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docs/source/basics.rst

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Intuitions behind clone2vec
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===========================
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The importance of clonal biology
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--------------------------------
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A **clone** is a group of cells that all come from a single ancestor cell at some point of development. Stem and progenitor cells
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divide and give rise to different specialized cell types. By studying clones, we can trace how individual cells contribute
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to tissues and organs, helping us understand which cells give rise to which structures and how different cell types emerge
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from the same starting population.
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Cells that seem identical at first glance can have very different fates. Even within one
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tissue, different clones generate a mix of different cell types, revealing hidden functional diversity among cell populations.
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By analyzing clones in detail, we can better understand development, disease, and how tissues regenerate.
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clone2vec: learning clonal contexts from barcoded scRNAseq data
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---------------------------------------------------------------
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When analyzing barcoded single-cell transcriptomics data, you notice many clones that have the same combinations of cell types
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or occupy similar transcriptional niches.
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.. image:: _static/images/similar_clones.png
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:alt: Clones similar to each other
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:width: 800
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:align: center
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This happens because a cell's lineage history has a big influence on its gene expression state (even within a single cell type).
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These similar-behaving clones are likely to arise from similar (and intuitively, we find,
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spatially nearby) progenitor cells. We were interested in categorizing these clone types in an unbiased way, so we developed **clone2vec**,
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which learns the "clonal context" of cells directly from transcriptional neighborhoods (without using cell type annotations).
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Our method is inspired by **word2vec**, a machine learning model used in language processing. In word2vec, each word is represented as
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a point in a multi-dimensional space based on its context. Words that appear together in similar contexts have similar meanings.
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For example, in a language model, "king" and "queen" are close to each other in meaning, just like "apple" and "banana" might be.
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Clone2vec works the same way, but instead of words we use clonal identities of cells. Just like word2vec learns relationships between
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words based on the company they keep, clone2vec learns relationships between clones based on the neighborhoods their cells occupy in gene
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expression space. If two clones consistently appear in similar transcriptional neighborhoods, the model will learn to place them close
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together in the clonal embedding space.
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.. image:: _static/images/pipeline.png
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:alt: Clone2vec pipeline
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:width: 800
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:align: center
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By mapping clones in this way, we can uncover relationships between cell types, predict how clones are functionally related, and explore
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how different cell lineages contribute to development. Our interactive application **clones2cells** makes this analysis interactive,
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allowing users to explore these complex patterns with simple visualizations.
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Advantages of clone2vec for analyzing cell lineages
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---------------------------------------------------
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Clone2vec embeds clonal data into a vector space, allowing continuous analysis of cellular behaviors.
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Unlike conventional methods, which often rely on binary fate assignments, clone2vec indirectly quantifies and compares the proportions of different
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cell types within clones, thereby capturing subtle variations in cell fate biases. Instead of cell types, the algorithm uses transcriptional
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neighbourhoods, therefore it's becoming more dropout-robust as soon as even within the single cell type clones with similar behaviour usually
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share similar transcriptional signatures.
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Clonal embeddings can be applied to address several critical research questions. Researchers can explore how positional signals influence
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cell fate decisions by mapping clone behaviors across spatial contexts (by leveraging known patterning
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systems such as the Hox code). Additionally, integration of multiple time points of injection allows the identification
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of specific developmental periods when cell fate decisions become restricted or flexible. Third, clone2vec also aids in elucidating molecular
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pathways and signaling networks that drive clonal expansion and influence lineage biases, thereby identifying both primary and auxiliary
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regulatory mechanisms that modulate developmental outcomes.
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This scalable framework offered by clone2vec can be adapted to other tissue systems in embryonic development, immunology, stem cell
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research, cancer studies, and tissue regeneration.
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Exploring the clonal atlas via clonal and transcriptional embeddings with clones2cells
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--------------------------------------------------------------------------------------
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The **clones2cells** viewer allows users to explore clonal relationships and gene expression patterns in an interactive way.
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The app visualizes how different clones relate to each other and how they map onto transcriptional space.
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On the left side (clone2vec UMAP), we show a clonal embedding, in which each dot is a clone. Clonal embeddings display the clones
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positioned relative to each other in a learned space. Clones that appear close together likely share similar fate potentials or arise
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from related progenitors. Users can click on an individual clone or select multiple clones using the lasso tool to visualize cells from
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the clone(s) on the right side (gene expression UMAP).
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.. image:: _static/images/clones_selection.png
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:alt: Clones selection
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:width: 800
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:align: center
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An example of clones2cells application can be found for the `Erickson, Isaev, et al. dataset <https://clones2cells.streamlit.app>`.

docs/source/index.rst

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:maxdepth: 2
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:hidden:
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basics
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tutorial
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api
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