Abstract
New approaches to lineage tracking have allowed the study of differentiation in multicellular organisms over many generations of cells. Understanding the phenotypic variability observed in these lineage trees requires new statistical methods. Whereas an invariant cell lineage, such as that for the nematode Caenorhabditis elegans, can be described by a lineage map, defined as the pattern of phenotypes overlaid onto the binary tree, a traditional lineage map is static and does not describe the variability inherent in the cell lineages of higher organisms. Here, we introduce lineage variability maps which describe the pattern of second-order variation in lineage trees. These maps can be undirected graphs of the partial correlations between every lineal position, or directed graphs showing the dynamics of bifurcated patterns in each subtree. We show how to infer these graphical models for lineages of any depth from sample sizes of only a few pedigrees. This required developing the generalized spectral analysis for a binary tree, the natural framework for describing tree-structured variation. When tested on pedigrees from C. elegans expressing a marker for pharyngeal differentiation potential, the variability maps recover essential features of the known lineage map. When applied to highly-variable pedigrees monitoring cell size in T lymphocytes, the maps show that most of the phenotype is set by the founder naive T cell. Lineage variability maps thus elevate the concept of the lineage map to the population level, addressing questions about the potency and dynamics of cell lineages and providing a way to quantify the progressive restriction of cell fate with increasing depth in the tree.
Highlights
The cells of developing organisms differentiate into their specialized types by integrating signals from their present surroundings with instructions inherited from their ancestors
By tracking how cell traits change with each successive cell division throughout the family, or lineage, tree, it has been possible to understand where and how these modifications are controlled at the single-cell level
Development in the nematode Caenorhabditis elegans is the classic example of how the lineage map can help untangle the roles of preprogrammed instruction and cell-to-cell communication [4,5,6] in cellular differentiation
Summary
The cells of developing organisms differentiate into their specialized types by integrating signals from their present surroundings with instructions inherited from their ancestors. This interplay of mechanisms generates the pattern of phenotypes that emerges in the cell lineage tree [1]. Measuring this phenotypic pattern requires recording two types of information: the phenotype of each cell and the family relationships between the cells. Lineage maps illustrate the successive bifurcations in phenotypes that underpin a particular differentiation pathway, providing an invaluable guide for experiments investigating the mechanisms involved in fate determination [3]. Development in the nematode Caenorhabditis elegans is the classic example of how the lineage map can help untangle the roles of preprogrammed instruction and cell-to-cell communication [4,5,6] in cellular differentiation
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