Biology subjects

Peter, B.

Publications and source records attributed to Peter, B..

11 recordsLinked to original sources

bioRxiv2026

Developmental Convergence Across Diverse Genetic Architectures in Childhood Apraxia of Speech

Childhood apraxia of speech (CAS) is a neurodevelopmental disorder of speech-motor planning and programming, associated with literacy, academic, and psychosocial difficulties. We performed whole-exome sequencing in 11 families comprising 21 affected and 15 unaffected individuals with phenotyping spanning speech, language, cognition, literacy, and motor function. We identified 60 prioritized variant observations representing 22 unique variants across 20 genes with family-based segregation analysis assessed in informative relatives; 5 arose de novo. Our cohort included multiple affected siblings and extended relatives, with several families carrying multiple prioritized variants, suggesting cumulative or oligogenic susceptibility. Speech and literacy impairment co-occurred with oral-motor, feeding, and fine-motor difficulties. BrainSpan co-expression analysis identified MECP2 and ANK2 as the genes with the highest observed connectivity in the sampled postnatal network. Exploratory analysis of the KOLF2.1J perturbation atlas in undifferentiated human induced pluripotent stem cells identified a positive LMO3 expression-response score following NIPBL repression and opposing LMO3 and ANK2 response directions within a cohesin-associated perturbation cluster. These observations motivate testing in human neural cells. Functional enrichment, protein-association, and developmental-expression analyses supported shared biological themes involving chromatin regulation, neuronal signaling, and extracellular-matrix organization. Among six families, multiple affected relatives shared prioritized variants across a unique set of several genes, demonstrating multilocus candidate profiles whose individual and combined effects may contribute to CAS susceptibility. We propose four novel CAS candidate genes: LMO3 and PCDH10, previously linked to human accelerated regions, as well as MYCBP2 and PTPRS. Our work provides multiple testable hypotheses for future variant-specific functional validation in speech-motor development.

genetics↗

bioRxiv2025

The Rise and Fall of SARM1 Base-Exchange Inhibitors

The sterile alpha and TIR motif containing 1 (SARM1) enzyme is a key driver of axonal degeneration in response to injury, making it an attractive target for treating chemotherapy-induced peripheral neuropathy (CIPN) and other nervous system diseases. In this study, we identified and optimised a new class of base-exchange inhibitors (BEXi) targeting SARM1 and explored their molecular interactions and conformational effects using cryo-EM, HDX-MS and SAXS. Although BEXi produced robust inhibition across all biochemical and cellular assay formats, application at sub-inhibitory concentrations consistently led to paradoxical SARM1 activation, and in neuronal assays, accelerated neurite degeneration. Further analysis showed that BEXi only delayed, rather than prevented, neurite degeneration when applied to primary neuronal cells, even at exceedingly high inhibitor concentrations. These results prompted us to discontinue BEXi development in favour of alternative strategies, underscoring the complexity of SARM1 as a therapeutic target and the need for comprehensive, mechanistically informed screening cascades.

neuroscience↗

bioRxiv2024

Fully-Automated Multicolour Structured Illumination Module for Super-resolution Microscopy

In the rapidly advancing field of biological imaging, there is a great need for high-resolution imaging techniques that are both cost-effective and accessible, for example to better observe and understand dynamics in intracellular processes. Structured illumination microscopy (SIM) is the method of choice to achieve high axial and lateral resolution in living samples due to its optical sectioning and minimal phototoxicity. However, the high cost and complexity of conventional SIM systems limit their wide application. In our work, we present an open-source, fully-automated, two-color structured illumination module that is compatible with commercially available microscope stands. The compact design, consisting of low-cost single-mode fiber-coupled lasers and a digital micromirror device (DMD), is integrated into the open-source acquisition and control software (ImSwitch) in order to realize real-time super-resolution imaging. This developed system achieves up to a 1.55-fold improvement in lateral resolution compared to conventional wide-field microscopy. To rationally design this module, we developed a model to ensure optimal DMD diffraction per-formance using tilt and roll pixels, thus covering a wide range of low-cost video projectors for use in coherent SIM setups. Our goal is to democratize SIM-based super-resolution microscopy by providing both comprehensive open-source documentation and a modular software framework that works with various hardware components (e.g. cameras, stages) and reconstruction algorithms. In this way, we try to upgrade as many devices as possible to the super-resolution realm.

cell biology↗

bioRxiv2024

Joint exome and metabolome analysis in individuals with dyslexia: Evidence for associated dysregulations of olfactory perception and autoimmune functions

Dyslexia is a learning disability that negatively affects reading, writing, and spelling development at the word level in 5%-9% of children. The phenotype is variable and complex, involving several potential cognitive and physical concomitants such as sensory dysregulation and immunodeficiencies. The biological pathogenesis is not well-understood. Toward a better understanding of the biological drivers of dyslexia, we conducted the first joint exome and metabolome investigation in a pilot sample of 30 participants with dyslexia and 13 controls. In this analysis, eight metabolites of interest emerged (pyridoxine, kynurenic acid, citraconic acid, phosphocreatine, hippuric acid, xylitol, 2-deoxyuridine, and acetylcysteine). A metabolite-metabolite interaction analysis identified Krebs cycle intermediates that may be implicated in the development of dyslexia. Gene ontology analysis based on exome variants resulted in several pathways of interest, including the sensory perception of smell (olfactory) and immune system-related responses. In the joint exome and metabolite analysis, the olfactory transduction pathway emerged as the primary pathway of interest. Although the olfactory transduction and Krebs cycle pathways have not previously been described in dyslexia literature, these pathways have been implicated in other neurodevelopmental disorders including autism spectrum disorder and obsessive-compulsive disorder, suggesting the possibility of these pathways playing a role in dyslexia as well. Immune system response pathways, on the other hand, have been implicated in both dyslexia and other neurodevelopmental disorders.

bioinformatics↗

bioRxiv2024

Selection for later flowering time in an orchid through frost damage and pollinator activity

Flowering time is a key trait for plant reproductive success ensuring both overlap with pollinator activity and favorable conditions for fruit development. To quantify selection on flowering time, we individually marked 1250 plants of the Small Spider Orchid, Ophrys araneola RchB., in six populations in Northern Switzerland and surveyed them during three years. We recorded the date of first flowering, frost damage, and fruiting success of individual plants. In addition, we analyzed historical records of the orchid and its only verified pollinator, the solitary bee Andrena combinata in Northern Switzerland, to estimate potential desynchronization due to climate change. We documented strong selection for later flowering driven by frost damage, with all populations showing significant selection for later flowering in at least one year. Selection for later flowering driven by pollination (fruit set) could only be analyzed in one population due to the overall low fruit set, where it was significant in one year. The historical data from between 1970 and 2019 indicated low synchronization between orchid flowering and bee occurrence, with mean flowering three weeks earlier than the mean peak of bee occurrence, corroborating selection for later flowering through fruit set. The data also showed a significant advance of flowering time and bee-occurrence in the last decades, but to a similar degree in orchids and bees, hence without an indication of increasing desynchronization through climate change. Our study shows that selection for later flowering is mostly caused by frost damage, but also by the little synchronized flowering and pollinator activity, which is however unlikely to be a consequence of climate change in this orchid.

evolutionary biology↗

bioRxiv2023

A data-fusion approach to identifying developmental dyslexia from multi-omics datasets

This exploratory study tested and validated the use of data fusion and machine learning techniques to probe high-throughput omics and clinical data with a goal of exploring the etiology of developmental dyslexia. Developmental dyslexia is the leading learning disability in school aged children affecting roughly 5-10% of the US population. The complex biological and neurological phenotype of this life altering disability complicates its diagnosis. Phenome, exome, and metabolome data was collected allowing us to fully explore this system from a behavioral, cellular, and molecular point of view. This study provides a proof of concept showing that data fusion and ensemble learning techniques can outperform traditional machine learning techniques when provided small and complex multi-omics and clinical datasets. Heterogenous stacking classifiers consisting of single-omic experts/models achieved an accuracy of 86%, F1 score of 0.89, and AUC value of 0.83. Ensemble methods also provided a ranked list of important features that suggests exome single nucleotide polymorphisms found in the thalamus and cerebellum could be potential biomarkers for developmental dyslexia and heavily influenced the classification of DD within our machine learning models.

bioinformatics↗

bioRxiv2020

Comparison of induced neurons reveals slower structural and functional maturation in humans than in apes

We generated induced excitatory sensory neurons (iNeurons, iNs) from chimpanzee, bonobo and human stem cells by expressing the transcription factor neurogenin-2 (NGN2). Single cell-RNA sequencing showed that genes involved in dendrite and synapse development are expressed earlier during iNs maturation in the chimpanzee than the human cells. In accordance, during the first two weeks of differentiation, chimpanzee and bonobo iNs showed repetitive action potentials and more spontaneous excitatory activity than human iNs, and extended neurites of higher total length. However, the axons of human iNs were slightly longer at 5 weeks of differentiation. The timing of the establishment of neuronal polarity did not differ between the species. Chimpanzee, bonobo and human neurites eventually reached the same level of structural complexity. Thus, human iNs develop slower than chimpanzee and bonobo iNs and this difference in timing likely depends on functions downstream of NGN2.

evolutionary biology↗

bioRxiv2020

A high-coverage Neandertal genome from Chagyrskaya Cave

We sequenced the genome of a Neandertal from Chagyrskaya Cave in the Altai Mountains, Russia, to 27-fold genomic coverage. We estimate that this individual lived ~80,000 years ago and was more closely related to Neandertals in western Eurasia (1,2) than to Neandertals who lived earlier in Denisova Cave (3), which is located about 100 km away. About 12.9% of the Chagyrskaya genome is spanned by homozygous regions that are between 2.5 and 10 centiMorgans (cM) long. This is consistent with that Siberian Neandertals lived in relatively isolated populations of less than 60 individuals. In contrast, a Neandertal from Europe, a Denisovan from the Altai Mountains and ancient modern humans seem to have lived in populations of larger sizes. The availability of three Neandertal genomes of high quality allows a first view of genetic features that were unique to Neandertals and that are likely to have been at high frequency among them. We find that genes highly expressed in the striatum in the basal ganglia of the brain carry more amino acid-changing substitutions than genes expressed elsewhere in the brain, suggesting that the striatum may have evolved unique functions in Neandertals.

genomics↗

bioRxiv2020

Democratizing water monitoring: Implementation of a community-based qPCR monitoring program for recreational water hazards.

Recreational water monitoring can be challenging due to the highly variable nature of pathogens and indicator concentrations, the myriad of potential biological hazards to measure for, and numerous access points, both official and unofficial, that are used for recreation. The aim of this study was to develop, deploy, and assess the effectiveness of a quantitative polymerase chain reaction (qPCR) community-based monitoring (CBM) program for the assessment of bacterial and parasitic hazards in recreational water. This study developed methodologies for performing qPCR in the field, then engaged with water management and monitoring groups, and tested the method in a real-world implementation study to evaluate the accuracy of CBM using qPCR both quantitatively and qualitatively. This study found high reproducibility between qPCR results performed by non-expert field users and expert laboratory results, suggesting that qPCR as a methodology could be amenable to a CBM program.

scientific communication and education↗

bioRxiv2020

A unified model of species abundance, genetic diversity, and functional diversity revealsthe mechanisms structuring ecological communities

Biodiversity accumulates hierarchically by means of ecological and evolutionary processes and feedbacks. Reconciling the relative importance of these processes is hindered by current theory, which tends to focus on a single spatial, temporal or taxonomic scale. We introduce a mechanistic model of community assembly, rooted in classic island biogeography theory, which makes temporally explicit joint predictions across three biodiversity data axes: i) species richness and abundances; ii) population genetic diversities; and iii) trait variation in a phylogenetic context. We demonstrate that each data axis captures information at different timescales, and that integrating these axes enables discriminating among previously unidentifiable community assembly models. We combine our massive eco-evolutionary synthesis simulations (MESS) with supervised machine learning to fit the parameters of the model to real data and infer processes underlying how biodiversity accumulates, using communities of tropical trees, arthropods, and gastropods as case studies that span a range of spatial scales.

evolutionary biology↗

bioRxiv2018

Human local adaptation of the TRPM8 cold receptor along a latitudinal cline

Ambient temperature is a critical environmental factor for all living organisms. It was likely an important selective force as modern humans recently colonized temperate and cold Eurasian environments. Nevertheless, as of yet we have limited evidence of local adaptation to ambient temperature in populations from those environments. To shed light on this question, we exploit the fact that humans are a cosmopolitan species that inhabits territories under a wide range of temperatures. Focusing on cold perception - which is central to thermoregulation and survival in cold environments-- we show evidence of recent local adaptation on TRPM8. This gene encodes for a cation channel that is, to date, the only temperature receptor known to mediate an endogenous response to moderate cold. The upstream variant rs10166942 shows extreme population differentiation, with frequencies that range from 5% in Nigeria to 88% in Finland (placing this SNP in the 0.02% tail of the FST empirical distribution). When all populations are jointly analysed, allele frequencies correlate with latitude and temperature beyond what can be explained by shared ancestry and population substructure. Using a Bayesian approach, we infer that the allele originated and evolved neutrally in Africa, while positive selection raised its frequency to different degrees in Eurasian populations, resulting in allele frequencies that follow a latitudinal cline. We infer strong positive selection, in agreement with ancient DNA showing high frequency of the allele in Europe 3,000 to 8,000 years ago. rs10166942 is important phenotypically because its ancestral allele is protective of migraine. This debilitating disorder varies in prevalence across human populations, with highest prevalence in individuals of European descent -precisely the population with the highest frequency of rs10166942 derived allele. We thus hypothesize that local adaptation on previously neutral standing variation may have contributed to the genetic differences that exist in the prevalence of migraine among human populations today.\n\nAuthor SummarySome human populations were likely under strong pressure to adapt biologically to cold climates during their colonization of non-African territories in the last 50,000 years. Such putative adaptations required genetic variation in genes that could mediate adaptive responses to cold. TRPM8 is potentially one such gene, being the only known receptor for the sensation of moderate cold temperature. We show that a likely regulatory genetic variant nearby TRPM8 has several signatures of positive selection rising its frequency in Eurasian populations during the last 25,000 years. While the genetic variant was and is rare in Africa, it is now common outside of Africa, with frequencies that strongly correlate with latitude and are highest in northern European populations. Interestingly, this same genetic variant has previously been strongly associated with migraine. This suggests that adaptation to cold has potentially contributed to the variation in migraine prevalence that exists among human groups today.

genetics↗