Development and function of the genital organs in the parthenogenetic oribatid mite Archegozetes longisetosus Aoki 1965

Archegozetes longisetosus Aoki 1965 is a parthenogenetic oribatid mite, that has a pantropical-disjunct distribution. It is a member of the family of Trhypochthoniidae. Its ease of rearing, rapid succession of generations and high fecundity fulfill central requirements of a suitable model organism. Roy A. Norton in 1993 founded a laboratory strain from a single puertorican female, Archegozetes longisetosus ran, which is since kept in laboratories worldwide. This laboratory strain lead to A. longisetosus being the most thoroughly studied oribatid mite. The species is of special interest in studies on evolutionary biology, as it is a member of a cluster of obligatory parthenogenetic species, for which molecular studies have indicated a very old age of probably more than a hundred million years. Detailed insight in the reproduction of A. longisetosus therefore does not only broaden our knowledge of a model organism, but may also contribute to a better understanding of the ancillary conditions of uni- vs. bisexual propagation, as well as the differential likelihood of long term stability in different forms of unisexual propagation. One step on the way towards this goal, and a necessary condition for future studies, is the acquisition of anatomical data regarding structure, function and development of organs and tissues. This cognitive interest lay at the starting point of the study at hand. With the aid of high-resolution synchrotron X-ray micro computer tomographies (SR-μCT), three-dimensional models of the genital organs and their precursors were obtained from all freeliving instars (larva to adult). As several models per instar at intervals of several days were obtained, important insight in developmental processes was gained. Already in the larva, germinative and somatic portions of the genital anlage can be distinguished. Further development proceeds continously, and largely independent from cuticular moulting. Precursors of the oviducts start to develop in the protonymphal stage, whereas proliferation of the germcells takes place during the deutonymphal stage. Ectodermal portions of the genital systems start development in the tritonymphal stage. The oviducts apparently do not form as evaginations of a coelomic sac containing germline cells, but either as lateral folds of the coelomic cavity or as lateral evaginations, which retrogradally form secondary contact sites to the germinative portion. Further investigations are needed to establish the mode of oviduct formation unequivocally. Three-dimensional models also facilitated the planning of semi- and ultrathin serial sectionings, which yielded histological and functional information. Observations made using electron- and lightmicroscopy included the onset of meiosis I in the tritonymphal stage, uptake of yolk precursors from the fat body into the oocyte via microvilli and coated pits, accumulation of egg shell material simultaneous to yolk accumulation, and the solidification of the egg shell upon passing into the oviduct. These observations justified a nomenclature of the genital system and the classification of the ovary as panoistic. Additionally, the oviducts could be described as a sheltered space for embryonal development. In summary, the results indicate that the loss of fertilization in the reproduction of A. longisetosus permits both anatomical and temporal compaction of the related processes, enabling relatively high average reproductive rate, even in the face of short-term unstable environmental conditions. The selection of methods permitted to demonstrate the mechanism of thelytoky by terminal fusion automixis with inverted (postreductional) meiosis in a functional context, and to present A. longisetosus as a promising model system also for questions beyond the borders of the taxon chelicerata.Archegozetes longisetosus Aoki 1965 ist eine parthenogenetische Hornmilbe mit pantropisch-disjunkter Verbreitung aus der Familie der Trhypochthoniidae. Durch ihre einfache Haltung, schnelle Generationenfolge und hohe Fruchtbarkeit erfüllt sie wesentliche Merkmale eines geeigneten Modellorganismus. 1993 wurde von Roy A. Norton aus einem einzelnen puertoricanischen Weibchen ein Laborstamm etabliert, A. longisetosus ran, der inzwischen weltweit in Laboren vertreten ist, was mit dazu führte, dass A. longisetosus mittlerweile die insgesamt am besten untersuchte Hornmilbe darstellt. Von besonderem Interesse ist die Art für evolutionsbiologische Studien, Da sie zu einem Schwarm obligat parthenogenetischer Linien gehört, für die molekulare Studien ein sehr hohes Alter von evtl. über hundert Millionen Jahren nahelegen. Ein genaues Verständnis der Fortpflanzungsvorgänge von A. longisetosus dient also nicht nur der Erweiterung unserer allgemeinen Kenntnis eines Modellorganismus, sondern darüber hinaus dem besseren Verständnis der Randbedingungen ein- und zweigeschlechtlicher Fortpflanzung, sowie der unterschiedlich langen Überlebenswahrscheinlichkeit der verschiedenen Formen eingeschlechtlicher Fortpflanzung. Ein Schritt auf dem Weg zu diesem Verständnis, und notwendige Bedingung für weiterführende Studien, ist der Aufbau einer anatomischen Datengrundlage zu Aufbau, Funktion und Entwicklung der an der Fortpflanzung beteiligten Organe und Gewebe. Dieses Erkenntnisinteresse lag der vorliegenden Arbeit zugrunde. Anhand hochauflösender Synchrotron- Röntgen- Mikro- Computer- Tomographien (SR-μCT) wurden dreidimensionale Modelle der Genitalorgane und ihrer Anlagen in allen freilebenden Stadien von der Larve bis zum Adultus erstellt. Da pro Entwicklungsstadium mehrere Modelle im Abstand weniger Tage erstellt werden konnten, konnten so wichtige Erkenntnisse über die Entwicklung der Genitalorgane gewonnen werden. So zeigte sich, dass schon in Larvenstadien ein somatischer und ein germinativer Anteil der Genitalanlage unterschieden werden kann. Die weitere Entwicklung dieser Anlage verläuft kontinuierlich, und weitgehend unabhängig von den Häutungen der Körperhülle. Vorläufer der Ovidukte beginnen sich ab der Protonymphe zu entwickeln, während die Vermehrung der Eizellen in der Deutonymphe stattfindet. Ab der Tritonymphe bilden sich auch die ektodermalen Anteile des Genitalsystems aus. Die Ovidukte bilden sich dabei wohl nicht als Evaginationen eines die Eizellen enthaltenden Coelomsackes, sondern entweder als randliche Abfaltungen des Genitalcoeloms, oder als laterale Evaginationen, die retrograd sekundären Kontakt zum germinativen Teil aufnehmen, eine Beobachtung, die noch weiterer Klärung bedarf. Sehr erleichtert durch die Modellserie wurde auch die Planung von Semi- und Ultradünnschnittserien ausgewählter Strukturen, die histologische und funktionelle Einsichten lieferten. So konnte das Einsetzen der Meiose in der Tritonymphe, die Aufnahme von Dottervorstufen aus dem Fettkörper in die Eizelle durch Mikrovilli und ‘coated pitsˊ, die Ablagerung von Eihüllenmaterial und dessen Verfestigung beim Übergang ins Ovidukt beobachtet werden. Durch diese Erkenntnisse konnte eine Nomenklatur des Genitalsystems begründet werden, das Ovar als funktionell panoistisch klassifiziert und die Ovidukte als geschützter Raum der Embryonalentwicklung beschrieben. Insgesamt ergeben sich Hinweise darauf, dass der Reproduktionsmodus durch Wegfall der Befruchtung die anatomische Verdichtung und Verschränkung der Prozesse erlaubt, was eine konstant hohe Reproduktionsrate auch unter kurzfristig wechselnden Lebensbedingungen ermöglicht. Mit der vorgestellten Methodenauswahl konnte der Reproduktionsmodus der Thelytokie mit terminaler Fusion und invertierter (postreduktionaler) Meiose im funktionalen Zusammenhang dargestellt, und A. longisetosus als aussichtsreiches Modellsystem für auch über den Bereich der Cheliceraten hinausweisenden Fragestellungen vorgestellt werden

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution

Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9-10-9 to P = 1.8-10-40) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9-10-3 to P = 1.2-10-13). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways