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Alters- und Adipositas-Effekte auf das Spermien-Methylom und die Konsequenzen für die nächste Generation
No full textBesides a growing tendency for delayed parenthood, sedentary lifestyle coupled with overnutrition has dramatically increased worldwide over the last few decades. Epigenetic mechanisms can help us understand the epidemics and heritability of complex traits like obesity to a significant extent. Majority of the research till now has focused on determining the impact of maternal factors on health and disease risk in the offspring(s).
This doctoral thesis is focused on deciphering the potential effects of male aging and obesity on sperm methylome, and consequences/transmission via germline to the next generation. In humans, this was assessed in a unique cohort of ~300 sperm samples, collected after in vitro fertilization/intracytoplasmic sperm injection, as well as in conceived fetal cord blood samples of the children. Furthermore, aging effect on sperm samples derived from a bovine cohort was analyzed.
The study identified that human male aging significantly increased the DNA methylation levels of the promoter, the upstream core element, the 18S, and the 28S regions of ribosomal DNA (rDNA) in sperm. Prediction models were developed to anticipate an individual’s age based on the methylation status of rDNA regions in his sperm. Hypermethylation of alpha satellite and LINE1 repeats in human sperm was also observed with aging. Epimutations, which are aberrantly methylated CpG sites, were significantly higher in sperm of older males compared to the younger ones. These effects on the male germline had a negative impact on embryo quality of the next generation. Consistent with these results, DNA methylation of rDNA regions, bovine alpha satellite, and testis satellite repeats displayed a significant positive correlation with aging sperm samples within the same individual and across different age-grouped bulls.
A positive association between human male obesity/body mass index (BMI) and DNA methylation of the imprinted MEG3 gene and the obesity-related HIF3A gene was detected in sperm. These BMI-induced sperm DNA methylation signatures were transmitted to next generation fetal cord blood (FCB) samples in a gender-specific manner. Males, but not female offsprings exhibited a significant positive correlation between father’s BMI and FCB DNA methylation in the two above-mentioned amplicons. Additionally, hypomethylation of IGF2 with increased paternal BMI was observed in female FCB samples. Parental allele-specific in-depth methylation analysis of imprinted genes using next generation sequencing technology also revealed significant correlations between paternal factors like age and BMI, and the corresponding father’s allele DNA methylation in FCB samples.
Deep bisulphite sequencing of imprinted genes in diploid somatic cord blood cells of offspring detected that the levels of DNA methylation signatures largely depended on the underlying genetic variant, i.e. sequence haplotypes. Allele-specific epimutations were observed in PEG1, PEG5, MEG3, H19, and IGF2 amplicons. For the former three genes, the non-imprinted unmethylated allele displayed more epimutations than the imprinted methylated allele. On the other hand, for the latter two genes, the imprinted allele exhibited higher epimutation rate than that of the non-imprinted allele.
In summary, the present study proved that male aging and obesity impacts the DNA methylome of repetitive elements and imprinted genes respectively in sperm, and also has considerable consequences on the next generation. Nevertheless, longitudinal follow-up studies are highly encouraged to elucidate if these effects can influence the risk of developing abnormal phenotype in the offspring during adulthood.Weltweit kann ein Trend zur späteren Elternschaft sowie die dramatische Zunahme eines bewegungsarmen Lebensstils in Kombination mit einer Überernährung beobachtet werden. Die Verbreitung sowie die Vererbung derartig komplexer Merkmale oder Erkrankungen lassen sich oftmals unter Berücksichtigung epigenetischer Mechanismen besser verstehen. Vorangegangene Studien untersuchten hierbei jedoch primär den Einfluss maternaler Faktoren auf die Gesundheit und das Krankheitsrisiko der nächsten Generation.
Diese Doktorarbeit hat das Ziel potentielle Altersinduzierte sowie Adipositas-bedingte Effekte auf das Methylom von Spermien sowie die damit einhergehenden Konsequenzen für die nächste Generation zu identifizieren. Hierfür stand eine humane Kohorte bestehend aus ~300 Spermienproben, welche nach einer in vitro Fertilisation bzw. Intrazytoplasmatischen Spermieninjektion gesammelt wurden, und das entsprechende Nabelschnurblut der mit Hilfe dieser Behandlungen gezeugten Kinder zur Verfügung. Ergänzend dazu wurde der Alterseffekt in bovinen Spermienproben analysiert.
Im Rahmen dieser Arbeit konnte eine signifikante Korrelation des männlichen Alterungsprozesses mit einer erhöhten DNA-Methylierung der ribosomalen DNA (rDNA) in der Promotorregion, dem strangaufwärts gelegenen Promotorelement (Upstream Core Element), der 18S- sowie der 28S-Region von Keimzellen aufgezeigt werden. Hierauf basierend wurde ein Vorhersageprogramm entwickelt, welches es ermöglicht anhand des Methylierungslevels der rDNA in den Spermien das Alter des entsprechenden Mannes zu berechnen. Weiterhin konnte beobachtet werden, dass mit dem Alterungsprozess in Spermien eine Hypermethylierung der Long Interspersed Nuclear Elements (LINE-1) und der Alpha-Satelliten-DNA einhergeht.
Des Weiteren zeigte der Vergleich von Spermien alter und junger Männer auf, dass Epimutationen, welche als fehlerhaft methylierte CpG-Stellen definiert werden, signifikant häufiger in Spermien alter Männer detektierbar sind. Allgemein zeigte sich zudem, dass diese altersabhängigen Effekte auf die Keimzellen sich negativ auf die Qualität der Embryonen auswirken. Übereinstimmend mit diesen Ergebnissen konnte auch in Spermien von Rindern dieser Alterseffekt nachgewiesen werden. Es zeigte sich mit zunehmendem Alter eine signifikant erhöhte Methylierung der rDNA-Regionen und der Alpha-/ Testis-Satelliten-DNAs sowohl innerhalb eines Individuums, als auch zwischen verschiedenen altersgruppierten Individuen.
Weiterhin konnte eine positive Korrelation des Body-Mass-Index (engl. body mass index; kurz: BMI) eines Mannes und der Methylierung in MEG3 und HIF3A in dessen Spermien detektiert werden. Anhand der untersuchten Nabelschnurblute konnte aufgezeigt werden, dass diese BMI-induzierten Methylierungsveränderungen in einem geschlechter-spezifischen Kontext an die nächste Generation weitergegeben werden. So war ausschließlich bei männlichen Nachkommen eine signifikant positive Assoziation des väterlichen BMIs und der DNA-Methylierung dieser beiden Gene im Nabelschnurblut nachweisbar. Eine mit dem väterlichen BMI einhergehende Hypomethylierung des Gens IGF2 war hingegen ausschließlich in den Nabelschnurblut-Proben weiblicher Nachkommen messbar. Die Auftrennung der Allele nach ihrer parentalen Herkunft, zeigte eine signifikante Korrelation zwischen den paternalen Faktoren, wie Alter und BMI, und dem Methylierungslevel des korrespondierenden paternalen Allels im Nabelschnurblut.
Mit Hilfe der Deep Bisulfite Sequenzierung diploider Zellen aus dem Nabelschnurblut der Nachkommen wurde die DNA-Methylierung geprägte Gene untersucht. Hierbei konnte aufgezeigt werden, dass das Methylierungslevel stark von der zu Grunde liegenden genetischen Variante (Haplotyp) abhängt. Allel-spezifische Epimutationen wurden in den untersuchten Amplikons der Gene PEG1, PEG5, MEG3, H19 und IGF2 nachgewiesen. Bei PEG1, PEG5 und MEG3 waren mehr Epimutationen der nicht-geprägten unmethylierten Allele, als der geprägten methylierten Allele detektierbar. Konträr hierzu war bei den Genen H19 und IGF2 eine erhöhte Epimutationsrate der geprägten und somit methylierten Allele nachweisbar.
Diese Doktorarbeit offenbart altersinduzierte sowie Adipositas-bedingte Einflüsse auf die DNA-Methylierung repetitiver Elemente und geprägter Gene in männlichen Keimzellen, sowie damit einhergehende potentielle Konsequenzen für die nächste Generation. Um schlussendlich jedoch eine Aussage treffen zu können, ob aufgrund dieser Effekte eine erhöhte Prädisposition der nächsten Generation zur Entwicklung anormaler Phänotypen besteht, müssen longitudinale Folgestudien durchgeführt werden
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
Increasing methylation of sperm rDNA and other repetitive elements in the aging male mammalian germline
Get PDFDeutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659Horizon 2020 Framework Programme http://dx.doi.org/10.13039/10001066
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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