Allele-specific transcriptional effects of subclonal copy number alterations enable genotype-phenotype mapping in cancer cells.

Subclonal copy number alterations are a prevalent feature in tumors with high chromosomal instability and result in heterogeneous cancer cell populations with distinct phenotypes. However, the extent to which subclonal copy number alterations contribute to clone-specific phenotypes remains poorly understood. We develop TreeAlign, which computationally integrates independently sampled single-cell DNA and RNA sequencing data from the same cell population. TreeAlign accurately encodes dosage effects from subclonal copy number alterations, the impact of allelic imbalance on allele-specific transcription, and obviates the need to define genotypic clones from a phylogeny a priori, leading to highly granular definitions of clones with distinct expression programs. These improvements enable clone-clone gene expression comparisons with higher resolution and identification of expression programs that are genomically independent. Our approach sets the stage for dissecting the relative contribution of fixed genomic alterations and dynamic epigenetic processes on gene expression programs in cancer.