Measures of genetic diversification in somatic tissues at bulk and single cell resolution

Abstract: Intra-tissue genetic heterogeneity is universal to both healthy and cancerous tissues. It emerges from the stochastic accumulation of somatic mutations throughout development and homeostasis. By combining population genetics theory and genomic information, genetic heterogeneity can be exploited to infer tissue organisation and dynamics in vivo. Here we show that single cell and bulk sequencing data inform on different aspects of the underlying stochastic processes. Bulk derived variant allele frequency spectra (VAF) show transitions from growing to constant stem cell populations with age in samples of healthy oesophagus epithelium. Single-cell mutational burden distributions allow a sample size independent measure of mutation and proliferation rates. Mutation rates in adult haematopietic stem cells are higher compared to inferences during development, suggesting additional proliferation independent effects. Furthermore, single cell derived VAF spectra contain information on the number of tissue specific stem cells. In haematopiesis, we find approximately 2x 10⁵HSCs, if all stem cells divide symmetrically. If HSCs also undergo asymmetric divisions, fewer HSCs could maintain homeostasis. A more precise estimate requires an independent measure of the asymmetric division rate p, which currently is complicated by the sparsity of single cell data.