Biology subjects

Koch, E.

Publications and source records attributed to Koch, E..

18 recordsLinked to original sources

bioRxiv2026

The role of chromosomal inversions in local adaptation and ecotype formation across a variable landscape in an intertidal snail

Adaption to environmental variation can be discrete or continuous, responding to sharp or gradual habitat transitions. Chromosomal inversions accentuate these adaptive responses as multiple loci respond in tandem across a habitat transition. Earlier studies of Littorina saxatilis (Olivi, 1792) have shown that three ecotypes segregate in different habitats supported by polymorphisms in a few inversions. However, many more large inversions are polymorphic in this species and potentially have adaptive effects in response to uncharacterised environmental gradients. We sampled 200 random shores representing all kinds of shore habitats present in a 12x12 km area of a Swedish archipelago, with L. saxatilis found at 196 sites. Environment and shell morphology were summarised using dimension reduction analyses, and Bayesian regression models were used to analyse the relationships between phenotype, environment and inversions. Phenotypic variation was a continuum with previously described ecotypes positioned in different parts. 18 inversions responded to at least one dimension of environmental variation, and over (12) half influenced the measured phenotypes. Overall, inversion arrangements explained 15% of phenotypic variation, with limited direct contributions from the environment (<1%). Chromosomal inversions thus are a major factor for local adaptation in L. saxatilis, supporting adaptation across a landscape more complex than the previously described ecotypes.

evolutionary biology↗

bioRxiv2026

Integrative multiomics profiling of cortical brain organoids reveals a druggable alternative splicing program in schizophrenia

Clozapine (CLZ) is the only available pharmacological option for treatment resistant schizophrenia (TRS), but its use is limited due to adverse drug reactions and potential cytotoxicity. Despite decades of research, the precise mechanisms of action of CLZ in the human brain remain poorly understood. To address this, we derived cortical brain organoids from a large cohort of schizophrenia (SCZ) patients and healthy controls and employed a comprehensive multiomics strategy to dissect the cellular mechanisms of long-term CLZ exposure of up to 24 weeks. We uncovered a SCZ-specific and metabolism-independent alternative splicing program that was amenable to non-toxic CLZ treatment. In-depth analysis revealed a key role of exon skipping and intron retention in glutamatergic neurons. This program was further found to recapitulate disease mechanisms in primary human brain tissue and capture splicing-mediated genetic signals of SCZ risk. These findings highlight alternative splicing as a promising avenue for therapeutic developments in TRS.

neuroscience↗

bioRxiv2026

Inference of elevated mutation rates and variant effects using 700k exomes

Genomic sequencing is now widely accessible for genetic diagnostics and is emerging as a component of newborn screening. This technological development generates the need to characterize incoming mutations, create comprehensive datasets of genes causing rare Mendelian disorders, and identify pathogenic variants. Large-scale exome sequencing datasets such as Genome Aggregation Database (gnomAD) have been assembled to help address these challenges. The recent release of gnomAD (v4; n = 730,947) uncovers millions of rare coding variants, many of which have arisen more than once by independent recurrent mutations in the rapidly growing recent human population. Here, we use newly developed theoretical understanding of sampling properties of rare variants to estimate key population genetics parameters of practical importance to human genetics such as demography history, mutation rate, and selection. Solely relying on population data, our method Population Inferred Estimates of Selection (PIES) identifies novel genes with loss-of-function mutational hotspots likely due to selection in spermatogonia. PIES efficiently estimates selection coefficients for heterozygous loss-of-function variants. Combining population genetics inference with variant effect predictors, PIES predicts pathogenic missense mutations and improves variant prioritization for genetic diagnostics and newborn screening.

genetics↗

bioRxiv2025

A computational SOX10 network-based selection strategy to identify new drug targets in uveal melanoma

Uveal melanoma (UM) is the most common intraocular malignancy in adults. In contrast to cutaneous melanoma (CM), effective treatment options for metastatic UM are limited. The transcription factor SOX10 is crucial for CM initiation and survival, making it an interesting candidate for new targeted therapies, but its relevance in UM was unclear. We found that SOX10 was widely expressed in UM and essential for proliferation, cell cycle progression, and survival. The effects were partially mediated by SOX10-related genes including MITF, highlighting high addiction of UM to the SOX10-MITF axis. Additionally, SOX10 knockdown induced massive transcriptomic changes. Due to a lack of specific inhibitors of SOX10 and MITF, a computational approach was used to identify druggable targets by curating a UM-specific protein interaction network to search for candidates downregulated upon SOX10 inhibition. Thereby, the E2F transcription factor family was identified and their potential as druggable target candidates in UM was confirmed using the pan-E2F inhibitor HLM006474, resulting in cell cycle arrest and apoptosis. Taken together, SOX10 is crucial for UM survival and SOX10-associated proteins may serve as promising targets for developing new therapeutic strategies in UM.

cancer biology↗

bioRxiv2023

Effects of Polyphosphate metabolism Mutations on Biofilm, Capsule Formation and Virulence Traits in Hypervirulent ST23 Klebsiella pneumoniae SGH10

The emergence of hypervirulent Klebsiella pneumoniae (hvKP) strains poses a significant threat to public health due to their high mortality rates and propensity to cause severe community-acquired infections in otherwise healthy individuals. The ability of hvKP to form biofilms and produce a protective capsule contributes to its enhanced virulence and is a significant challenge to effective antibiotic treatment. Therefore, understanding the molecular mechanisms underlying hvKP virulence and biofilm formation is crucial for developing new therapeutic strategies. Polyphosphate Kinase 1 (PPK1) is an enzyme responsible for inorganic polyphosphate synthesis and plays a vital role in regulating various physiological processes in bacteria. In this study, we investigated the impact of polyP metabolism on the biofilm and capsule formation and virulence traits in hvKP using Dictyostelium discoideum amoeba as a model host. We found that the PPK1 null-mutant was impaired in biofilm and capsule formation and showed attenuated virulence in D. discoideum compared to the wild-type strain. We performed a shotgun proteomic analysis of the PPK1 mutant and wild-type strain to gain further insight into the underlying molecular mechanism. The results revealed that the PPK1 mutant had a differential expression of proteins (DEP) involved in capsule synthesis (Wzi - Ugd), biofilm formation (MrkC-D-H), synthesis of the colibactin genotoxin precursor (ClbB), as well as proteins associated with the synthesis and modification of lipid A (ArnB -LpxC - PagP). These proteomic findings corroborate the phenotypic observations and indicate that the PPK1 mutation is associated with impaired biofilm and capsule formation and attenuated virulence in hypervirulent K. pneumoniae. Overall, our study highlights the importance of polyP synthesis in regulating extracellular biomolecules and virulence in K. pneumoniae and provides insights into potential therapeutic targets for treating K. pneumoniae infections.

microbiology↗

bioRxiv2022

Recurrent mutation in the ancestry of a rare variant

Recurrent mutation produces multiple copies of the same allele which may be co-segregating in a population. Yet most analyses of allele-frequency or site-frequency spectra assume that all observed copies of an allele trace back to a single mutation. We develop a sampling theory for the number of latent mutations in the ancestry of a rare variant, specifically a variant observed in relatively small count in a large sample. Our results follow from the statistical independence of low-count mutations, which we show to hold for the standard neutral coalescent or diffusion model of population genetics as well as for more general coalescent trees. For populations of constant size, these counts are given by the Ewens sampling formula. We develop a Poisson sampling model for populations of varying size, and illustrate it using new results for site-frequency spectra in an exponentially growing population. We apply our model to a large data set of human SNPs and use it to explain dramatic differences in site-frequency spectra across the range of mutation rates in the human genome.

evolutionary biology↗

bioRxiv2022

Mutation rates and adaptive variation among the clinically dominant clusters of Mycobacterium abscessus

Mycobacterium abscessus (Mab) is a multi-drug resistant pathogen increasingly responsible for severe pulmonary infections. Analysis of whole genome sequences (WGS) of Mab demonstrates dense genetic clustering of clinical isolates collected from disparate geographic locations. This has been interpreted as supporting patient-to-patient transmission, but epidemiological studies have contradicted this interpretation. Here we present evidence for a slowing of the Mab molecular clock rate coincident with the emergence of phylogenetic clusters. We find that clustered isolates are enriched in mutations affecting DNA repair machinery and have lower spontaneous mutation rates in vitro. We propose that Mab adaptation to the host environment through variation in DNA repair genes affects the organisms mutation rate and that this manifests as phylogenetic clustering. These results inform our understanding of niche switching for facultative pathogens and challenge the model of transmission as the major mode of dissemination of clinically dominant Mab clusters.

genomics↗

bioRxiv2022

Correlation of biomechanics and cancer cell phenotype by combined Brillouin and Raman spectroscopy of U87-MG glioblastoma cells

The elucidation of biomechanics furthers understanding of brain tumor biology. Brillouin spectroscopy is a new optical method that addresses viscoelastic properties down to subcellular resolution in contact-free manner. Moreover, it can be combined with Raman spectroscopy to obtain co-localized biochemical information. Here, we applied co-registered Brillouin and Raman spectroscopy to U87-MG human glioblastoma cells in vitro. Using 2D and 3D cultures, we related biomechanical properties with local biochemical composition at subcellular level, as well as cell phenotype. Brillouin and Raman mapping of adherent cells showed that the nucleus and nucleoli are stiffer than the perinuclear region and the cytoplasm. The biomechanics of cell cytoplasm is affected by culturing conditions, i.e. cells grown as spheroids being stiffer than adherent cells. Inside the spheroids, the presence of lipid droplets as assessed by Raman spectroscopy reveals higher Brillouin shifts which is not related to local stiffness increase, but due to a higher refractive index combined with a lower mass density. This highlights the importance of locally defined biochemical reference data for a correct interpretation of the Brillouin shift of cells and tissue in future studies investigating the biomechanics of brain tumor models by Brillouin spectroscopy.

biophysics↗

bioRxiv2022

Candidates for Drug Repurposing to Address the Cognitive Symptoms in Schizophrenia

In the protein-protein interactome, we have previously identified a significant overlap between schizophrenia risk genes and genes associated with cognitive performance. Here, we further studied this overlap to identify potential candidate drugs for repurposing to treat the cognitive symptoms in schizophrenia. We first defined a cognition-related schizophrenia interactome from network propagation analyses, and identified drugs known to target more than one protein within this network. Thereafter, we used gene expression data to further select drugs that could counteract schizophrenia-associated gene expression perturbations. Additionally, we stratified these analyses by sex to identify sex-specific pharmacological treatment options for the cognitive symptoms in schizophrenia. After excluding drugs contraindicated in schizophrenia, we identified eight drug candidates, most of which have anti-inflammatory and neuroprotective effects. Due to gene expression differences in male and female patients, four of those drugs were also selected in our male-specific analyses, and the other four in the female-specific analyses. Based on our bioinformatics analyses of disease genetics, we suggest eight candidate drugs that warrant further examination for repurposing to treat the cognitive symptoms in schizophrenia, and suggest that these symptoms could be addressed by sex-specific pharmacological treatment options.

genetics↗

bioRxiv2022

A theory of cortical map formation in the visual brain

The cerebral cortex receives multiple afferents from the thalamus that segregate by stimulus modality forming cortical maps for each sense. In vision, the primary visual cortex maps the multiple dimensions of the visual stimulus in patterns that vary across species for reasons unknown. Here we introduce a general theory of cortical map formation, which proposes that map diversity emerges from species variations in the thalamic afferent density sampling sensory space. In the theory, increasing afferent sampling density enlarges the cortical domains representing the same visual point, allowing the segregation of afferents and cortical targets by multiple stimulus dimensions. We illustrate the theory with an afferent-density model that accurately replicates the maps of different species through afferent segregation followed by thalamocortical convergence pruned by visual experience. Because thalamocortical pathways use similar mechanisms for axon segregation and pruning, the theory may extend to other sensory areas of the mammalian brain.

neuroscience↗

bioRxiv2021

Longitudinal effects of using and discontinuing CNS medications on cognitive functioning

PurposeTo investigate the longitudinal effect of using and discontinuing central nervous system (CNS) medications on cognitive performance. MethodsUsing longitudinal cognitive data from healthy adults aged 25-100 years (N = 2,188) from four test waves five years apart, we investigated both the link between use of CNS medications (opioids, antidepressants, and anxiolytics, hypnotics and sedatives) on cognitive task performance (episodic memory, semantic memory, visuospatial ability) across 15 years, and the effect of discontinuing these medications in linear mixed effects models. ResultsWe found that opioid use was associated with decline in visuospatial ability, whereas antidepressant use was associated with decline in semantic memory over 15 years. A link between drug discontinuation and cognitive improvement was seen for opioids, antidepressants as well as for anxiolytics, hypnotics and sedatives. ConclusionsAlthough our results may be confounded by subjacent conditions, they suggest that long-term use of CNS medications may have domain-specific negative effects on cognitive performance over time, whereas the discontinuation of these medications may partly reverse these effects. These results open up for future studies that address subjacent conditions on cognition to develop a more complete understanding of the cognitive effects of CNS medications. Key pointsO_LIOpioid use was associated with decline in visuospatial ability, and individuals discontinuing using opioids showed improvement in visuospatial ability compared to individuals continuing using opioids. C_LIO_LIAntidepressant use was associated with decline in semantic memory, and individuals discontinuing using antidepressants showed improvement in semantic memory compared to individuals continuing using antidepressants. C_LIO_LIFor anxiolytics, hypnotics and sedatives there was no difference between continued users and non-users, but drug discontinuation was associated with more positive cognitive development both in episodic memory and visuospatial ability. C_LI

pharmacology and toxicology↗

bioRxiv2021

Altered cortical processing of sensory input in Huntington disease mouse models

Huntington disease (HD), a hereditary neurodegenerative disorder, manifests as progressively impaired movement and cognition. Although early abnormalities of neuronal activity in striatum are well established in HD models, there are fewer in vivo studies of the cortex. Here, we record local field potentials (LFPs) in YAC128 HD model mice versus wild-type mice. In multiple cortical areas, limb sensory stimulation evokes a greater change in LFP power in YAC128 mice. Mesoscopic imaging using voltage-sensitive dyes reveal more extensive spread of evoked sensory signals across the cortical surface in YAC128 mice. YAC128 layer 2/3 sensory cortical neurons ex vivo show increased excitatory events, which could contribute to enhanced sensory responses in vivo. Cortical LFP responses to limb stimulation, visual and auditory input are also significantly increased in zQ175 HD mice. Results presented here extend knowledge of HD beyond ex vivo studies of individual neurons to the intact cortical network.

neuroscience↗

bioRxiv2021

Sex-specific effects of polygenic risk for schizophrenia on lifespan cognitive functioning in healthy individuals

Polygenic risk for schizophrenia has been associated with lower cognitive ability and age-related cognitive change in healthy individuals. Despite well-established neuropsychological sex differences in schizophrenia patients, genetic studies on sex differences in schizophrenia in relation to cognitive phenotypes are scarce. Here, we investigated whether the effect of a polygenic risk score (PRS) for schizophrenia on childhood, midlife and late life cognitive function in healthy individuals is modified by sex, and if PRS is linked to accelerated cognitive decline. Using a longitudinal data set from healthy individuals aged 25-100 years (N = 1,459) spanning a 25-year period, we found that PRS was associated with lower cognitive ability (episodic memory, semantic memory, visuospatial ability), but not with accelerated cognitive decline. A significant interaction effect between sex and PRS was seen on cognitive task performance, and sex-stratified analyses showed that the effect of PRS was male-specific. In a sub-sample, we observed a male-specific effect of the PRS on school performance at age 12 (N = 496). Our findings of sex-specific effects of schizophrenia genetics on cognitive functioning across the life-span indicate that the effects of underlying disease genetics on cognitive functioning is dependent on biological processes that differ between the sexes.

genomics↗

bioRxiv2020

Polygenic adaptation of rosette growth variation in Arabidopsis thaliana populations

The rate at which plants grow is a major functional trait in plant ecology. However, little is known about its evolution in natural populations. Here, we investigate evolutionary and environmental factors shaping variation in the growth rate of Arabidopsis thaliana. We used plant diameter as a proxy to monitor plant growth over time in environments that mimicked latitudinal differences in the intensity of natural light radiation, across a set of 278 genotypes sampled within four broad regions, including an outgroup set of genotypes from China. A field experiment conducted under natural conditions confirmed the ecological relevance of the observed variation. All genotypes markedly expanded their rosette diameter when the light supply was decreased, demonstrating that environmental plasticity is a predominant source of variation to adapt plant size to prevailing light conditions. Yet, we detected significant levels of genetic variation both in growth rate and growth plasticity. Genome-wide association studies revealed that only 2 single nucleotide polymorphisms associate with genetic variation for growth above Bonferroni confidence levels. However, marginally associated variants were significantly enriched among genes with an annotated role in growth and stress reactions. Polygenic scores computed from marginally associated variants confirmed the polygenic basis of growth variation. For both light regimes, phenotypic divergence between the most distantly related population (China) and the various regions in Europe is smaller than the variation observed within Europe, indicating that some level of stabilizing selection constrains the evolution of growth rate. We observed that Spanish genotypes, however, reach a significantly larger size than Northern European genotypes. Tests of adaptive divergence and analysis of the individual burden of deleterious mutations reveal that adaptive processes have played a more important role in shaping regional differences in rosette growth than maladaptive evolution.

evolutionary biology↗

bioRxiv2019

Maintenance of adaptive dynamics in a bottlenecked range-edge population that retained outcrossing

During range expansion, edge populations are expected to face increased genetic drift, which in turn can alter and potentially compromise adaptive dynamics, preventing the removal of deleterious mutations and slowing down adaptation. Here, we contrast populations of the European sub-species Arabidopsis lyrata ssp petraea, which expanded its Northern range after the last glaciation. We document a sharp decline in effective population size in the range-edge population and observe that non-synonymous variants segregate at higher frequencies. We detect a 4.9% excess of derived non-synonymous variants per individual in the range-edge population, suggesting an increase of the genomic burden of deleterious mutations. Inference of the fitness effects of mutations and modeling of allele frequencies under the explicit demographic history of each population predicts a depletion of rare deleterious variants in the range-edge population, but an enrichment for fixed ones, consistent with the bottleneck effect. However, the demographic history of the range-edge population predicts a small net decrease in per-individual fitness. Consistent with this prediction, the range-edge population is not impaired in its growth and survival measured in a common garden experiment. We further observe that the allelic diversity at the self-incompatibility locus, which ensures strict outcrossing and evolves under negative frequency-dependent selection, has remained unchanged. Genomic footprints indicative of selective sweeps are broader in the Northern population but not less frequent. We conclude that the outcrossing species A. lyrata ssp petraea shows a strong resilience to the effect of range expansion.

evolutionary biology↗

bioRxiv2019

Restoring ancestral phenotypes by reduction of plasticity is a general pattern in gene expression during adaptation to different stressors in Tribolium castaneum

Plasticity and evolution are two processes individuals to respond to environmental change, but how both are related and impact each other is still controversial. We studied plastic and evolutionary responses in gene expression of Tribolium castaneum after exposure to new environments that differed from ancestral conditions in temperature, humidity or both. Using experimental evolution with ten replicated lines per condition, we were able to demonstrate adaptation after 20 generations. We measured gene expression in each condition in adapted selection lines and control lines to infer evolutionary and plastic changes. We found more evidence for changes in mean expression (shift in the intercept of reaction norms) in adapted lines than for changes in plasticity (shifts in slopes). Plasticity was mainly preserved and was responsible for a large part of the phenotypic divergence in expression between ancestral and new conditions. However, we found that genes with the largest evolutionary changes in expression also evolved reduced plasticity and often showed expression levels closer to the ancestral stage. Results obtained in the three different conditions were similar suggesting that restoration of ancestral expression levels during adaptation is a general evolutionary pattern. We increased the sample size in the most stressful condition and were then able to detect a positive correlation between proportion of genes with reversion of the ancestral plastic response and mean fitness per selection line.

evolutionary biology↗

bioRxiv2018

The effects of demography and genetics on the neutral distribution of quantitative traits

1Neutral models for quantitative trait evolution are useful for identifying phenotypes under selection in natural populations. Models of quantitative traits often assume phenotypes are normally distributed. This assumption may be violated when a trait is affected by relatively few genetic variants or when the effects of those variants arise from skewed or heavy-tailed distributions. Traits such as gene expression levels and other molecular phenotypes may have these properties. To accommodate deviations from normality, models making fewer assumptions about the underlying trait genetics and patterns of genetic variation are needed. Here, we develop a general neutral model for quantitative trait variation using a coalescent approach by extending the framework developed by SO_SCPLOWCHRAIBERC_SCPLOW and LO_SCPLOWANDISC_SCPLOW (2015). This model allows interpretation of trait distributions in terms of familiar population genetic parameters because it is based on the coalescent. We show how the normal distribution resulting from the infinitesimal limit, where the number of loci grows large as the effect size per mutation becomes small, depends only on expected pairwise coalescent times. We then demonstrate how deviations from normality depend on demography through the distribution of coalescence times as well as through genetic parameters. In particular, population growth events exacerbate deviations while bottlenecks reduce them. This model also has practical applications, which we demonstrate by designing an approach to simulate from the null distribution of QST, the ratio of the trait variance between subpopulations to that in the overall population. We further show that it is likely impossible to distinguish sparsity from skewed or heavy-tailed distributions of mutational effects using only trait values sampled from a population. The model analyzed here greatly expands the parameter space for which neutral trait models can be designed.

evolutionary biology↗

bioRxiv2018

An insulin, AMPK, and steroid hormone-mediated metabolic switch regulates the transition between growth and diapause in C. elegans

The balance between growth and quiescence depends on the global metabolic state. The dauer larva of C. elegans, a developmentally arrested stage for survival under adverse environment, undergoes a major metabolic transition. Here, we show that this switch involves the concerted activity of several regulatory pathways. Whereas the steroid hormone receptor DAF-12 controls dauer morphogenesis, the insulin pathway maintains low energy expenditure through DAF-16/FoxO, which also requires AAK-2/AMPK. DAF-12 and AAK-2 separately promote a shift in the molar ratios between competing enzymes at two key branch points within the central carbon metabolic pathway. This way, carbon atoms are diverted from the TCA cycle and directed to gluconeogenesis. When both AAK-2 and DAF-12 are suppressed, the TCA cycle is active and the developmental arrest is bypassed. Hence, the metabolic status of each developmental stage is defined by stoichiometric ratios within the constellation of metabolic enzymes and controls the transition between growth and quiescence.

biochemistry↗