Biology subjects

Vicario, R.

Publications and source records attributed to Vicario, R..

3 recordsLinked to original sources

bioRxiv2026

A comprehensive atlas of somatic mutation rates and mutational signatures in normal human cells

Over the course of a lifetime, somatic mutations accrue in normal human cells, causing variation in cell phenotype and engendering somatic evolution with outcomes ranging from the adaptive immune system to cancer. To inform understanding of somatic evolution in the human body we report the mutation rates and mutational signatures of 53 normal cell types. Most show evidence of linear mutation accumulation over time with single base substitution mutation rates ranging from ~3.5/year/diploid genome in spermatogonia and sperm, to ~20/year in postmitotic neurons, ~50/year in mitotically active colorectal epithelial cells, ~60/year in kidney proximal tubule cells and hepatocytes, 100s/year in sun-exposed skin epidermal cells and 10-50/year in the remainder. Certain cell types, including skin epidermis, cardiac myocytes, bladder urothelium, kidney proximal tubule cells, and hepatocytes, show substantial variability in mutation burdens around the linear age trend, indicating the influence of additional factors which differ between individuals and modulate mutation accumulation, including exogenous mutagen exposures. At least 18 single-base substitution and nine small insertion and deletion mutational signatures are present, some in all cell types, some in a subset and others in a single cell type. Known exogenous mutagen exposures and endogenous mutational processes account for some mutational signatures, but the origins and mechanisms underlying many are uncertain. This comprehensive survey of mutagenesis provides a foundation for understanding somatic evolution of human cell populations in health and disease.

genomics↗

bioRxiv2024

Mechanism of neurodegeneration mediated by clonal inflammatory microglia

Langerhans cell Histiocytosis (LCH) and Erdheim-Chester disease (ECD) are clonal myeloid disorders, associated with MAP-Kinase activating mutations and an increased risk of neurodegeneration. Surprisingly, we found pervasive PU.1+ microglia mutant clones across the brain of LCH and ECD patients with and without neurological symptoms, associated with microgliosis, reactive astrocytosis, and neuronal loss. The disease predominated in the grey nuclei of the rhombencephalon, a topography attributable to a local proliferative advantage of mutant microglia. Presence of clinical symptoms was associated with a longer evolution of the disease and a larger size of PU.1+ clones (p= 0.0003). Genetic lineage tracing of PU.1+ clones suggest a resident macrophage lineage or a bone marrow precursor origin depending on patients. Finally, a CSF1R-inhibitor depleted mutant microglia and limited neuronal loss in mice suggesting an alternative to MAPK inhibitors. These studies characterize a progressive neurodegenerative disease, caused by clonal proliferation of inflammatory microglia (CPIM), with a decade(s)-long preclinical stage of incipient disease that represent a therapeutic window for prevention of neuronal death.

immunology↗

bioRxiv2024

A microglia clonal inflammatory disorder in Alzheimer's Disease

Somatic genetic heterogeneity resulting from post-zygotic DNA mutations is widespread in human tissues and can cause diseases, however few studies have investigated its role in neurodegenerative processes such as Alzheimers Disease (AD). Here we report the selective enrichment of microglia clones carrying pathogenic variants, that are not present in neuronal, glia/stromal cells, or blood, from patients with AD in comparison to age-matched controls. Notably, microglia-specific AD-associated variants preferentially target the MAPK pathway, including recurrent CBL ring-domain mutations. These variants activate ERK and drive a microglia transcriptional program characterized by a strong neuro-inflammatory response, both in vitro and in patients. Although the natural history of AD-associated microglial clones is difficult to establish in human, microglial expression of a MAPK pathway activating variant was previously shown to cause neurodegeneration in mice, suggesting that AD-associated neuroinflammatory microglial clones may contribute to the neurodegenerative process in patients. One-Sentence SummaryA subset of Alzheimer Disease patients carry mutant microglia somatic clones which promote neuro-inflammation.

neuroscience↗