Biology subjects

Normand, R.

Publications and source records attributed to Normand, R..

8 recordsLinked to original sources

bioRxiv2026

A Community-Driven Single-Cell PBMC Reference Integrating Landmark Datasets Spanning Health and Disease

Blood provides an accessible window into human health, yet the absence of a peripheral blood mononuclear cells (PBMCs) reference with standardized immune cell annotations has constrained comparisons between single-cell RNA sequencing (scRNAseq) studies. Here, we present HARP (Human Cell Atlas Reference for PBMCs), an integrated atlas of ~9 million PBMCs from >2,600 donors across 15 studies spanning four continents, encompassing diverse populations, neonates to 97 years, across health and diverse immune-related diseases. We developed optimized integration workflows, including novel label-free metrics to assess integration quality, and generated community-driven consensus annotations for 192 immune cell subsets, identifying rare populations representing as few as 0.004% of PBMCs. HARP reveals coordinated cellular modules associated with age, sex, and disease, identifies female-biased interferon and inflammatory gene programs and their perturbation by COVID-19, and uncovers a novel sexual dimorphism in prostaglandin signaling. Finally, we introduce scTiger, a hierarchical label-transfer framework that accurately projects these 192 cell annotations onto ~18 million additional PBMCs, providing a robust and transferable reference for harmonizing future PBMC studies. HARP provides a high-resolution community-driven reference atlas for PBMC annotation and analysis, as a basis for emerging clinical applications of single-cell genomics.

immunology↗

bioRxiv2026

A mosaic of genomic architectures underpins parasitism loss in a jawless vertebrate

Lampreys are the only ancestrally parasitic vertebrate lineage, yet parasitism has been repeatedly lost alongside a suite of life-history changes, such as loss of migration and juvenile feeding and accelerated maturation. Combining whole-genome resequencing, haplotype-resolved assemblies, hybrid-zone genotyping, multi-tissue transcriptomics, and sperm phenotyping, we map this life-history syndrome in European Lampetra to six chromosomes spanning a mosaic of genomic architectures: a [~]20 Mb low-recombination region on chromosome 1 lacking chromosomal rearrangements within Lampetra but involving inter-specific rearrangements across deep lamprey lineages; a translocated inversion with ecotype-dependent sperm-velocity effects; and ecotype-divergent deletions overlapping genes crucial for nervous system (CNTNAP2) and reproductive development (FSHR). However, this genomic basis is not shared with a convergent sister lineage, pointing to independent routes to a recurring life-history transition in lampreys.

evolutionary biology↗

bioRxiv2025

Meta-analysis reveals the tempo of evolutionary parallelism of local adaptation between native and introduced ranges of plant species

Invasive species are valuable systems for evaluating evolutionary predictability, as populations in native and introduced ranges evolve separately, yet often encounter similar environmental challenges that select for parallel patterns of local adaptation across each range. However, it remains unclear how pervasive and strong such parallelism is and how rapidly it evolves. To address these questions, we first extended cline theory to predict evolutionary patterns of trait cline parallelism between ranges. We then carried out a meta-analysis of clinal divergence in native and introduced populations of the same plant species and evaluated the tempo of trait cline parallelism between ranges. We found that clines in introduced ranges were somewhat shallower than native range clines, and directions of clinal divergence were, on average, partially aligned between ranges, with extensive variation in parallelism among traits and species, including counter-clines between native and introduced ranges. The degree of evolutionary parallelism of clinal divergence strongly increased, and the prevalence of counter-clines decreased, with the time since introduction, where greater parallelism in older introductions was primarily caused by increased alignment in the direction of clinal divergence between ranges rather than changes in their relative magnitudes of divergence. We argue that these observations are consistent with a two-phased process of cline evolution across introduced ranges. In the first phase, misaligned clines between introduced and native ranges can arise during range expansions, often owing to demographic and genetic constraints that initially hinder the evolution of local adaptation within the new range. During the second phase, the evolution of local adaptation eventually resolves early instances of maladaptation across introduced ranges, leading to strong trait cline parallelism between native and introduced ranges.

evolutionary biology↗

bioRxiv2025

Immune-parenchymal multicellular niches are shared across distinct thyroid autoimmune diseases

Thyroid hormone, produced in the thyroid gland, regulates metabolism, development, and cardiac function. The thyroid is susceptible to autoimmune attack by both cellular and humoral immunity exemplified by Hashimotos thyroiditis (HT) and Graves Disease (GD), respectively. In HT, immune-mediated destruction impairs thyroid hormone production, while in GD, stimulating autoantibodies promote over-production. Here, we generated a multi-modal atlas of 604,076 human thyroid and blood cells from HT, GD, and control patients. We found that, despite markedly different clinical presentations and distinct antigenic triggers, HT and GD exhibit convergent cellular dynamics resulting in a shared continuum of immune infiltration. Along this continuum, a key feature is a thyrocyte niche containing CD8+ T cells that may segregate pathogenic T cells from regions with preserved thyroid hormone production. These findings of a shared disease continuum characterized by spatially defined immune niches provide a new framework for understanding tissue homeostasis in human autoimmune disease.

immunology↗

bioRxiv2023

Interpretable Inflammation Landscape of Circulating Immune cells

Inflammation is a biological phenomenon involved in a wide variety of physiological and pathological processes. Although a controlled inflammatory response is beneficial for restoring homeostasis, it can become unfavorable if dysregulated. In recent years, major progress has been made in characterizing acute and chronic inflammation in specific diseases. However, a global, holistic understanding of inflammation is still elusive. This is particularly intriguing, considering the crucial function of inflammation for human health and its potential for modern medicine if fully deciphered. Here, we leverage advances in the field of single-cell genomics to delineate the full spectrum of circulating immune cell activation underlying inflammatory processes during infection, immune-mediated inflammatory diseases and cancer. Our single-cell atlas of >6.5 million peripheral blood mononuclear cells from 1047 patients and 19 diseases allowed us to learn a comprehensive model of inflammation in circulating immune cells. The atlas expanded our current knowledge of the biology of inflammation of immune-mediated diseases, acute and chronic inflammatory diseases, infection and solid tumors, and laid the foundation to develop a precision medicine framework using unsupervised as well as explainable machine learning. Beyond a disease-centered analysis, we charted altered activity of inflammatory molecules in peripheral blood cells, depicting discriminative inflammation-related genes to further understand mechanisms of inflammation. Finally, we have laid the groundwork for developing precision medicine diagnostic tools for patients experiencing pathologic inflammation by learning a classifier for inflammatory diseases, presenting cells in circulation as a powerful resource for patient diagnosis.

immunology↗

bioRxiv2021

A single-cell and spatial atlas of autopsy tissues reveals pathology and cellular targets of SARS-CoV-2

The SARS-CoV-2 pandemic has caused over 1 million deaths globally, mostly due to acute lung injury and acute respiratory distress syndrome, or direct complications resulting in multiple-organ failures. Little is known about the host tissue immune and cellular responses associated with COVID-19 infection, symptoms, and lethality. To address this, we collected tissues from 11 organs during the clinical autopsy of 17 individuals who succumbed to COVID-19, resulting in a tissue bank of approximately 420 specimens. We generated comprehensive cellular maps capturing COVID-19 biology related to patients demise through single-cell and single-nucleus RNA-Seq of lung, kidney, liver and heart tissues, and further contextualized our findings through spatial RNA profiling of distinct lung regions. We developed a computational framework that incorporates removal of ambient RNA and automated cell type annotation to facilitate comparison with other healthy and diseased tissue atlases. In the lung, we uncovered significantly altered transcriptional programs within the epithelial, immune, and stromal compartments and cell intrinsic changes in multiple cell types relative to lung tissue from healthy controls. We observed evidence of: alveolar type 2 (AT2) differentiation replacing depleted alveolar type 1 (AT1) lung epithelial cells, as previously seen in fibrosis; a concomitant increase in myofibroblasts reflective of defective tissue repair; and, putative TP63+ intrapulmonary basal-like progenitor (IPBLP) cells, similar to cells identified in H1N1 influenza, that may serve as an emergency cellular reserve for severely damaged alveoli. Together, these findings suggest the activation and failure of multiple avenues for regeneration of the epithelium in these terminal lungs. SARS-CoV-2 RNA reads were enriched in lung mononuclear phagocytic cells and endothelial cells, and these cells expressed distinct host response transcriptional programs. We corroborated the compositional and transcriptional changes in lung tissue through spatial analysis of RNA profiles in situ and distinguished unique tissue host responses between regions with and without viral RNA, and in COVID-19 donor tissues relative to healthy lung. Finally, we analyzed genetic regions implicated in COVID-19 GWAS with transcriptomic data to implicate specific cell types and genes associated with disease severity. Overall, our COVID-19 cell atlas is a foundational dataset to better understand the biological impact of SARS-CoV-2 infection across the human body and empowers the identification of new therapeutic interventions and prevention strategies.

genomics↗

bioRxiv2020

Tumor-educated uncommitted hematopoietic stem cells promote a metastatic switch

Myeloid skewing of hematopoietic cells is a prominent promoter of metastasis. However, little is known about their education and differentiation pattern from hematopoietic stem and progenitor cells (HSPCs) during tumor progression and metastasis. Here we show that metastatic tumors dictate a unique differentiation pattern of HSPCs towards a specific myeloid progeny. Using single cell RNA-sequencing analysis integrated with proteomic screen of tumor secretome, we demonstrate that highly metastatic tumors dictate a long-lived differentiation of HSPCs towards monocyte-dendritic progenitors (MDPs) while low-metastatic tumors promote their differentiation into granulocyte-monocyte progenitors (GMPs). This effect is driven by IL-6 axis that is highly active in metastatic tumors. Consequently, loss and gain of function of IL-6 in tumor cells resulted in decreased and increased metastasis and corresponding MDP levels, respectively. Consistently, IL-6-educated MDPs but not GMPs obtained from highly metastatic tumors, adoptively transferred into mice bearing low metastatic tumors resulted in increased metastasis due to their further differentiation into immunosuppressive (M2) macrophages. Overall, our study reveals a new role for tumor-derived IL-6 that hijacks HSPC differentiation program towards myeloid cells that contribute to metastasis.

cancer biology↗

bioRxiv2018

Immune cellular homeostasis in early life is determined by genetic variants of cellular production and turnover

Complex physiological functionality is often the outcome of multiple interacting cell-types, yet mechanistically how a large number of trait-associated genes yield a single multi-cellular network governing the phenotype has not been well defined. Individuals immune-cellular profiles at homeostasis show high heritability and inter-individual variation with functional and clinical implications. We profiled immune cellular variation by mass-cytometry in 55 genetically diverse mouse strains. We identify 788 genes associated with cellular homeostasis, supporting a polygenic model where 52% of genes correspond to core homeostatic functions whose genetic variants suffice to predict phenotype. Trait genes form a multi-cellular network architecture showing increased functional complexity over evolutionary timescales for shared regulation to all cells, specialized cell-specific programs, and between-cell synchronization. Contrasting to human studies suggests the regulatory network expands with environmental exposure history. Our findings shed light on the origin of immune-cellular variation and regulatory architectures that may generalize to other environmentally sensitive systems.

immunology↗