Efficient differential expression analysis of large-scale single cell transcriptomics data using dreamlet

Hoffman, Gabriel E.; Lee, Dong‐Hoon; Bendl, Jaroslav; Fnu, Prashant; Hong, Aram; Casey, Clara; Alvia, Marcela; Shao, Zhiping; Argyriou, Stathis; Therrien, Karen; Venkatesh, Sanan; Voloudakis, Georgios; Haroutunian, Vahram; Fullard, John F.; Roussos, Panos

doi:10.1101/2023.03.17.533005

Cited by 13 publications

(2 citation statements)

References 77 publications

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“…3A ). We then performed differential expression (DE) analysis, separately for every major lineage (CD8 + T, CD4 + T, Myeloid, NK/ILC and B cells), comparing each tissue group against the remaining five tissue groups using a pseudo-bulk linear mixed model approach that accounts for the major nuisance covariates in our data (e.g., donor ID, sex, donation site, CMV status)( Supplementary Table 5 ) 31 . The sets of genes from each tissue group that were significantly DE in three or more of the major immune lineages were then merged and hierarchically clustered, resulting in ten gene expression groups and five lineage-tissue groups ( Fig.…”

Section: Tissue Is a Major Determinant Of Immune Cell Identity And Fu...mentioning

confidence: 99%

Multimodal profiling reveals tissue-directed signatures of human immune cells altered with age

Wells,

Rainbow,

Mark

et al. 2024

Preprint

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The immune system comprises multiple cell lineages and heterogeneous subsets found in blood and tissues throughout the body. While human immune responses differ between sites and over age, the underlying sources of variation remain unclear as most studies are limited to peripheral blood. Here, we took a systems approach to comprehensively profile RNA and surface protein expression of over 1.25 million immune cells isolated from blood, lymphoid organs, and mucosal tissues of 24 organ donors aged 20-75 years. We applied a multimodal classifier to annotate the major immune cell lineages (T cells, B cells, innate lymphoid cells, and myeloid cells) and their corresponding subsets across the body, leveraging probabilistic modeling to define bases for immune variations across donors, tissue, and age. We identified dominant tissue-specific effects on immune cell composition and function across lineages for lymphoid sites, intestines, and blood-rich tissues. Age-associated effects were intrinsic to both lineage and site as manifested by macrophages in mucosal sites, B cells in lymphoid organs, and T and NK cells in blood-rich sites. Our results reveal tissue-specific signatures of immune homeostasis throughout the body and across different ages. This information provides a basis for defining the transcriptional underpinnings of immune variation and potential associations with disease-associated immune pathologies across the human lifespan.

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Section: Tissue Is a Major Determinant Of Immune Cell Identity And Fu...mentioning

confidence: 99%

Multimodal profiling reveals tissue-directed signatures of human immune cells altered with age

Wells,

Rainbow,

Mark

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…P-values were adjusted for multiple testing using FDR. In parallel, we also performed differential expression analysis using a pseudobulked generalized linear mixed model (DREAMLET 69 ), accounting for random patient and fixed tumor site effects, and performed gene set enrichment analysis (GSEA) with the same set of pathways.…”

Section: Differential Gene and Pathway Activitymentioning

confidence: 99%

Ongoing genome doubling promotes evolvability and immune dysregulation in ovarian cancer

McPherson,

Vázquez-García,

Myers

et al. 2024

Preprint

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Whole-genome doubling (WGD) is a critical driver of tumor development and is linked to drug resistance and metastasis in solid malignancies. Here, we demonstrate that WGD is an ongoing mutational process in tumor evolution. Using single-cell whole-genome sequencing, we measured and modeled how WGD events are distributed across cellular populations within tumors and associated WGD dynamics with properties of genome diversification and phenotypic consequences of innate immunity. We studied WGD evolution in 65 high-grade serous ovarian cancer (HGSOC) tissue samples from 40 patients, yielding 29,481 tumor cell genomes. We found near-ubiquitous evidence of WGD as an ongoing mutational process promoting cell-cell diversity, high rates of chromosomal missegregation, and consequent micronucleation. Using a novel mutation-based WGD timing method,doubleTime, we delineated specific modes by which WGD can drive tumor evolution: (i) unitary evolutionary origin followed by significant diversification, (ii) independent WGD events on a pre-existing background of copy number diversity, and (iii) evolutionarily late clonal expansions of WGD populations. Additionally, through integrated single-cell RNA sequencing and high-resolution immunofluorescence microscopy, we found that inflammatory signaling and cGAS-STING pathway activation result from ongoing chromosomal instability and are restricted to tumors that remain predominantly diploid. This contrasted with predominantly WGD tumors, which exhibited significant quiescent and immunosuppressive phenotypic states. Together, these findings establish WGD as an evolutionarily ‘active’ mutational process that promotes evolvability and dysregulated immunity in late stage ovarian cancer.

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Single-nucleus transcriptomic profiling of human orbitofrontal cortex reveals convergent effects of aging and psychiatric disease

Fröhlich,

Gerstner,

Gagliardi

et al. 2024

Nat Neurosci

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Aging is a complex biological process and represents the largest risk factor for neurodegenerative disorders. The risk for neurodegenerative disorders is also increased in individuals with psychiatric disorders. Here, we characterized age-related transcriptomic changes in the brain by profiling ~800,000 nuclei from the orbitofrontal cortex from 87 individuals with and without psychiatric diagnoses and replicated findings in an independent cohort with 32 individuals. Aging affects all cell types, with LAMP5+LHX6+ interneurons, a cell-type abundant in primates, by far the most affected. Disrupted synaptic transmission emerged as a convergently affected pathway in aged tissue. Age-related transcriptomic changes overlapped with changes observed in Alzheimer’s disease across multiple cell types. We find evidence for accelerated transcriptomic aging in individuals with psychiatric disorders and demonstrate a converging signature of aging and psychopathology across multiple cell types. Our findings shed light on cell-type-specific effects and biological pathways underlying age-related changes and their convergence with effects driven by psychiatric diagnosis.

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Efficient differential expression analysis of large-scale single cell transcriptomics data using dreamlet

Cited by 13 publications

References 77 publications

Multimodal profiling reveals tissue-directed signatures of human immune cells altered with age

Multimodal profiling reveals tissue-directed signatures of human immune cells altered with age

Ongoing genome doubling promotes evolvability and immune dysregulation in ovarian cancer

Single-nucleus transcriptomic profiling of human orbitofrontal cortex reveals convergent effects of aging and psychiatric disease

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