Biology subjects

Kampman, L.

Publications and source records attributed to Kampman, L..

5 recordsLinked to original sources

bioRxiv2026

Massive-scale single-nucleus multi-omics identifies novel rare noncoding drivers of Parkinson's disease

Most genetic variants contributing to complex diseases reside in the noncoding genome. While common variants uncovered by genome-wide association studies often fail to explain much of the observed heritability of these diseases, rare variants often have higher effect sizes and cumulatively explain a larger portion of heritability. However, rare variants, particularly rare noncoding variants, have remained under-characterized largely due to the difficulties of accurately predicting variant functionality at scale, given that each individual carries an average of [~]10,000 rare variants. Here, we generated multi-omic data from >3.3 million nuclei sampled from five brain regions across a cohort of 80 individuals with Parkinsons disease (PD) and 21 neurologically normal control individuals with matched 30x whole-genome sequencing. We use this data to identify cell type-specific features of PD, map cell type-specific chromatin accessibility and expression quantitative trait loci, and train machine learning models to predict the effect of variants on gene regulation. We identify rare noncoding variants statistically associated with sporadic PD and extend our approaches to predict drivers of familial PD of unknown genetic origin. Our results underscore the significance of rare noncoding variants in complex diseases and provide a roadmap for applying similar approaches in other disease systems.

genetics↗

bioRxiv2026

Complete definition of how mutations affect antibodies used to prevent RSV

New antibodies targeting the F protein of RSV have substantially reduced infant hospitalizations. However, viral resistance is a concern: one antibody failed clinical trials due to a resistant strain, and sporadic resistance mutations to the most widely used antibody (nirsevimab) have been identified. Here we define how RSV F mutations affect antibody neutralization. We first provide a biophysical model of how the buffering of bivalent IgG binding combines with the lower Fab potency of nirsevimab to subtype B to make resistance to this antibody more common in subtype B than A strains. We then perform pseudovirus deep mutational scanning to safely measure how nearly all mutations to F affect its cell entry function and neutralization by IgG and Fab forms of nirsevimab, clesrovimab, and several other key antibodies. We use these measurements to enable real-time surveillance of RSV sequences for antibody resistance, and show that resistant strains have arisen sporadically but are currently rare. Overall, our work shows how Fab potency and epitope specificity combine to determine how viral mutations impact antibody neutralization, enables monitoring for natural RSV strains resistant to antibodies of public-health importance, and can help guide development of future antibodies with resilience to viral escape.

microbiology↗

bioRxiv2025

Spike mutations that affect the function and antigenicity of recent KP.3.1.1-like SARS-CoV-2 variants

SARS-CoV-2 is under strong evolutionary selection to acquire mutations in its spike protein that reduce neutralization by human polyclonal antibodies. Here we use pseudovirus-based deep mutational scanning to measure how mutations to the spike from the recent KP.3.1.1 SARS-CoV-2 strain affect cell entry, binding to ACE2 receptor, RBD up/down motion, and neutralization by human sera and clinically relevant antibodies. The spike mutations that most affect serum antibody neutralization sometimes differ between sera collected before versus after recent vaccination or infection, indicating these exposures shift the neutralization immunodominance hierarchy. The sites where mutations cause the greatest reduction in neutralization by post-vaccination or infection sera include receptor-binding domain (RBD) sites 475, 478 and 487, all of which have mutated in recent SARS-CoV-2 variants. Multiple mutations outside the RBD affect sera neutralization as strongly as any RBD mutations by modulating RBD up/down movement. Some sites that affect RBD up/down movement have mutated in recent SARS-CoV-2 variants. Finally, we measure how spike mutations affect neutralization by three clinically relevant SARS-CoV-2 antibodies: VYD222, BD55-1205, and SA55. Overall, these results illuminate the current constraints and pressures shaping SARS-CoV-2 evolution, and can help with efforts to forecast possible future antigenic changes that may impact vaccines or clinical antibodies. ImportanceThis study measures how mutations to the spike of a SARS-CoV-2 variant that circulated in early 2025 affect its function and recognition by both the polyclonal antibodies produced by the human immune system and monoclonal antibodies used as prophylactics. These measurements are made with a pseudovirus system that enables safe study of viral protein mutations using virions that can only infect cells once. The study identifies mutations that decrease recognition by current human antibody immunity; many of these mutations are increasingly being observed in new viral variants. It also shows the importance of mutations that move the spikes receptor binding domain up or down. Overall, these results are useful for forecasting viral evolution and assessing which newly emerging variants have reduced recognition by immunity and antibody prophylactics.

microbiology↗

bioRxiv2023

Signatures of Jamming in the Cellular Potts Model

We explore the jamming transition in the Cellular Potts Model (CPM) as a function of confinement, cell adhesion, and cell shape. To accurately characterize jamming, we compare Potts simulations of unconfined single cells, cellular aggregates, and confluent monolayers as a function of cell adhesion energies and target cell shape. We consider metrics that may identify signatures of the jamming transition, including diffusion coefficients, anomalous diffusion exponents, cell shape, cell-cell rearrangements, and velocity correlations. We find that the onset of jamming coincides with an abrupt drop in cell mobility, rapid transition to sub-diffusive behavior, and cessation of rearrangements between neighboring cells that is unique to confluent monolayers. Velocity correlations reveal collective migration as a natural consequence of high energy barriers to neighbor rearrangements for certain cell types. Cell shapes across the jamming transition in the Potts model are found to be generally consistent with predictions of vertex-type simulations and trends from experiment. Finally, we demonstrate that changes in cell shape can fluidize cellular monolayers at cellular interaction energies where jamming otherwise occurs.

biophysics↗

bioRxiv2022

Evolutionary rescue is promoted in compact cellular populations

Mutation-mediated drug resistance is one of the primary causes for the failure of modern antibiotic or chemotherapeutic treatment. Yet, in the absence of treatment many drug resistance mutations are associated with a fitness cost and therefore subject to purifying selection. While, in principle, resistant subclones can escape purifying selection via subsequent compensatory mutations, current models predict such evolutionary rescue events to be exceedingly unlikely. Here, we show that the probability of evolutionary rescue, and the resulting long-term persistence of drug resistant subclones, is dramatically increased in dense microbial populations via an inflation-selection balance that stabilizes the less-fit intermediate state. Tracking the entire evolutionary trajectory of fluorescence-augmented "synthetic mutations" in expanding yeast colonies, we trace the origin of this balance to the opposing forces of radial population growth and a clone-width-dependent weakening of selection pressures, inherent to crowded populations. Additionally conducting agent-based simulations of tumor growth, we corroborate the fundamental nature of the observed effects and demonstrate the potential impact on drug resistance evolution in cancer. The described phenomena should be considered when predicting the evolutionary dynamics of any sufficiently dense cellular populations, including pathogenic microbial biofilms and solid tumors, and their response to therapeutic interventions. Our experimental approach could be extended to systematically study rates of specific evolutionary trajectories, giving quantitative access to the evolution of complex adaptations.

biophysics↗