Simultaneous Brain Cell Type and Lineage Determined by scRNA-Seq Reveals Stereotyped Cortical Development
This week we profile a recent publication in Cell Systems from Donovan Anderson (pictured, left) the laboratory of Dr. Marshall Horwitz (right) at the Allen Discovery Center for Lineage Tracing and UW.
Can you provide a brief overview of your lab’s current research focus?
Our research addresses the germline and somatic genetic origin of hematologic malignancies and uses that as a paradigm for understanding development. Towards that end, we’ve realized that acquired mutations can also help illuminate the history of cell divisions, even during normal non-cancer development, and have worked on approaches we dub, “Phylogenetic Fate Maps.”
What is the significance of the findings in this publication?
In Donovan’s recent Cell Systems paper we show that a commonly occurring type of somatic mutation, loss of heterozygosity (LOH), can be detected at the single-cell level by scRNA-seq. Consequently, in one fell swoop, we show it is possible using scRNA-seq to both identify a cell based on its gene expression signature and infer its lineage based on LOH events shared with other cells. We further show that in females, we can register the branches of the resulting phylogeny to the time in development, around gastrulation, when X-chromosome activation takes place.
What are the next steps for this research?
We want to extend the approach for use in humans. There are now powerful genetically engineered recorder systems that record lineage and signaling events directly to the genome, using CRISPR and related genome-editing methods, but these approaches obviously cannot be used in people or for retrospective analysis in other species that are long-lived or not easily manipulated in the laboratory. In the Cell Systems paper, we worked with hybrid offspring of mice from a cross involving two different strains. Consequently, we could “phase” the genome and determine the locus’ parent of origin, which is necessary for identifying LOH events. For the method to work similarly in people, we need to use computational approaches to appropriately identify parental haplotypes (or perform studies of trios involving a person and both their parents). There are some interesting new approaches along these lines that make inventive use of public genealogical databases that we plan to look into.
If you’d like us to mention your funding sources, please list them.
We are extremely grateful that the work was supported by the Allen Discovery Center for Lineage Tracing, through a grant funded by the Paul G. Allen Frontiers Group.