Publications

Monothalamid (single-chambered) foraminifera are a common constituent of high latitudinal coastal and deep-sea biota but are under-researched, and a limited number of species are described. Here, we present the first DNA barcoding study of monothalamid foraminifera collected from methane seeps along the Vestnesa and Svyatogor Ridge off NW Svalbard. Samples were taken from active pockmarks focusing on typical seep microhabitats characterized by microbial mats, and tubeworms. Additionally, reference samples were obtained from adjacent zones outside the pockmarks. We report here DNA barcode sequences of the 18S rRNA gene for seven monothalamid species of which three are described based on molecular and morphological data, the other four remain undescribed or undetermined. Conqueria bolivari sp. nov. has an elongate tubular shape and finely agglutinated test with a silvery, glossy surface. It branches with Conqueria laevis from the deep Weddell Sea and an undescribed Conqueria sp. from the Greenland Sea. Hilla arctica sp. nov. is elongated to broadly pyriform with a white, finely agglutinated test. It branches as a sister to Hilla argentea from South Georgia in the monothalamid Clade Y. Senguptiella vestnesensis gen. nov. sp. nov. branches in the monothalamid Clade C. It is rounded, with a finely agglutinated, reflective test wall. We also obtained DNA barcode sequences for undescribed Hippocrepinella sp. (Clade D) and Bathysiphon sp. (Clade BM) and two undetermined monothalamids (Clade Y and Clade Storthosphaera). Our study contributes to the efforts of obtaining DNA barcoding data for Arctic marine biodiversity and shows that monothalamid foraminifera are an important component of polar benthic communities.

Aims: Liver cytochromes (CYPs) play an important role in drug metabolism but display a large interindividual variability resulting both from genetic and environmental factors. Most drug dose adjustment guidelines are based on genetics performed in healthy volunteers. However, hospitalized patients are not only more likely to be the target of new prescriptions and drug treatment modifications than healthy volunteers, but will also be more subject to polypharmacy, drug-drug interactions, or to suffer from disease or inflammation affecting CYP activities. Methods: We compared predicted phenotype based on genetic data and measured phenotype using the Geneva cocktail to determine the extent of drug metabolizing enzyme variability in a large population of hospitalized patients (>500) and healthy young volunteers (>300). We aimed to assess the correlation between predicted and measured phenotype in the two populations. Results: We found that, even in cases where the genetically predicted metabolizer group correlates well with measured CYP activity at group level, this prediction lacks accuracy for the determination of individual metabolizer capacities. Drugs can have a profound impact on CYP activity, but even after combining genetic and drug treatment information, the activity of a significant proportion of extreme metabolizers could not be explained. Conclusions: Our results support the use of measured metabolic ratios in addition to genotyping for accurate determination of individual metabolic capacities to guide personalized drug prescription.

The misfolding and aggregation of TAR DNA binding protein-43 (TDP-43), leading to the formation of cytoplasmic inclusions, emerge as a key pathological feature in a spectrum of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD). TDP-43 shuttles between the nucleus and cytoplasm but forms nuclear bodies (NBs) in response to stress. These NBs partially colocalise with nuclear speckles and paraspeckles that sequester RNAs and proteins, thereby regulating many cellular functions. The laboratory of Steven Brown has recently found that the non-POU domain-containing octamer-binding protein (NONO), a component of paraspeckles, forms novel nuclear speckle-like structures in mouse cortical neurons in response to stress and sleep deprivation. These findings suggest the possibility of a functional link between NONO and TDP-43, potentially contributing to TDP-43 proteinopathy. Here, we demonstrate that pathological phenotypes caused by TDP-43 gain of function-locomotor defects and life span shortening-are exacerbated by silencing the Drosophila homolog of NONO, no on or off transient A (NonA). Additionally, NonA silencing results in an increase in nuclear TDP-43 NBs. These results provide supporting evidence for the functional link between NONO and TDP-43 and lay the foundation for dissecting underlying mechanisms.

Since leaving Africa, human populations have gone through a series of range expansions. While the genomic signatures of these expansions are well detectable on a continental scale, the genomic consequences of small-scale expansions over shorter time spans are more challenging to disentangle. The medieval migration of the Walser people from their homeland in ssouthern Switzerland (Upper Valais) into other regions of the Alps is a good example of such a comparatively recent geographic and demographic expansion in humans. While several studies from the 1980s, based on allozyme markers, assessed levels of isolation and inbreeding in individual Walser communities, they mostly did so by focusing on a single community at a time. Here, we provide a comprehensive overview of genetic diversity and differentiation based on samples from multiple Walser, Walser-homeland, and non-Walser Alpine communities, along with an idealized (simulated) Swiss reference population (Ref-Pop). To explore genetic signals of the Walser migration in the genomes of their descendants, we use a set of forensic autosomal STRs as well as uniparental markers. Estimates of pairwise F based on autosomal STRs reveal that the Walser-homeland and Walser communities show low to moderate genetic differentiation from the non-Walser Alpine communities and the idealized Ref-Pop. The geographically more remote and likely more isolated Walser-homeland community of Lötschental and the Walser communities of Vals and Gressoney appear genetically more strongly differentiated than other communities. Analyses of mitochondrial DNA revealed the presence of haplogroup W6 among the Walser communities, a haplogroup that is otherwise rare in central Europe. Our study contributes to the understanding of genetic diversity in the Walser-homeland and Walser people, but also highlights the need for a more comprehensive study of the population genetic structure and evolutionary history of European Alpine populations using genome-wide data.

Dental morphology varies greatly throughout evolution, including in the human lineage, but little is known about the biology of this variation. Here, we use multiomics analyses to examine the genetics of variation in tooth crown dimensions. In a human cohort with mixed continental ancestry, we detected genome-wide significant associations at 18 genome regions. One region includes EDAR, a gene known to impact dental features in East Asians. Furthermore, we find that EDAR variants increase the mesiodistal diameter of all teeth, following an anterior-posterior gradient of decreasing strength. Among the 17 novel-associated regions, we replicate 7/13 in an independent human cohort and find that 4/12 orthologous regions affect molar size in mice. Two association signals point to compelling candidate genes. One is ∼61 kb from PITX2, a major determinant of tooth development. Another overlaps HS3ST3A1, a paralogous neighbor of HS3ST3B1, a tooth enamel knot factor. We document the expression of Pitx2 and Hs3st3a1 in enamel knot and dental epithelial cells of developing mouse incisors. Furthermore, associated SNPs in PITX2 and HS3ST3A1 overlap enhancers active in these cells, suggesting a role for these SNPs in gene regulation during dental development. In addition, we document that Pitx2 and Hs3st3a1/Hs3st3b1 knockout mice show alterations in dental morphology. Finally, we find that associated SNPs in HS3ST3A1 are in a DNA tract introgressed from Neanderthals, consistent with an involvement of HS3ST3A1 in tooth size variation during human evolution.

Amniote integumentary appendages constitute a diverse group of micro-organs, including feathers, hair and scales. These structures typically develop as genetically controlled units, the spatial patterning of which emerges from a self-organized chemical Turing system with integrated mechanical feedback. The seemingly purely mechanical patterning of polygonal crocodile head scales provides an exception to this paradigm. However, the nature and origin of the mechanical stress field driving this patterning remain unclear. Here, using precise in ovo intravenous injections of epidermal growth factor protein, we generate Nile crocodile embryos with substantially convoluted head skin, as well as hatchlings with smaller polygonal head scales resembling those of caimans. We then use light-sheet fluorescence microscopy to quantify embryonic tissue-layer geometry, collagen architecture and the spatial distribution of proliferating cells. Using these data, we build a phenomenological three-dimensional mechanical growth model that recapitulates both normal and experimentally modified patterning of crocodile head scales. Our experiments and numerical simulations demonstrate that crocodile head scales self-organize through compressive folding, originating from near-homogeneous skin growth with differential stiffness of the dermis versus the epidermis. Our experiments and theoretical morphospace analyses indicate that variation in embryonic growth and material properties of skin layers provides a simple evolutionary mechanism that produces a diversity of head-scale patterns among crocodilian species.

We aim to investigate the time toxicity of patients with gastroenteropancreatic neuroendocrine tumours treated with Lutetium-177 Dotatate in a single institution.

In an effort to halt the global decline of large carnivores, reintroductions have become increasingly popular to establish satellite populations and reduce the risk of stochastic events. These artificial range expansions are typically formed by a small number of founders, which can lead to changes in population genetic structure. For instance, serial founder events can lead to neutral and even deleterious alleles reaching higher than expected frequencies along the front end of an expansion, referred to as gene surfing. One of the world’s most extensive range expansion programmes has been for endangered African wild dogs (Lycaon pictus). In this study, we examine the effect of continent-wide translocations on spatial genetic diversity, by determining what effect genetic surfing has on population structure in wild dogs, and measuring how long it will take for population structure to homogenize in the face of ongoing dispersal. We used a set of microsatellite loci to look at surfing alleles in five populations across southern Africa, and simulated the movement of these alleles forward in time under the current demographic scenario. We found that it would take about 150 generations for the expanding population to be 50% introgressed with genes from the free-roaming population. With the current rate of translocations, genetic differentiation in southern Africa will disappear, overturning the effects of genetic drift or surfing alleles. Understanding genetic patterns in expanding populations is of great interest to conservation, and we demonstrate that reintroduction programmes can help restore genetic diversity, and consequently adaptive potential, in recovering wildlife populations.

Reptiles showcase an extensive array of skin colours and patterns, yet little is known about the genetics of reptile colouration. Here, we investigate the genetic basis of the Clown colour morph found in captive-bred ball pythons (Python regius) to study skin pigmentation and patterning in snakes. We obtained samples by crowdsourcing shed skin from commercial breeders and hobbyists. We applied a case-control design, whole-genome pool sequencing, variant annotation, histological analyses, and electron microscopy imaging. We identified a missense mutation in a transmembrane region of the melanocortin-1 receptor (MC1R) associated with the Clown phenotype. In classic avian and mammalian model species, MC1R is known for controlling the type and amount of melanin produced. In contrast, our results suggest that MC1R signalling might play a key role in pattern formation in ball pythons, affecting xanthophore-melanophore distribution. This work highlights the varied functions of MC1R across different vertebrate lineages and promotes a novel model system to study reptile colouration.

Benthic foraminifera are one of the major groups of marine protists that also occur in freshwater and terrestrial habitats. They are widely used to monitor current and past environmental conditions. Over the last three decades, thousands of DNA sequences have been obtained from benthic foraminiferal isolates. The results of this long-term effort are compiled here in the form of the first curated benthic foraminiferal ribosomal reference dataset (BFR2). The present dataset contains over 5000 sequences of a fragment of the 18S rDNA gene, which is recognized as the DNA barcode of foraminifera. The sequences represent 279 species and 204 genera belonging to 91 families. Thirteen percent of these sequences have not been assigned to any morphologically described group and may represent species new to science. Furthermore, forty-five percent of the sequences have not been previously published. The BFR2 dataset aims to collect all DNA barcodes of benthic foraminifera and to provide a much-needed reference dataset for the rapidly developing field of molecular foraminiferal studies.