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Principles of gene and regulatory evolution as inferred from cross-species comparisons in primates
Get PDFThe sequence contained in the 3.2 Gb long haploid stretches of our DNA has been registered but we are still far from having decoded the information that it contains. Among the approaches that facilitate a closer insight into the relevance of individual elements for existent phenotypes is the comparative approach. It extends beyond focusing solely on one species, instead exploiting the knowledge gained from investigating patterns of evolutionary change. Evolutionary comparisons have an advantage over other techniques that rely on genetic change, in that they inform on the types of changes that have evidently occurred in nature. In this thesis, I bridge advances made in gathering genetic information and in generating high-throughput functional assays in a cross-species context to answer fundamental questions in evolutionary genomics.
To be able to rely on recently developed genome-wide functional assays like RNA-seq, we should know the amount of error that these measurements contain. Using genetic variation between species, I contribute to estimating the precision with which we measure expression. We further evaluate and compare computational methods that are designed to remove this noise, using our substitution-based error estimates as the ground truth.
Then, I study multiple aspects of gene and regulatory evolution by leveraging cross-species data on DNA, expression, accessibility and the activity of regulatory and protein sequences. An important current task in genomics is to improve our ability to read and interpret the regulatory code that governs expression. Therefore, I study how constraint is reflected in a range of functional properties of cis-regulatory elements (CREs), using their tissue-specificity as a proxy for functional importance. Based on theoretical considerations and patterns seen in the case of genes, pleiotropic CREs that are utilized in all or the majority of tissues are expected to be under most constraint. This turns out to be true for the conservation patterns of transcription factor binding site repertoires, whereas the exact binding sites as well as the underlying sequences show even lower conservation than that of tissue-specific CREs. Considering the highly conserved accessibility of pleiotropic CREs and the conserved downstream gene expression, these findings suggest pervasive compensatory evolution acting within the sequences of pleiotropic CREs and, likely, across functionally orthologous tissue-specific CREs. This study underlines the importance to evaluate CRE conservation and functionality using metrics beyond simple sequence conservation.
Further, I touch another currently highly debated aspect of genome evolution: The role of newly evolved elements in species-specific rewiring of gene regulatory networks. Transposable element-derived regulatory and gene sequences are gaining increasing attention due to their ability to expand the genome in a clade- or species-specific manner. In addition, some types of TEs, such as long terminal repeat (LTR) elements, carry binding sites for important transcription factors active in pluripotent stem or other cell types. This leads to new regulatory sequences and transcripts. While some of these have been proposed or indeed shown to contribute to the cellular phenotypes, in the current study we revisit one such candidate long non-coding gene, ESRG, and find that in spite of its high expression in human pluripotent stem cells, it is dispensable to the function of these cells. We also find no evidence for selection using sequence divergence and polymorphism-based analyses. This study is a reminder to be careful in interpreting expression as a sign of function.
Finally, I combine evolutionary and functional measures to assess the association between genetic and phenotypic evolution. Specifically, I focus on the association between brain evolution and the evolution of a particular brain developmental gene TRNP1 across over 30 mammalian species. I find that TRNP1 coding sequence evolution, TRNP1-dependent proliferation rates and the activity of a cis-regulatory element of TRNP1 co-evolve with brain size and the degree of gyrification. These findings advance our evolutionary and neu- rodevelopmental understanding of how larger and more folded brains evolve. Moreover, with the increasing availability of high-quality genomes and possibilities to assay genetic variants in massively parallel assays, this and similar studies are demonstrations of how evolutionary information can be leveraged by combining phylogenetic approaches with functional assays
Novel molecular targeted therapies in pheochromocytomas, paragangliomas and neuroendocrine tumors
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Essays on deliberate errors in surveys
Get PDFSurveys have always been prone to deliberate errors by the involved actors (e.g., interviewers or respondents). Such errors can bias survey estimates, lead to biased inferences in survey data analysis, and undermine trust in survey data. This dissertation contributes to the literature on preventing and identifying such behavior. The first four contributions focus on deliberate errors by face-to-face interviewers (e.g., fabrication of parts of or entire interviews). The fifth contribution investigates inattentive responding which is a type of deliberate error by web survey respondents.
The first contribution analyzes the deterrence effect of interview audio recordings in face-to-face interviews. With respondent consent, interviews are audio-recorded and these recordings are later used to evaluate the interviewers’ behavior. Without recordings, the interviewers’ behavior is not observable. Using detailed timestamp data and multiple analysis approaches, we show that audio recordings substantially reduce the prevalence of likely deliberate interviewer errors. The second contribution illustrates how multilevel modeling can be an effective analysis approach to identify fraudulent interviewers. In particular, the developed model focuses on the fraudulent interviewers’ behavior over the field period. The method is applied to survey data containing verified falsifications and further data without verified falsifications. The model identifies the verified falsifiers in the former dataset and flags multiple suspicious interviewers in the latter. The third contribution proposes another approach to identifying error-prone interviewers. We exploit that adult self-reported height is stable within short timespans and identify interviewers as error-prone if 1) self-reported heights frequently and substantially differ from measured heights or 2) self-reported heights change frequently and substantially over panel waves. Using multilevel models, we apply the identification approach to four survey datasets and identify several error-prone interviewers. The fourth contribution develops a multivariate approach to analyzing interviewer errors. Using data from ten waves of a yearly panel survey conducted in ten countries (i.e., 100 country-years), we apply multiple indicators of interviewer error both on the interviewer and country-year level. To identify exceptional country-years and interviewers, we use isolation forests and show that interviewer errors are particularly prevalent in several country-years. The results led to the exclusion of multiple country-years from the publicly released data and emphasize the importance of taking the fieldwork institute into account when analyzing interviewer errors. The fifth contribution focuses on preventing and identifying inattentive responding (i.e., providing responses without regard to the question content) in web surveys. As a preventive measure, we experimentally tested the efficacy of so-called commitment pledges that ask respondents to commit to providing accurate responses but found no effect on multiple indicators of inattentive responding. Concerning identification measures, we conducted a further experiment on widely used attention checks and show that large proportions of respondents likely pass such checks by chance. As an alternative, we propose a timestamp-based clustering approach to identify clusters of likely inattentive respondents which is applied to multiple datasets.
The contributions on measures to prevent deliberate errors may guide practitioners in designing surveys. The developed and tested identification methods may guide practitioners and applied researchers who seek to assess the quality of their data. In sum, this dissertation contributes to avoiding the prevalence and (potentially detrimental) consequences of deliberate errors in surveys
Nociceptive pain in neuromuscular disorders - a low interventional pilot study to assess musculoskeletal pain in neuromuscular diseases
Get PDFCharacterization and quantification of offshore methane emissions using airborne in situ measurements of methane, ethane and methane isotopologues
Get PDFMethane (CH4) is the second-most important long-lived anthropogenic greenhouse gas after carbon dioxide and, because of its short lifetime, is an attractive target for rapid emission reduction. Atmospheric CH4 mole fractions have almost tripled since pre-industrial times due to human activity. A concurrent decline in the 13CH4/12CH4 isotopic ratio of CH4 (expressed as δ13C(CH4)) since 2007 points to a significant change in CH4 sources and sinks, since those vary in their
δ13C(CH4) signatures. So far, the understanding of the underlaying drivers is insufficient, which hampers both prioritizing mitigation actions and predicting future CH4 trends.
This dissertation aims at a more detailed characterization of anthropogenic CH4 emissions using airborne in situ measurement methods. Thereby, the focus is on the sector of offshore fossil fuel production, which is understudied so far. Driven by the hypothesis that emission inventories using generic scaling methods are not able to estimate emissions with sufficient accuracy, airborne measurement data gathered around offshore installations is analyzed and compared with different
inventory data. Moreover, it is investigated, whether emissions can be better characterized by using the latest airborne laser spectroscopy methods. To this end, an existing direct laser absorption spectrometer is adapted for the high-resolution and continuous airborne measurement of the tracers C2H6 and δ13C(CH4), and deployed on research aircraft to study offshore emissions.
The first part presents the analyses of an airborne study conducted by the British Antarctic Service (BAS) in the southern North Sea in 2019. CH4 emission rates from offshore gas installations were derived by applying the well-established mass balance method. They were then compared with direct operator-reporting, estimates from regional point source inventories and a globally gridded inventory, which uses national reported emissions in the framework of the United Nations Framework Convention on Climate Change (UNFCCC) and infrastructure data for a spatial downscaling. The findings reveal significant deviations between the derived emission rates and the estimates in the existing inventories. The inventories underestimate emissions by factors from 6 to 279, with the global inventory deviating the most. Notably, the operator-based facility-level reporting corresponds with the calculated flux, which only deviates by a factor of 0.64. The comparison with estimates from airborne measurements in other offshore regions shows that CH4 emission rates are comparable and do not depend on oil- and gasproduction rates, which are typically used for emission estimates in inventories.
The second part of the thesis describes the characterization and adaptation of the DLR-QCLS, a fast and precise Quantum-cascade and Interband-cascade laser spectrometer, enabling it to measure the tracers C2H6 and isotopic CH4 (13C(CH4); 12C(CH4)), to then use the isotopic ratio δ13C(CH4) to derive source signatures from offshore point sources. The laboratory characterization shows that, given the instrument precision (0.86‰ (1σ, 2 Hz)), source detection is feasible for strong fossil fuel plumes larger than approximately 250 ppb CH4, depending on the individual source signature. Furthermore, the qualitative detection of source signatures is demonstrated. During two aircraft campaigns the DLR-QCLS detected C2H6 and δ13C(CH4) signals from offshore oil installations, from which characteristic C2H6 to CH4 ratios and source signatures were calculated. Nonetheless, it is necessary to refine the methodology both in laboratory settings and during field operations in order to achieve a better correspondence between
the quantitative measurement of δ13C(CH4) and estimated source signatures.Methan (CH4) ist nach Kohlendioxid das zweitwichtigste anthropogene Treibhausgas und wegen seiner kurzen Lebenszeit von etwa einer Dekade besonders interessant für kurzfristig wirkende Mitigationsstrategien. Atmosphärische CH4 Konzentrationen haben sich seit der industriellen Revolution jedoch fast verdreifacht. Seit 2007 erfährt CH4 zudem einen beschleunigten Anstieg, wobei parallel ein Absinken des Verhältnisses der Methanisotopologe 13CH4/12CH4, ausgedrückt als δ13C(CH4), zu beobachten ist. Dies deutet auf eine Veränderung der Zusammensetzung der Methanquellen und/oder Senken hin, da diese sich in ihren δ13C(CH4) Signaturen unterscheiden. Das unzureichende Detailverständnis des Methanbudgets erschwert sowohl die Priorisierung von Mitigationsmaßnahmen als auch zuverlässige Prognosen des zukünftigen Methantrends.
Das Ziel dieser Dissertation ist eine detailliertere Charakterisierung anthropogener Methanemissionen mittels flugzeuggestützter in-situ Messmethoden. Der Fokus liegt dabei auf dem bisher unzureichend untersuchten Sektor der Offshore-Öl- und Gasproduktion. Um die Hypothese zu untersuchen, dass Emissionskataster Offshore-Emissionen mittels generischer Methoden nur unzureichend abschätzen, werden flugzeuggestützte Messungen von Offshore-Anlagen ausgewertet
und die berechneten Emissionen mit Angaben in Emissionskatastern verglichen. Darüber hinaus ist die Adaption als auch der flugzeuggetragene Einsatz von Laser-Absorptionsspektroskopie zur hochaufgelösten und kontinuierlichen Messung der Tracer C2H6 und δ13C(CH4) ein weiteres Ziel dieser Arbeit, um Offshore-Emissionen besser zu charakterisieren.
Der erste Teil beschäftigt sich mit der Analyse der Daten einer Flugzeugmesskampagne, die 2019 in der südlichen Nordsee vom British Antarctic Service (BAS) durchgeführt wurde. Mit der etablierten Massenbilanzmethode wurden CH4-Emissionsraten von Gasplattformen bestimmt. Diese wurden mit Betreiberdaten, als auch mit verschiedenen regionalen und einem globalen Emissionskataster verglichen. Letzteres nutzt Emissionen, die von Ländern aufgrund der Klimarahmenkonvention der Vereinten Nationen (UNFCCC) berichtet werden, um diese mittels Infrastrukturdaten räumlich zu verteilen. Die Emissionskataster unterschätzen die aus den Messungen abgeleiteten Emissionen deutlich um Faktoren zwischen 6 und 279, wobei das globale Kataster die größte Abweichung zeigt. Direkt gemeldete Betreiberdaten für den jeweiligen Messtag zeigen die beste Übereinstimmung mit den Messungen, die um den Faktor 0.64 abweichen. Die hier diskutierten Messungen und ein Vergleich mit Messungen in anderen Offshore-Regionen zeigt, dass die beobachteten Emissionen nicht linear mit Öl- oder Gasproduktionsraten korrelieren, wie typischerweise für Emissionsabschätzungen von Katastern angenommen.
Der zweite Teil der Arbeit umfasst die Adaptierung und Charakterisierung des DLR-Laser-Absorptionsspektrometers (DLR-QCLS) für die schnelle und hochaufgelöste Messung der Tracer C2H6 und δ13C(CH4), um isotopische Quellsignaturen von Offshore-Punktquellen abzuleiten. Laborversuche mit der neuen Laserkonfiguration zeigen, dass Quellsignaturen qualitativ detektiert werden können. Bei der höchsten instrumentellen Auflösung (0.86‰ (1σ, 2 Hz)) ist eine Detektion
von fossilen Quellen mit Methanerhöhungen von mehr als 250 ppb, abhängig von der individuellen Quellsignatur, möglich. Das DLR-QCLS wurde bei zwei Flugzeugmesskampagnen zur Messung von δ13C(CH4) und C2H6 eingesetzt. Dabei wurden Emissionen von Offshore-Ölplattformen detektiert und deren charakteristische C2H6 zu CH4 Verhältnisse und Quellsignaturen bestimmt.
Die in dieser Arbeit durchgeführten Analysen zeigen, dass das DLR-QCLS für eine quantitative Messung von Quellsignaturen bei in-situ Messungen und vorbereitend im Labor weiter optimiert werden muss, um eine bessere Übereinstimmung von Quellsignaturen zu erhalten
Inwiefern beeinflussen Faktoren von Virtuellen Patient*innen die klinische Entscheidungsfindung von Studierenden
Get PDFIntroduction: In medical education, virtual patients (VPs) are a suitable method to teach clinical reasoning (CR) and to support the visualization of this reasoning process in a safe environment. One aim of our study was to investigate differences in CR and diagnostic accuracy between female and male medical students. Another aim was to examine the influence of patient-dependent contextual factors - skin color, socioeconomic status, and sexual orientation - on CR and diagnostic accuracy when processing VPs.
Methods: During the summer semester 2020, we provided 15 VPs online for students enrolled in medical schools in Bavaria and collected the interactions of the 179 participating students, divided into the groups "male" and "female students", in the VP system CASUS including, among others, collected findings, differential diagnoses, final diagnosis and therapy options. The data from this randomized study was exported and analyzed pseudonymously.
Results: We found some significant differences in CR between female and male students. For example, female students documented more findings, differential diagnoses, tests, and treatment options and wrote a brief summary of VPs more frequently, but we did not find significant differences in diagnostic accuracy. Contextual factors had a different impact on CR, for example, we found that male students documented more differential diagnoses and female students documented more treatment options for "Black" VPs.
Conclusions: Our study showed significant differences between male and female students and there is a possibility that prejudice against minorities plays a role in this. The significant differences between male and female medical students should be considered in the design of curricula and training programs and diversity education should be incorporated into the medical curriculum
Chemical communication in the spider Pisaura mirabilis
Get PDFChemical communication represents one of the most ancient and widespread forms of communication and has been extensively studied for more than a hundred years. Yet, for most of this period, research on chemical communication has been largely driven by traditional views on sex roles in reproduction, leading to biased literature that is skewed towards females chemically signalling and males detecting those signals. It was only in the last one to two decades that research slowly began to include investigations on male chemicals and females exerting choice based on those. While most of our understanding of chemical com-munication comes from studies on insects, other taxonomical groups, such as spiders, lag behind. Motivated by the need to expand our understanding on the functions of chemicals in a reproductive context for both sexes in this taxonomical group, I investigated in this thesis the influence of silk- and cuticle-borne chemical communication on male mate search and reciprocal assessment between male and female spiders. Specifically, I aimed to understand the role of silk- and cuticle-borne chemicals during inter-sexual communication in the web less hunting spider Pisaura mirabilis, a species known for its peculiar mating behaviour that involves male offering of nuptial-gifts to the female.
Mate search is essential part of reproduction and particularly challenging in solitary animals, such as cursorial spiders, that live widespread in their habitats. Trails, which are paths in the environment for example created by pheromone deposition on a substrate, represent one of the most efficient and target-oriented means for mate search. Specifically, trails increase the chances of finding mates compared to random search, especially if these trails convey directionality information that indicate the movements of the trail producer. Yet, trail directionality is rarely investigated and poorly understood. In Chapter 1, I investigated presence of directionality information in female spider silk trails by exposing males to unidi-rectionally deposited female silk, and scoring male trail-following direction with reference to female movement. I further explored potential influences of female phenotypic traits on male trail-following behaviour. I found overall lack of general directional trail-following (i.e., males following trails in female direction). However, males followed trails more often when they were unwashed (opposed to washed with solvents to remove putative chemicals) or sourced from females that were relatively larger (opposed to smaller) than the male. These results suggest context-dependent male directional trail-following, possibly reflecting male mate choice, and likely based on chemical trail attributes assessed through probing of silk lines that convey information on female quality.
Male mate choice has traditionally been overlooked, with mate preferences and choices largely attributed to females only. However, when there is large variation in female quality and/or when mating is costly for males, as for costly spider nuptial-gifts, selection should favour male discriminatory abilities and choice. Female reproductive potential varies with female developmental and reproductive state, and/or body condition, and males are expected to exert mate choice towards females that are of higher reproductive value. In Chapters 2 and 3, I studied male behavioural responses in the form of courtship investment or trail-following, when sequentially or simultaneously exposed to silk sourced from females varying in their phenotypic states. Females signal their developmental and reproductive state, but not mating state, as well as their body condition. Males adjusted their courtship investment and exerted trail-following choices based on these female states. Specifically, males courted adult females more often than juvenile or adult ones, preferred high-condition females over low-condition ones, and did not differentiate between mated and unmated females, whereas males decreased their courtship towards females that carried their fertilized egg-sacs. Such differentiated male behavioural responses might reflect a male strategy in light of the high costs of courtship.
In the context of mate assessment, male chemicals are rarely viewed as secondary sexual traits that potentially affect female mating decisions. However, male chemicals are also important for reproduction as they potentially affect female mate choice either by reliably reflecting male underlying qualities or by manipulating the female into matings. In Chapters 4 and 5, I explored the presence and variation of male chemical signalling via the nuptial-gift and its role in female mate choice. For this purpose, I observed female mate acceptance behaviours to chemical properties of male gift silk, and investigated whether these behaviours are influenced by male phenotypic traits. I found that chemicals appear to be present on the silk covering male nuptial-gifts, shown by higher female acceptance of gifts with unwashed opposed to silk washed with solvents. However, there was no variation in mass-dependent silk-borne chemical signalling, as females accepted gifts produced by males of high and low mass equally likely. While male silk-borne chemicals prime female responses in mate choice, females may base their mate choice on directly accessible mate traits instead of silk-borne ones, most likely due to the male’s ability to use silk to mask non-nutritive gift contents and cheat females into mating in this system.
Overall, this dissertation provides important knowledge on chemical communication in a reproductive context and without the limitations of traditional views on fixed sex roles. I show that an impressive variety of conditions and innate states influence both chemical signalling and mate choice, with the latter itself presenting in many facets ranging from courtship investment, trail-following decisions to direct mate acceptance. Both sexes in my model species assess and produce chemicals, consequently influencing mate choice decisions in the other sex. My work highlights the importance of conducting research unobstructed by sex-biases, as only such unbiased research offers to opportunity to fully understand inter-sexual chemical communication
The fear of injustice
Get PDFVictim sensitivity – the dispositional sensitivity to self-related injustice – has been associated with a preference for right-wing political actors, anti-immigration attitudes, and a tendency to refrain from pro-environmental behaviour. This dissertation draws on theoretical assumptions and prior research to examine the psychological processes that explain the association of victim sensitivity with political attitudes and behaviour. Three manuscripts, including eight empirical studies, provide insights into the link between the sensitivity to perceiving oneself as a victim of moral transgressions and a right-wing political orientation, and into the motivational and social-cognitive processes that explain the antisocial tendencies of victim-sensitive individuals in the contexts of immigration and climate action. I discuss theoretical and practical insights, methodological limitations as well as avenues for future research