The narrow-headed vole, collared lemming and common vole were the most abundant small mammal species across the Eurasian Late Pleistocene steppe-tundra environment. Previous ancient DNA studies of... Show moreThe narrow-headed vole, collared lemming and common vole were the most abundant small mammal species across the Eurasian Late Pleistocene steppe-tundra environment. Previous ancient DNA studies of the collared lemming and common vole have revealed dynamic population histories shaped by climatic fluctuations. To investigate the extent to which species with similar adaptations share common evolutionary histories, we generated a dataset comprised the mitochondrial genomes of 139 ancient and 6 modern narrow-headed voles from several sites across Europe and northwestern Asia covering approximately the last 100 thousand years (kyr). We inferred Bayesian time-aware phylogenies using 11 radiocarbon-dated samples to calibrate the molecular clock. Divergence of the main mtDNA lineages across the three species occurred during marine isotope stages (MIS) 7 and MIS 5, suggesting a common response of species adapted to open habitat during interglacials. We identified several time-structured mtDNA lineages in European narrow-headed vole, suggesting lineage turnover. The timing of some of these turnovers was synchronous across the three species, allowing us to identify the main drivers of the Late Pleistocene dynamics of steppe- and cold-adapted species. Show less
Luo, J.; Noordam, R.; Jukema, J.W.; Dijk, K.W. van; Hagg, S.; Grassmann, F.; ... ; Heemst, D. van 2022
Aim: Mitochondrial DNA dysfunction has been implicated in the pathogenesis of cardiovascular diseases. We aimed to investigate the associations between leukocyte mitochondrial DNA (mtDNA) abundance... Show moreAim: Mitochondrial DNA dysfunction has been implicated in the pathogenesis of cardiovascular diseases. We aimed to investigate the associations between leukocyte mitochondrial DNA (mtDNA) abundance, as a proxy of mitochondrial function, and coronary artery disease (CAD) and heart failure (HF) in a cohort study and approximate the causal nature of these relationships using Mendelian randomization (MR) in genetic studies. Methods and results: Multivariable-adjusted Cox regression analyses were conducted in 273 619 unrelated participants of European ancestry from the UK Biobank (UKB). For genetic studies, we first performed MR analyses with individual-level data from the UKB using a weighted genetic risk score (GRS); two-sample MR analyses were subsequently performed using summary-level data from the publicly available three consortia/biobank for CAD and two for HF. MR analyses were performed per database separately and results were subsequently meta-analysed using fixed-effects models. During a median follow-up of 11.8 years, restricted cubic spline Cox regression analyses showed associations between lower mtDNA abundance and higher risk of CAD and HF. Hazard ratios for participants in the lowest quintile of mtDNA abundance compared with those in the highest quintile were 1.08 (95% confidence interval: 1.03, 1.14) and 1.15 (1.05, 1.24) for CAD and HF. Genetically, no evidence was observed for a possible non-linear causal effect using individual-level weighted genetic risk scores calculated in the UKB on the study outcomes; the pooled odds ratios (95% confidence interval) from two-sample MR of genetically predicted per one-SD decrease in mtDNA abundance were 1.09 (1.03, 1.16) for CAD and 0.99 (0.92, 1.08) for HF, respectively. Conclusion: Our findings support a possible causal role of lower leukocyte mtDNA abundance in higher CAD risk, but not in HF. Show less
Luo, J.; Noordam, R.; Jukema, J.W.; Dijk, K.W. van; Hägg, S.; Grassmann, F.; ... ; Heemst, D. van 2022
AimMitochondrial DNA dysfunction has been implicated in the pathogenesis of cardiovascular diseases. We aimed to investigate the associations between leukocyte mitochondrial DNA (mtDNA) abundance,... Show moreAimMitochondrial DNA dysfunction has been implicated in the pathogenesis of cardiovascular diseases. We aimed to investigate the associations between leukocyte mitochondrial DNA (mtDNA) abundance, as a proxy of mitochondrial function, and coronary artery disease (CAD) and heart failure (HF) in a cohort study and approximate the causal nature of these relationships using Mendelian randomization (MR) in genetic studies.Methods and resultsMultivariable-adjusted Cox regression analyses were conducted in 273 619 unrelated participants of European ancestry from the UK Biobank (UKB). For genetic studies, we first performed MR analyses with individual-level data from the UKB using a weighted genetic risk score (GRS); two-sample MR analyses were subsequently performed using summary-level data from the publicly available three consortia/biobank for CAD and two for HF. MR analyses were performed per database separately and results were subsequently meta-analysed using fixed-effects models. During a median follow-up of 11.8 years, restricted cubic spline Cox regression analyses showed associations between lower mtDNA abundance and higher risk of CAD and HF. Hazard ratios for participants in the lowest quintile of mtDNA abundance compared with those in the highest quintile were 1.08 (95% confidence interval: 1.03, 1.14) and 1.15 (1.05, 1.24) for CAD and HF. Genetically, no evidence was observed for a possible non-linear causal effect using individual-level weighted genetic risk scores calculated in the UKB on the study outcomes; the pooled odds ratios (95% confidence interval) from two-sample MR of genetically predicted per one-SD decrease in mtDNA abundance were 1.09 (1.03, 1.16) for CAD and 0.99 (0.92, 1.08) for HF, respectively.ConclusionOur findings support a possible causal role of lower leukocyte mtDNA abundance in higher CAD risk, but not in HF. Show less
Het hoofddoel van dit proefschrift is het ontrafelen van de causale rol van oxidatieve stress, gemeten door antioxidanten spiegels in bloed en mitochondriaal DNA-kopieaantal (mtDNA-CN), bij het... Show moreHet hoofddoel van dit proefschrift is het ontrafelen van de causale rol van oxidatieve stress, gemeten door antioxidanten spiegels in bloed en mitochondriaal DNA-kopieaantal (mtDNA-CN), bij het ontstaan van chronische ziekten. In dit proefschrift is de nadruk gelegd op het onderzoek naar cardiometabole ziekten en verwante risicofactoren door het toepassen van conventionele epidemiologische technieken in combinatie met Mendeliaanse Randomisatie. De studies beschreven in dit proefschrift hebben antwoord gegeven op twee hoofdvragen na toepassing van innovatieve epidemiologische onderzoeksmethoden op populatieniveau, namelijk: 1) of mitochondriale disfunctie een causale risicofactor is in de ontwikkeling van atherosclerotische cardiovasculaire ziekten en verwante risicofactoren, en 2) of antioxidanten in de voeding klinisch relevante voordelen opleveren bij de preventie van atherosclerotische cardiovasculare ziekten. Daarnaast werpt dit proefschrift licht op de rol van ontsteking, welke een bron kan zijn van verhoogde oxidatieve stress , bij neurologische aandoeningen. Show less
Kursun, O.; Yemisci, M.; Maagdenberg, A.M.J.M. van den; Karatas, H. 2021
Background Neuroinflammation has an important role in the pathophysiology of migraine, which is a complex neuro-glio-vascular disorder. The main aim of this review is to highlight findings of... Show moreBackground Neuroinflammation has an important role in the pathophysiology of migraine, which is a complex neuro-glio-vascular disorder. The main aim of this review is to highlight findings of cortical spreading depolarization (CSD)-induced neuroinflammatory signaling in brain parenchyma from the inflammasome perspective. In addition, we discuss the limited data of the contribution of inflammasomes to other aspects of migraine pathophysiology, foremost the activation of the trigeminovascular system and thereby the generation of migraine pain. Main body Inflammasomes are signaling multiprotein complexes and key components of the innate immune system. Their activation causes the production of inflammatory cytokines that can stimulate trigeminal neurons and are thus relevant to the generation of migraine pain. The contribution of inflammasome activation to pain signaling has attracted considerable attention in recent years. Nucleotide-binding domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) is the best characterized inflammasome and there is emerging evidence of its role in a variety of inflammatory pain conditions, including migraine. In this review, we discuss, from an inflammasome point of view, cortical spreading depolarization (CSD)-induced neuroinflammatory signaling in brain parenchyma, the connection with genetic factors that make the brain vulnerable to CSD, and the relation of the inflammasome with diseases that are co-morbid with migraine, including stroke, epilepsy, and the possible links with COVID-19 infection. Conclusion Neuroinflammatory pathways, specifically those involving inflammasome proteins, seem promising candidates as treatment targets, and perhaps even biomarkers, in migraine. Show less
BackgroundAspergillus niger is a ubiquitous filamentous fungus widely employed as a cell factory thanks to its abilities to produce a wide range of organic acids and enzymes. Its genome was one of... Show moreBackgroundAspergillus niger is a ubiquitous filamentous fungus widely employed as a cell factory thanks to its abilities to produce a wide range of organic acids and enzymes. Its genome was one of the first Aspergillus genomes to be sequenced in 2007, due to its economic importance and its role as model organism to study fungal fermentation. Nowadays, the genome sequences of more than 20 A. niger strains are available. These, however, do not include the neotype strain CBS 554.65.ResultsThe genome of CBS 554.65 was sequenced with PacBio. A high-quality nuclear genome sequence consisting of 17 contigs with a N50 value of 4.07 Mbp was obtained. The assembly covered all the 8 centromeric regions of the chromosomes. In addition, a complete circular mitochondrial DNA assembly was obtained. Bioinformatic analyses revealed the presence of a MAT1-2-1 gene in this genome, contrary to the most commonly used A. niger strains, such as ATCC 1015 and CBS 513.88, which contain a MAT1-1-1 gene. A nucleotide alignment showed a different orientation of the MAT1–1 locus of ATCC 1015 compared to the MAT1–2 locus of CBS 554.65, relative to conserved genes flanking the MAT locus. Within 24 newly sequenced isolates of A. niger half of them had a MAT1–1 locus and the other half a MAT1–2 locus. The genomic organization of the MAT1–2 locus in CBS 554.65 is similar to other Aspergillus species. In contrast, the region comprising the MAT1–1 locus is flipped in all sequenced strains of A. niger.ConclusionsThis study, besides providing a high-quality genome sequence of an important A. niger strain, suggests the occurrence of genetic flipping or switching events at the MAT1–1 locus of A. niger. These results provide new insights in the mating system of A. niger and could contribute to the investigation and potential discovery of sexuality in this species long thought to be asexual. Show less
The aim of this thesis was to investigate long term population dynamic processes in Black-tailed Godwit populations resulting from habitat fragmentation on three different spatial scales by using... Show moreThe aim of this thesis was to investigate long term population dynamic processes in Black-tailed Godwit populations resulting from habitat fragmentation on three different spatial scales by using genetics. We demonstrated that egg shell membranes provide a good alternative DNA source for population genetic studies compared to blood samples. Through the usage of egg shell membranes we could conduct the genetic studies in this thesis a large spatial scales. Genetic population structuring was studied here because Black-tailed Godwit breeding areas seemed geographically fragmented and it was unclear if this had led to genetic separation and inbreeding as well. On a local scale we did not detect any genetic populations structuring as an effect of habitat fragmentation. We showed that habitat fragmentation, although geographically visible, has not yet lead to genetic differences between Dutch breeding populations. As such it seems that Dutch breeding areas of the Black-tailed Godwit consist of a single panmictic population. On a global scale this thesis confirmed the presence of three genetically distinct groups now recognized as subspecies. However, no clear genetic differences were found between L. l. limosa across most of its current breeding range. Possibly, there is some genetic differentiation between L. l. limosa breeding areas in the Netherlands and Sweden. Show less
Wolbachia are intracellular, symbiotic bacteria, known for their ability to manipulate the reproduction mechanism of their arthropod hosts, for example by inducing parthenogenesis. In this thesis,... Show moreWolbachia are intracellular, symbiotic bacteria, known for their ability to manipulate the reproduction mechanism of their arthropod hosts, for example by inducing parthenogenesis. In this thesis, I studied the causes, consequences and dynamics of a parthenogenesis-inducing (PI) Wolbachia infection in two hosts, the parasitoid wasps Tetrastichus coeruleus (Hymenoptera: Eulophidae) and Asobara japonica (Hymenoptera: Braconidae). Interestingly, both T. coeruleus and A. japonica have Wolbachia-infected parthenogenetic populations and uninfected sexual populations. The main conclusions of this thesis are as follows. First, different scenarios may occur for the spread of PI-Wolbachia infection in different host species. Wolbachia has spread via vertical transmission through populations of T. coeruleus, whereas in A. japonica Wolbachia has spread via horizontal transmission. Second, different barriers may prevent migration and gene flow between Wolbachia-infected and uninfected populations in different host species. In T. coeruleus the different populations occur in different ecological environments, whereas in A. japonica there seems to be a geographical barrier between the different populations. Third, different ages of the PI-Wolbachia infection may have different consequences for the host species. The occasional male production by Wolbachia-infected A. japonica might be explained by the relatively young age of the infection. The Wolbachia infection in T. coeruleus seems to be older. Last, a PI-Wolbachia infection can have severe consequences for the sexual functionality of infected males and females. PI-Wolbachia seems to induce cytoplasmic incompatibility in infected A. japonica males. PI-Wolbachia-infected T. coeruleus females exhibited a degradation of receptivity to matings and of spermathecal morphology. Show less
The interspecific relationships in the genus Triturus are incompletely known. InCHAPTER 2, we attempt to resolve them by using allozyme and mtDNA data. Despitethe large number of markers used,... Show moreThe interspecific relationships in the genus Triturus are incompletely known. InCHAPTER 2, we attempt to resolve them by using allozyme and mtDNA data. Despitethe large number of markers used, relationships continue to elude us. The resultssuggest that speciation in the group occurred during a short time period (the end of theMiddle Miocene). Paleogeographic reconstructions of the presumed centre of origin (theBalkans) support this hypothesis. We proposed here that T. macedonicus should beraised to full species given its allopatric distribution and high genetic divergence with T.carnifex.The best way to test the scenario presented in CHAPTER 2 is to look at multipleindependent markers that, unfortunately, were not readily available. CHAPTER 3describes the process through which dozens of markers were designed and tested for thegenus Triturus. Out of more than fifty markers tested, five provided promising resultswith enough variability to study the phylogeny and phylogeography of the genus. Thisopened the door not only for CHAPTER 4, but also for 5 and 6.Taking CHAPTER 2 as the starting point and with the tools developed inCHAPTER 3, CHAPTER 4 attempts to decipher the history of the genus Triturus. Thestudy includes samples from 15 individuals of the seven species of the group. Locationswere selected to cover most of the variability in the group, with the exception of areasclose to other species. Hybridization is known to occur in these areas, and could bias theinferences made. Results show that all the genes, except the two mtDNA ones, haveincongruent phylogenetic signals. We used phylogenetic networks to visualize thealternative phylogenetic signals and have built a phylogenetic tree based on a Bayesianhierarchical method that obtains the species tree based on individual gene trees. Thisapproach successfully resolved the branching order of the newts, although time intervals are very narrow, confirming the near simultaneous speciation scenario of CHAPTER 2.We also found a high genetic differentiation between the two forms of the southerncrested newt (T. karelinii) and proposed that they should be raised to full species (T.karelinii and T. arntzeni).As described in CHAPTER 4, hybridization can have a confounding effect onphylogenetic inferences. Incomplete lineage sorting can also produce similar patterns asgene flow, further complicating matters. CHAPTER 5 takes a new approach indistinguishing between gene flow and incomplete lineage sorting, only possible inspecies with very well defined species borders and limited dispersal capability as thenewts, which limits gene flow to a narrow geographical region.As can be seen in the previous chapters, the crested newts show complex(although interesting) patterns resulting from compound interactions, especially in theBalkans. The marbled newts, on the other hand, are only two species, and therefore wecan cover their evolutionary history in more detail, as it is simpler. CHAPTER 6 studiesthe phylogeography of the two species of marbled newts. Being just a pair and not agroup of species, relationships are not problematic. Their sibling relationship is wellestablished (see CHAPTER 2). This chapter also explores how differences in ecologicalconditions (see CHAPTER 8) along a hybrid zone affect its structure and the amount ofgene flow between species.The morphological distinction of adults of the two marbled species is relativelystraightforward, even though variation is present. Eggs and larvae, on the contrary, areeasy to spot and collect, but impossible to distinguish. CHAPTER 7 describes a cheapand fast molecular technique that allowed the identification of the large number ofsamples used in CHAPTERS 8 and 9.Based on a morphological and genetic identification of individuals of the twospecies of marbled newts and published distributional data, CHAPTER 8 identifiedecological factors associated with the range border of the two species of marbled newt.Ecological models defining the distribution of the two species differed in four mainareas: the northern most region of contact close to Aveiro, the rest of the coastal area(see also CHAPTER 9), the region coinciding with the Tejo river, and the remaindercontact zone going until Madrid. In the coastal area of Portugal, close to Caldas da Rainha, the northern marblednewt was found where only pygmy marbled newts were thought to occur. Thisprompted a detailed study on the distribution of the two species in this area described inCHAPTER 9. This study revealed a small pocket of populations of the northern speciessurrounded by populations of its sister southern species. Given the distance of thispocket to the main distribution, we believe that the enclave was created by T. pygmaeusmoving north, superseding T. marmoratus, rather than the latter species expandingsouthwards. Show less
