and heatwaves. Models reproduced the overall direction and magnitude of changes during the extreme events, with accurate timing and little bias. Changes in volume-averaged and surface temperatures and Schmidt stability were simulated more accurately than changes in bottom temperature, maximum buoyancy frequency, or mixed layer depth. However, in most cases the model error was higher (30-100%) during extreme events compared to reference periods. As a consequence, while 1D lake models can be used to study effects of extreme weather events, the increased uncertainty in the simulations should be taken into account when interpreting results.
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| 25. |
- Mesman, Jorrit P., 1993-, et al.
(author)
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The role of internal feedbacks in shifting deep lake mixing regimes under a warming climate
- 2021
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In: Freshwater Biology. - : John Wiley & Sons. - 0046-5070 .- 1365-2427. ; 66:6, s. 1021-1035
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Research review (peer-reviewed)abstract
- Climate warming is causing changes in the physics of deep lakes, such as longer summer stratification, increased water column stability, reduced ice cover, and a shallower depth of winter overturns. An ultimate consequence of warming would be a transition to a different mixing regime. Here we investigate the role of physical, chemical, and biological feedback mechanisms that unfold during a shift in mixing regime, and whether these feedbacks could prompt and stabilise the new regime. Although climate, interannual temperature variation, and lake morphometry are the main determinants of a mixing regime, when climate change causes shifts in mixing regime, internal feedback mechanisms may gain in importance and modify lake ecosystem functioning.We review the role of these feedbacks in three mixing regime shifts: from polymictic to seasonally stratified, from dimictic to monomictic, and from holomictic to oligomictic or meromictic.Polymictic lakes of intermediate depth (c. 3–10 m mean depth) could experience seasonal stratification if a stratification event triggers phytoplankton blooms or dissolved organic matter release, reducing transparency and therefore further heating the surface layer. However, this feedback is only likely to have influence in small and clear lakes, it would be easily disturbed by weather conditions, and the resulting stratified state does not remain stable in the long term, as stratification is lost in winter.The ice-albedo feedback might cause an accelerated shift from ice-covered (dimictic) to ice-free (monomictic) winters in sufficiently deep (mean depth 50 m or more) lakes, where temperature memory is carried over from one winter to the next. Nevertheless, there is an ongoing debate into whether this process can persist during natural weather variations and overcome self-stabilising mechanisms such as thermal insulation by snow. The majority of studies suggest that a gradual transition from dimictic to monomictic is more likely than an abrupt transition.A shift from a holomictic to a meromictic regime can occur if anoxia is triggered by incomplete mixing and an increase in deep-water density—through the accumulation of solutes—exceeds a density decrease by hypolimnetic warming. A shift to meromixis would strongly alter the biology of a lake and might be difficult to reverse. If solutes accumulate only minimally in the hypolimnion, an oligomictic regime is formed, in which years with complete and incomplete mixing alternate.Understanding the importance of feedback mechanisms and the role of biogeochemistry when lakes shift in mixing regime could lead to a better understanding of how climate change affects lake ecosystems.
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