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Last updated: 2018-08-25

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Cardelino : Integrating whole exomes and single-cell transcriptomes to reveal phenotypic impact of somatic variants

Decoding the clonal substructures of somatic tissues sheds light on cell growth, development and differentiation in health, ageing and disease. Targeted DNA sequencing, whole exome sequencing, and most recently single-cell DNA sequencing have been applied to reconstruct trees describing this clonal substructure. However, the functional and phenotypic differences between clonal populations identified have been difficult to characterise and remain unclear in most cases.

To address this, we present cardelino (https://github.com/PMBio/cardelino), a computational method to assign single-cell transcriptome profiles to nodes in a clonal tree, based on variants identified from single-cell RNA-seq data. After validating the model on simulated data, we apply cardelino to matched single-cell RNA-seq and exome sequencing data from 32 human dermal fibroblast lines.

The somatic mutation landscape reveals non-neutral clonal evolution in a subset of these healthy donors. In line with this evolutionary selection pressure, we identify gene expression differences between clones. Interestingly, cell cycle and proliferation pathways separate clones repeatedly in our fibroblast samples. In summary, we develop and apply an approach that allows for reconstructing transcriptome profiles of clonal subpopulations within tissues. This has the potential to inform on mutational processes at single-cell resolution, both in cancer and healthy ageing.

Key findings:

A new approach for integrating DNA-seq and single-cell RNA-seq data to reconstruct clonal substructure and single-cell transcriptomes.
A new computational method to map single-cell RNA-seq profiles to clones.
Evidence for non-neutral evolution of clonal populations in human fibroblasts.
Proliferation and cell cycle pathways are commonly distorted in mutated clonal populations, with implications for cancer and ageing.

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