A "DNA Typewriter" Reconstructs a Mouse Lineage From Fertilised Egg to 1.28 Million Cells

How a single fertilised egg divides in order to become hundreds of cell types is hard to observe directly in mammals, because the embryo is inside the mother. A team led by Jay Shendure at the University of Washington and the Seattle Hub for Synthetic Biology in the United States published in Science a study that gets around this problem with a "recorder inside the cell."

Letting cells write their own family tree

The DNA Typewriter is a molecular recorder designed so that a CRISPR-based editing tool writes short sequences into a specific stretch of DNA one after another. Because records accumulate each time a cell divides, reading each cell's record later lets researchers trace back which cell split from which and where. The researchers applied this device to mouse embryos to record about two weeks of development, then combined it with single-cell transcriptome analysis to obtain gene expression and lineage for 1.28 million cells at the same time.

The result was a single time-calibrated lineage tree rooted at the fertilised egg. The two daughter cells from the first division were clearly distinguished by an editing burst and served as controls for each other. The researchers quantified "clonal dominance," in which certain cell lineages expand disproportionately during gastrulation, and confirmed that sibling cells in the tree are of the same type far more often than by chance and that sibling cells of different types mark the point of final differentiation. They also reconstructed a timeline showing when cell types diverged.

Significance and limits

This is the first large-scale demonstration that mammalian development can be drawn as a "map anchored to lineage," and it could become basic data for tracing the origins of congenital diseases and developmental abnormalities. However, the results come from a single mouse embryo, and the method cannot be used in people because the recorder must be introduced genetically. Because of limits in recording density and cell capture rate, parts of the lineage tree rely on estimation.