TreeAlign – allele-specific transcriptional effects of subclonal copy number alterations enable genotype-phenotype mapping in cancer cells

Cancer is a complex disease characterized by genetic alterations that drive the growth and spread of tumor cells. One aspect of this complexity lies in the presence of subclonal copy number alterations, which are variations in the number of copies of DNA segments within different populations of cancer cells. Understanding how these alterations contribute to the diverse behavior of cancer cells is crucial for developing effective treatments.

Recent research at Sloan Kettering Cancer Center has shed light on this topic with the development of a computational tool called TreeAlign. This innovative approach integrates single-cell DNA and RNA sequencing data from the same cell population to accurately capture the effects of subclonal copy number alterations on gene expression.

TreeAlign allows researchers to decode the impact of these alterations on the dosage of genes, as well as the influence of allelic imbalance on allele-specific transcription. Importantly, it does not require prior knowledge of genetic clones, allowing for a more detailed analysis of distinct cell populations with unique expression profiles.

Overview of TreeAlign

Fig. 1

a TreeAlign takes raw count data from scRNA-seq, the copy number matrix and the phylogenetic tree from scDNA-seq. By recursively assigning the expression profiles to phylogenetic subtrees, TreeAlign infers the clone-of-origin of cells identified in scRNA-seq and the dosage effects of subclonal CNAs. b Allelic imbalance can be inferred from DNA data and RNA data. We assume a positive correlation between the two measurements to improve clone assignment. c Graphical model of TreeAlign.

By employing TreeAlign, scientists can compare gene expression between different clones at a higher resolution, uncovering expression programs that are independent of genomic alterations. This breakthrough paves the way for a deeper understanding of the interplay between fixed genetic changes and dynamic epigenetic processes in shaping the behavior of cancer cells.

The development of TreeAlign represents a significant advancement in cancer research, offering a powerful tool for dissecting the molecular mechanisms underlying tumor heterogeneity. By elucidating how subclonal copy number alterations influence gene expression, researchers can identify new therapeutic targets and develop more personalized treatment strategies for cancer patients.

In the fight against cancer, understanding the intricate interplay between genetic and epigenetic factors is essential. With the introduction of TreeAlign, researchers are now equipped with a powerful tool to unravel the complexity of cancer biology, ultimately paving the way for more effective treatments and improved patient outcomes.

Shi H, Williams MJ, Satas G, Weiner AC, McPherson A, Shah SP. (2024) Exploiting allele-specific transcriptional effects of subclonal copy number alterations for genotype-phenotype mapping in cancer cell populations. Nat Commun 15, 2482. [article]

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