Seignon, M. | Search bioRxiv

bioRxiv2024

Rates of evolution differ between cell types identified by single-cell RNAseq in threespine stickleback

Rates of evolutionary change vary by gene. While some broad gene categories are highly conserved with little divergence over time, others undergo continuous selection pressure and are highly divergent. Here, we combine single-cell RNA sequencing (scRNAseq) with evolutionary genomics to understand whether certain cell types exhibit faster evolutionary divergence (using their characteristic genes), than other types of cells. Merging scRNAseq with population genomic data, we show that cell types differ in the rate at which their characteristic genes evolve, as measured by allele frequency divergence among many populations (FST) and between species (dN/dS ratios). Neutrophils, B cells, and fibroblasts exhibit elevated FST at characteristic genes, while eosinophils in the intestine and thrombocytes in the head kidney exhibit lower FST than the average for 1000 random genes. Gene network centrality also differed between immune- and non-immune-associated genes, and closeness centrality was positively related to gene FST. These results highlight the value of merging single cell RNA sequencing technology with evolutionary population genomic data, and reveal that genes which define immune cell types exhibit especially rapid evolution.

evolutionary biology↗

bioRxiv2020

Single-cell multimodal glioma analyses reveal epigenetic regulators of cellular plasticity and environmental stress response

Glioma intratumoral heterogeneity enables adaptation to challenging microenvironments and contributes to universal therapeutic resistance. Here, we integrated 914 single-cell DNA methylomes, 55,284 single-cell transcriptomes, and bulk multi-omic profiles across 11 adult IDH-mutant or IDH-wild-type gliomas to delineate sources of intratumoral heterogeneity. We found that local DNA methylation instability, or epimutation burden, was elevated in more aggressive tumors, reflected intratumoral variability, linked with transcriptional disruption, and associated with environmental stress response. We show that the activation of cell-state specific transcription factors is impacted by epimutations and that loosened epigenetic control may facilitate cellular plasticity. Our analyses support that somatic copy number alterations (SCNAs) promote epigenetic instability and that SCNAs largely precede epigenetic and transcriptomic diversification during glioma evolution. We confirmed the link between genetic and epigenetic instability by analyzing larger cohorts of bulk longitudinally collected and spatially separated DNA methylation data. Increased DNA methylation instability was associated with accelerated disease progression, and recurrently selected DNA methylation changes were enriched for environmental stress response pathways. Our work provides an integrative framework to better understand glioma evolution and highlights the importance of epigenetic heterogeneity in shaping therapeutic response.

cancer biology↗