Cell lineage analysis in humans

Delineating a cell’s history, where it came from and what has happened to it, can provide clues as to how tissues and organs are formed and function in the healthy state and in disease. The gold standard for tracing the relationships between cells and their progeny, is performed through prospective labeling with dyes or genetics tags. In this procedure, individual cells are labeled in order to track their clonal progeny at a later time point. These methodologies are, however, not applicable to study the composition of cell lineages in humans. Recently, the development of technologies for single cell sequencing has opened up the possibility to infer cell lineage relationships through the analysis of naturally occurring somatic mutations. During normal cell division, some new random mutations occur, forming an evolving barcode, which carries information about its developmental relationship to other cells. As such, the history of a cell is written in its genome, and every acquired mutation gets passed on to daughter cells. Shared somatic mutations may thus be used to trace backward across cell lineages, and the life history of an organism.

The goal of this thesis is to explore the possibility of using genetic variation as cell lineage marks to compute the evolutionary history of human cells as they divide. This work involves the development of new experimental and analytical methods, and the application of these to study the origins and lineage relationships of human cell populations. The methods and results described here, are intended to provide a contribution towards future applications for cell lineage tracing in man.

List of scientific papers

I. Mikael Rydén*, Mehmet Uzunel*, Joanna Hård*, Erik Borgström, Jeff E Mold, Erik Arner, Niklas Mejhert, Daniel P Andersson, Yvonne Widlund, Moustapha Hassan, Christina V Jones, Kirsty L Spalding, Britt-Marie Svahn, Afshin Ahmadian, Jonas Frisén, Samuel Bernard, Jonas Mattsson, Peter Arner. Transplanted bone marrow derived cells contribute to human adipogenesis. Cell Metabolism. 2015;22(3):408-17. *Co-first authors.
https://doi.org/10.1016/j.cmet.2015.06.011

II. Joanna Hård*, Ezeddin Al Hakim*, Marie Kindblom*, Åsa K. Björklund, Bengt Sennblad, Ilke Demirci, Marta Paterlini, Pedro Reu, Erik Borgström, Patrik L. Ståhl, Jakob Michaelsson, Jeff E. Mold and Jonas Frisén. Conbase: a software for unsupervised discovery of somatic mutations in single cells through read phasing. Genome Biology. 2019;20(1):68. *Co-first authors.
https://doi.org/10.1186/s13059-019-1673-8

III. Joanna Hård, Jeff Mold, Carl-Johan Eriksson, Pietro Berkes, Åsa Björklund, Bengt Sennblad, Jack Kuipers, Katharina Jahn, Jakob Michaelsson, Jonas Frisén. Human memory and effector CD8 T cell development after vaccination. [Manuscript]