This thesis pioneers diatom molecular identification and quantification through genome-scale methods, with four key aims: (i) reviewing DNA/RNA sequencing methods in aquatic biomonitoring to... Show moreThis thesis pioneers diatom molecular identification and quantification through genome-scale methods, with four key aims: (i) reviewing DNA/RNA sequencing methods in aquatic biomonitoring to highlight their strengths and limitations; (ii) unraveling the evolutionary history of Nitzschia palea and investigating species delimitation within the species complex; (iii) identifying silica genes in N. palea for insights into ecology and evolution; and (iv) assessing a genome-scale quantification method for diatom biomonitoring to improve accuracy and scalability in estimating abundances. The review (Chapter 2) emphasizes disparities between molecular and morphology-based approaches and introduces the challenges in accurately estimating species abundances. Chapter 3 explores N. palea's evolutionary history using transcriptome data and reveals reticulate evolutionary patterns resulting in a putative hybrid between populations with different morphological characteristics. Chapter 4 pinpoints silica genes in N. palea and reveals variations among different populations that may lead to differences in silica metabolism. Chapter 5 introduces a genome-scale quantification approach that provides a promising alternative for molecular diatom biomonitoring due to its improved taxonomic resolution and quantification accuracy. In summary, this thesis underscores that genome-scale methods' have a critical role in diatom identification and quantification, and in advancing our understanding of microalgal taxonomy, ecology, and evolution. Show less
From an evolutionary perspective, stress is an adaptive system that is necessary togenerate appropriate responses to stochastic and unpredictable events, and copeaccordingly with the environment.... Show moreFrom an evolutionary perspective, stress is an adaptive system that is necessary togenerate appropriate responses to stochastic and unpredictable events, and copeaccordingly with the environment. The physiological response to stress has beenremarkably conserved in vertebrate evolution. However, the threats to ourinternal “equilibrium” have changed between our ancestral environments and ourcurrent modern societies, and the demands for survival have evolved. Theglucocorticoid receptor (GR) is a timeless component of stress adaptation, as it is atthe intersection between the environmental stressors (i.e., physical, or psychosocial)and the genome. Therefore, the GR represents a valuable therapeutic target instress- and glucocorticoid-related disorders. This thesis provides new insightsinto the molecular mechanisms underlying GR signaling in metabolic diseases andbrain function and highlights the promise and importance of selectivity in novel GRtargeting treatments. Show less
Metabolomics, proteomics, and genomics analyses provide profound insight into human biology and disease pathophysiology. In this thesis, we explored the methodological challenges facing these OMICs... Show moreMetabolomics, proteomics, and genomics analyses provide profound insight into human biology and disease pathophysiology. In this thesis, we explored the methodological challenges facing these OMICs technologies and illustrated their applications in epidemiological studies. In part one, we focused on some of the methodological challenges facing OMICs research. These challenges included handling missing data in metabolomics, measurement agreement between high throughput proteomic measurements with standard clinical measurements, and challenges in developing prediction models using metabolomic data. The second part of this thesis addressed various epidemiological research questions by utilizing genomic data and metabolomics measurements (Metabolon and Nightingale platforms) and using advanced data analysis methods. These studies provided important insights into the associations between metabolites and hepatic triglyceride content, the associations of between the size of cytosine-adenine-guanine nucleotide repeats in the huntingtin gene with metabolomic profile, and the associations of the man-made per- and polyfluoroalkyl substances (PFAS) with metabolite levels. Show less
Bertola, L.D.; Vermaat, M.; Lesilau, F.; Chege, M.; Tumenta, P.N.; Sogbohossou, E.A.; ... ; Vrieling, K. 2022
Background Previous phylogeographic studies of the lion (Panthera leo) have improved our insight into the distribution of genetic variation, as well as a revised taxonomy which now recognizes a... Show moreBackground Previous phylogeographic studies of the lion (Panthera leo) have improved our insight into the distribution of genetic variation, as well as a revised taxonomy which now recognizes a northern (Panthera leo leo) and a southern (Panthera leo melanochaita) subspecies. However, existing whole range phylogeographic studies on lions either consist of very limited numbers of samples, or are focused on mitochondrial DNA and/or a limited set of microsatellites. The geographic extent of genetic lineages and their phylogenetic relationships remain uncertain, clouded by massive sampling gaps, sex-biased dispersal and incomplete lineage sorting. Results In this study we present results of low depth whole genome sequencing and subsequent variant calling in ten lions sampled throughout the geographic range, resulting in the discovery of >150,000 Single Nucleotide Polymorphisms (SNPs). Phylogenetic analyses revealed the same basal split between northern and southern populations, as well as four population clusters on a more local scale. Further, we designed a SNP panel, including 125 autosomal and 14 mitochondrial SNPs, which was tested on >200 lions from across their range. Results allow us to assign individuals to one of these four major clades (West & Central Africa, India, East Africa, or Southern Africa) and delineate these clades in more detail. Conclusions The results presented here, particularly the validated SNP panel, have important applications, not only for studying populations on a local geographic scale, but also for tracing samples of unknown origin for forensic purposes, and for guiding conservation management of ex situ populations. Thus, these genomic resources not only contribute to our understanding of the evolutionary history of the lion, but may also play a crucial role in conservation efforts aimed at protecting the species in its full diversity. Show less
DNA carries various forms of information. Out of these forms of information the most well-known is classical genetic information. Throughout this dissertation we discuss what is often referred to... Show moreDNA carries various forms of information. Out of these forms of information the most well-known is classical genetic information. Throughout this dissertation we discuss what is often referred to as the second layer of information on DNA: DNA mechanics. A sequence consisting of only A’s and T’s will bend differently from a sequence of G’s and C’s. An important consequence of this mechanical layer of information is the positioning of nucleosomes. Nucleosomes consist of 147 base pairs of DNA wrapped around a protein core, like a string around a spool. By either allowing or restricting access to a binding site, a nucleosome may serve as an on/off switch, of which the location is extremely important. A third layer of information on DNA is translation speed. Translation speed refers to the rate at which a protein is created, and it depends on the codons used in a genetic sequence. The research in this thesis investigates how these layers of information are multiplexed. It uses multiple novel approaches, one of them being the use of weighted graphs consisting of all possible DNA sequences to find the very best and very worst nucleosome-attracting sequences. Show less
Cardiovascular disease and diabetes are one of the leading causes of death worldwide. Multiple genetic and non-genetic factors play a role in this process. This dissertation aims to study the... Show moreCardiovascular disease and diabetes are one of the leading causes of death worldwide. Multiple genetic and non-genetic factors play a role in this process. This dissertation aims to study the interplay between genetic factors and lifestyle factors (eg sleep, nutrition, physical activity) with diseases such as cardiovascular disease and risk factors for cardiovascular disease (diabetes). For example, 12 blood biomarkers associated with insulin resistance have been identified, 5 of which are specifically much higher in subjects with diabetes. In addition, it appeared that a short sleep duration and poor sleep quality are associated with poorer lipids in the blood (eg cholesterol and LDL) and more insulin resistance. With regard to sleep, 59 new genetic variants have also been identified with regard to blood lipids (HDL, LDL, triglycerides). In addition, the results indicate that a better lifestyle can also help reduce the development of new cardiovascular diseases in people with an increased genetic risk. This is particularly interesting to prevent diseases in persons at high risk. All in all, this thesis has provided new insights into the various factors that are potentially important in the development of cardiovascular disease and diabetes. Show less
In this thesis we reflect on the effects differential DNA binding of the estrogen receptor α (ERα) can have on the behavior of breast cancer and which factors can contribute to this. ERα is a... Show moreIn this thesis we reflect on the effects differential DNA binding of the estrogen receptor α (ERα) can have on the behavior of breast cancer and which factors can contribute to this. ERα is a transcription factor than can drive tumor cell proliferation and approximately 70% off all breast tumors is thought to be dependent on the activity of this hormone-mediated transcription factor. After stimulation of ERα a wild variety of co-factors are recruited, leading to the assembly of a transcriptional complex. Although there are multiple ways of targeting the action of ERα and thereby inhibiting tumor growth, still a significant proportion of patients develop a recurrence. Cross-resistance between the different endocrine therapy options can occur, but a proportion of patients that relapse on one type of therapy can still benefit from a different treatment modality, illustrating the existence of multiple resistance mechanisms which can be treatment selective. A better understanding of ERα-biology and the development of endocrine therapy resistance, can lead the way to the discovery of novel biomarkers and potential drug targets, that can further increase patient survival. Show less
In dit proefschrift worden de moleculaire mechanismen behandeld die onderliggend zijn aan artrose. Specifiek wordt genoomwijd onderzocht welke genen anders tot expressie komen in aangedaan... Show moreIn dit proefschrift worden de moleculaire mechanismen behandeld die onderliggend zijn aan artrose. Specifiek wordt genoomwijd onderzocht welke genen anders tot expressie komen in aangedaan vergeleken met gezond kraakbeen van artrose patienten. Dit in de context van epigenetische regulatie van gen expressie, specifiek door DNA methylatie in het licht van de lokale genetische context in de vorm van puntmutaties. Show less
The four possible segments A, T, C and G that link together to form DNA molecules, and with their ordering encode genetic information, are not only different in name, but also in their physical and... Show moreThe four possible segments A, T, C and G that link together to form DNA molecules, and with their ordering encode genetic information, are not only different in name, but also in their physical and chemical properties. The result is that DNA molecules with different sequences have different physical behavior. For instance, one sequence may lead to a very flexible DNA molecule, another to a very stiff one. A DNA molecule with a given sequence may be straight, or intrinsically curved. This leads to an interplay between the information stored in a DNA molecule on one hand, and the physical properties of that molecule on the other. This is of great importance in our cells, where lengths of DNA far longer than the size of the cells that contain them need to be significantly folded up. The research presented in this thesis looks at how we can model this interplay, what its effects can be, and whether nature has made use of it to encode mechanical signals into real genomes. Show less
The explosive increase in infections by pathogens is a major problem in the clinic today. The theme of this thesis was to find novel antibiotics from actinomycetes. Next-generation... Show more The explosive increase in infections by pathogens is a major problem in the clinic today. The theme of this thesis was to find novel antibiotics from actinomycetes. Next-generation sequencing revealed that the biosynthetic potential of actinomycetes had been grossly underestimated. In this thesis, different antibiotics-eliciting strategies, including microbial cocultivation, streptomycin-resistant mutation, overexpression of pathway-specific activator, variation of culture conditions, were utilized to enforce fluctuations in the production of bioactive compounds in actinomycetes, after which, NMR-based metabolic profiling was used to facilitate uncovering those elicited molecules. This pipeline allowed the discovery of new antibiotics involving various chemical skeletons, such as 7-prenylisatin, methoxylated isocoumarins, endophenazines, and C-glycosylpyranonaphthoquinones. On the other hand, genome-mining methodology enabled the discovery of a group of endophenasides and leucanicidin in Kitasatospora sp. MBT66, whereby the rhamnosylation of both scaffold are executed by a same promiscuous glycosyltransferase. Last but not least, a novel antibiotic termed lugdunomycin with unprecedented chemical scaffold, as well as a number of new angucycline-type antibiotics, were characterized from Streptomyces sp. QL37. The biosynthetic pathway of lugdunomycin was deciphered by genetic knockout and OSMAC (One Strain MAny Compound) strategy. In summary, this thesis explores an interface of genomics and metabolomics to accelerate new antibiotics discovery. Show less
This thesis spans several years of work dedicated to understanding fish genomes. In the first chapter it describes the genome of the first fish for which the entire genome was sequenced through a... Show moreThis thesis spans several years of work dedicated to understanding fish genomes. In the first chapter it describes the genome of the first fish for which the entire genome was sequenced through a large-scale international project, Fugu rubripes. the pufferfish. In particular, it highlights how this fish has a genome that contains as many genes as the human genome, although it is ten times smaller. It also shows that the majority of genes that are found in the human genome can be found in this fish genome as well. In the second chapter we compared fish genomes to the human genome to find regions that have been preserved during evolution and which are therefore likely to have a function, even though they are not genes. We showed that indeed they are functional, and they help to regulate other genes. Knowing all the genes in the genome we could then interrogate how they are expressed, i.e. if they are switched __on__ or __off__ and in particular in chapter 4 we looked at how a specific gene is in charge of gradually switching off genes that are inherited from the mother in a newborn fish embryo. Finally in the last chapter since genome sequencing is now becoming much cheaper and simpler to achieve we set out to map the genome of the common carp and we discuss the best approaches and strategies to obtain a good genome sequence for this species. The common carp is a candidate model system for high-troughput screening. Show less
In this thesis, a configurable generalisation of some well-known distance measures is introduced. Parameters are given to use this metric in the area of law enforcement, but also molecular biology.... Show moreIn this thesis, a configurable generalisation of some well-known distance measures is introduced. Parameters are given to use this metric in the area of law enforcement, but also molecular biology. With a valid distance measure, it is possible to analyse data by using a dimension reduction technique. One of these techniques is analysed and extended. Show less
On 17-18 March, 2007, the Center for Ethics of Science and Technology (CEST), Chulalongkorn University, Thailand, (in collaboration with the European Academy of Environment and Economy, Germany),... Show moreOn 17-18 March, 2007, the Center for Ethics of Science and Technology (CEST), Chulalongkorn University, Thailand, (in collaboration with the European Academy of Environment and Economy, Germany), organised an international workshop on “Technology and Culture: Genetics and its Ethical and Social Implications in Asia and Europe.” The workshop was part of the Eighth Asian Bioethics Conference, and also part of the Asia-Europe Workshop Series 2006/2007 organised by the Asia Europe Foundation and the European Alliance for Asian Studies. Show less
