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Kessler, M.

Publications and source records attributed to Kessler, M..

10 recordsLinked to original sources

DIMPLE: A Tree-Guided Divide-and-Conquer Framework for ILS-Aware Phylogenetic Network Inference on Large-Scale Data

Inferring evolutionary histories of species provides a foundation for comparative genomics and evolutionary analyses. Extensive evidence of reticulate evolution motivates the inference of phylogenetic networks, which represent relationships that species trees cannot capture. However, accurate reconstruction of large phylogenetic networks remains a major challenge because of the vast space of possible network topologies. Here, we propose DIMPLE, a divide-and-conquer framework for phylogenetic network inference without an explicit restriction on network level. DIMPLE uses a tree-of-blobs (TOB), which represents the tree-like relationships between regions of potential reticulation while leaving relationships within those regions unresolved. Within each unresolved region, DIMPLE partitions the set of taxa into pairwise-disjoint subsets, each containing at most a user-specified number of taxa. Multiple division runs are allowed, and subsets from different runs may overlap. DIMPLE infers a subnetwork on each subset, merges the subnetworks within each region, and uses the TOB to assemble the resulting networks into a network on the full taxon set. Experiments with true inputs demonstrate accurate merging, with improved reticulation recovery over existing methods on higher-level networks. With estimated inputs, DIMPLE achieves competitive topological accuracy and more consistently recovers hybrid ancestry than competing methods across varying levels of network complexity. Its computational requirements support analyses of hundreds of taxa. Applications to fern and gymnosperm datasets recover documented hybridization and previously reported phylogenetic conflict.

bioinformatics↗

Paleogene mass extinction and ongoing Neogene recolonization shape the tropical African flora

Tropical regions are known to host most of the global biodiversity, yet species richness varies drastically between continents. Tropical Africa has long been recognized as the "odd man out", exhibiting lower plant diversity compared to other tropical continents, but the underlying causes remain debated. Here, we use ferns as a model group to explore the processes responsible for the low diversity of African plants. We find that the current fern diversity in Africa, particularly in humid regions, is up to 84% lower than under similar climatic conditions in the Americas and Asia. Unlike on these continents, where 55-60% of extant fern diversity is the result of in-situ diversification of Gondwanan lineages, only 16% of African fern diversity originates from such lineages. This discrepancy points to significant African extinction periods during the Paleogene and mid-Miocene, likely driven by elevated temperatures and aridification. In contrast, 54% of the extant African fern diversity can be attributed to approximately 530 intercontinental dispersal events during the Neogene, indicating ongoing recolonization of Africa. Our findings provide unprecedented insight into the evolutionary forces shaping plant diversity in tropical Africa and highlight the potential risks posed by ongoing climate change to its botanical heritage.

ecology↗

Organoid-based modeling of platinum resistance identifies KRT17 as both a response mediator and biomarker for targeted therapy in ovarian cancer

Variable platinum responses drive high mortality in high-grade serous ovarian cancer (HGSOC), but to date, there is no molecular approach to define resistance levels for clinical decision-making. Here, we developed the organoid drug resistance assay (ODR-test) with patient-derived organoids from our ovarian cancer biobank and found that all HGSOC patients develop molecular resistance under exposure to carboplatin, although with varying clinical implications. Sustained phenotypic reprogramming and cellular plasticity under carboplatin pressure emerged as a conserved mechanism irrespective of the basal resistance level. Transcriptional and proteomic analyses revealed changes in cell adhesion and differentiation in post-platinum lines as adaptive responses that drive the increase in resistance. We identified Keratin 17 (KRT17) as a mediator of developing platinum resistance and validated its function by CRISPR/Cas9 and overexpression. Additionally, we found that KRT17 expression status (K-score) is a significant negative prognostic histopathological biomarker in a large cohort (N=384) of advanced HGSOC patients. In organoids, increased KRT17 levels enhanced sensitivity to PI3K/Akt inhibitors Alpelisib and Afuresertib, highlighting the potential of KRT17 as a stratification biomarker for targeted therapies.

cancer biology↗

GLOBAL BIOGEOGRAPHY AND EVOLUTIONARY DRIVERS OF FERNS WITH CHLOROPHYLLOUS SPORES

About 14% of all fern species have chlorophyllous spores. Unlike their counterparts, chlorophyllous spores lack dormancy and have a shorter viability (i.e. only a few days in some species). Such spores should limit long-distance dispersal and be more susceptible to harsher climatic conditions raising questions about the evolutionary and ecological advantages of this trait. This study aims to assess the global biogeography of chlorophyllous-spored ferns evaluating their underlying environmental and evolutionary drivers. We studied the global distribution of 10,995 fern taxa across 556 geographical regions, and assessed the association of the proportional representation of 1387 chlorophyllous-spored species (CSS) with environmental variables using generalized linear mixed models. To assess the influence of phylogenetic relationships on the distribution of this trait across the phylogeny and across geographic regions, we calculated the phylogenetic signal and phylogenetic distances among species in different assemblages. Species richness of chlorophyllous-spored ferns peaked in the tropics while their proportional representation was highest in temperate and island floras. The proportion of CSS was positively influenced by water availability, but negatively by variables associated with temperature. Spore type was strongly conserved phylogenetically, and CSS assemblages were phylogenetically clustered towards higher latitudes. Our study provides strong evidence that chlorophyllous spores do not limit the geographical distribution of fern species. Their latitudinal distribution patterns can be explain both for environmental and phylogenetic drives.

ecology↗

The transaminase-omega-amidase pathway is a redox switch in glutamine metabolism that generates alpha-ketoglutarate

Oxidative stress is caused by short-lived molecules and metabolic changes belong to the fastest cellular responses. Here we studied how the endothelial cell metabolome reacts to acute oxidative challenges (menadione or H2O2) to identify redox-sensitive metabolic enzymes. H2O2 selectively increased -ketoglutaramate (KGM), a largely uncharacterized metabolite produced by glutamine transamination and a yet unrecognized intermediate of endothelial glutamine catabolism. The enzyme nitrilase-like 2 {omega}-amidase (NIT2) converts KGM to -ketoglutarate (KG). Reversible oxidation of specific cysteine in NIT2 by H2O2 inhibited its catalytic activity. Furthermore, a variant in the NIT2 gene that decreases its expression is associated with high plasma KGM level in humans. Endothelial-specific knockout mice of NIT2 exhibited increased levels of KGM and impaired angiogenesis. Knockout of NIT2 impaired endothelial cell proliferation and sprouting and induced senescence. In conclusion, we show that the glutamine transaminase-{omega}-amidase pathway is a metabolic switch in which NIT2 is the redox-sensitive enzyme. The pathway is modulated in humans and functionally important for endothelial glutamine metabolism.

physiology↗

A deep catalog of protein-coding variation in 985,830 individuals

Coding variants that have significant impact on function can provide insights into the biology of a gene but are typically rare in the population. Identifying and ascertaining the frequency of such rare variants requires very large sample sizes. Here, we present the largest catalog of human protein-coding variation to date, derived from exome sequencing of 985,830 individuals of diverse ancestry to serve as a rich resource for studying rare coding variants. Individuals of African, Admixed American, East Asian, Middle Eastern, and South Asian ancestry account for 20% of this Exome dataset. Our catalog of variants includes approximately 10.5 million missense (54% novel) and 1.1 million predicted loss-of-function (pLOF) variants (65% novel, 53% observed only once). We identified individuals with rare homozygous pLOF variants in 4,874 genes, and for 1,838 of these this work is the first to document at least one pLOF homozygote. Additional insights from the RGC-ME dataset include 1) improved estimates of selection against heterozygous loss-of-function and identification of 3,459 genes intolerant to loss-of-function, 83 of which were previously assessed as tolerant to loss-of-function and 1,241 that lack disease annotations; 2) identification of regions depleted of missense variation in 457 genes that are tolerant to loss-of-function; 3) functional interpretation for 10,708 variants of unknown or conflicting significance reported in ClinVar as cryptic splice sites using splicing score thresholds based on empirical variant deleteriousness scores derived from RGC-ME; and 4) an observation that approximately 3% of sequenced individuals carry a clinically actionable genetic variant in the ACMG SF 3.1 list of genes. We make this important resource of coding variation available to the public through a variant allele frequency browser. We anticipate that this report and the RGC-ME dataset will serve as a valuable reference for understanding rare coding variation and help advance precision medicine efforts.

genetics↗

Hyper-Cryptic Radiation of a Tropical Montane Plant Lineage

Species are seen as the fundamental unit of biotic diversity, and thus their delimitation is crucial for defining measures for diversity assessments and studying evolution. Differences between species have traditionally been associated with variation in morphology. And yet, the discovery of cryptic diversity suggests that the evolution of distinct lineages does not necessarily involve trait differences. Here, we analyze 1,684,987 variant sites and over 4000 genes for more than 400 samples to show how a tropical montane plant lineage (Geonoma undata species complex) is composed of numerous unrecognized genetic groups that are not morphologically distinct. We find that 11 to 14 clades do not correspond to the three currently recognized species. Most clades are genetically independent and geographic distance and topography are the most important factors determining this genetic divergence. This lineage does not match the model of an adaptive radiation, but instead, constitutes the first example of a hyper-cryptic plant radiation in tropical mountains.

evolutionary biology↗

Global diversification of the common moonwort ferns (Botrychium lunaria group, Ophioglossaceae) was mainly driven by Pleistocene climatic shifts

The cosmopolitan Botrychium lunaria group belong to the most species rich genus of the family Ophioglossaceae and was considered to consist of two species until molecular studies in North America and northern Europe led to the recognition of multiple new taxa. Recently, additional genetic lineages were found scattered in Europe, emphasizing our poor understanding of the global diversity of the B. lunaria group, while the processes involved in the diversification of the group remain unexplored. We conducted the first global phylogenetic study of the group including 513 ingroup accessions sequenced for four non-coding plastid loci. We recovered ten well-supported clades, although relationships between clades were inconsistent between Bayesian and Maximum Likelihood analyses. We treated each clade at the species level, except for one clade including two ploidy levels, resulting in the recognition of 11 species, 5 of which are unnamed. In contrast to previous studies, we found species diversity to be equally distributed across the northern hemisphere, with 7-8 species per continent. We estimated the stem age of the B. lunaria group at 2.4-5.1 million years, with most species 1.8-2.6 million years old, and subspecies 0.5-1.0 million years old. Diversification thus coincided with Pleistocene climatic fluctuations that strongly affected the areas inhabited by the group, suggesting that diversification was driven by climatically induced cycles of extinction, dispersal, and migration. Furthermore, ecological differentiation between species suggests these complex population dynamics were associated with adaptations to specific environmental conditions. We found limited evidence that speciation is driven by polyploidization and hybridization. We show that the B. lunaria group has greater species level diversity than previously assumed and suspect that further cryptic species may await discovery, especially in the B. neolunaria clade.

evolutionary biology↗

Peptide Ancestry Informative Markers in Uterine Neoplasms from Women of European, African and Asian Ancestry

Characterization of ancestry-linked peptide variants in disease-relevant patient tissues represents a foundational step to connect patient ancestry with molecular disease pathogenesis. Nonsynonymous single nucleotide polymorphisms (SNPs) encoding missense substitutions within tryptic peptides exhibiting high allele frequencies in European, African, and East Asian populations, termed peptide ancestry informative markers (pAIMs), were prioritized from 1000 genomes. In silico analysis shows that as few as 20 pAIMs can determine ancestry proportions similarly to >260K SNPs (R2=0.9905). Multiplexed proteomic analysis of >100 human endometrial cancer cell lines and uterine leiomyoma tissues resulted in the quantitation of 62 pAIMs that correlate with self-described race and genotype-confirmed patient ancestry. Candidates include a D451E substitution in GC vitamin D-binding protein previously associated with altered vitamin D levels in African and European populations. These efforts describe a generalized set of markers for proteoancestry assessment that will further support studies investigating the impact of ancestry on the human proteome and how this relates to the pathogenesis of uterine neoplasms.

cancer biology↗

Preservation of stemness in high-grade serous ovarian cancer organoids requires low Wnt environment

High-grade serous ovarian cancer (HGSOC) likely originates from the fallopian tube (FT) epithelium. Here, we established 15 organoid lines from HGSOC primary tumor deposits that closely match the parental tumor mutational profile and phenotype. We found that Wnt pathway activation leads to growth arrest of these cancer organoids. Moreover, active BMP signaling is almost always required for generation of HGSOC organoids, while healthy FT organoids depend on BMP suppression by Noggin. Interestingly, FT organoids modified by stable shRNA knockdown (KD) of p53, PTEN, and Retinoblastoma (RB), also require a low Wnt environment for long-term growth, while FT organoid medium triggers growth arrest. Thus, early changes in the stem cell niche environment are needed to support outgrowth of these genetically altered cells. Indeed, comparative analysis of gene expression pattern and phenotype of normal and KD organoids confirmed that depletion of tumor suppressors triggers changes in the regulation of stemness and differentiation.

cancer biology↗