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

Abstract

A novel approach for integrating DNA-seq and single-cell RNA-seq data to reconstruct clonal substructure for single-cell transcriptomes. • Evidence for non-neutral evolution of clonal populations in human fibroblasts. • Proliferation and cell cycle pathways are commonly distorted in mutated clonal populations. AbstractDecoding the clonal substructures of somatic tissues sheds light on cell growth, development and differentiation in health, ageing and disease. DNA-sequencing, either using bulk or using single-cell assays, has enabled the reconstruction of clonal trees from frequency and co-occurrence patterns of somatic variants. However, approaches to systematically characterize phenotypic and functional variations between individual clones are not established. Here we present cardelino (https://github.com/PMBio/cardelino), a computational method for inferring the clone of origin of individual cells that have been assayed using single-cell RNA-seq (scRNA-seq). After validating our model using simulations, we apply cardelino to matched scRNA-seq and exome sequencing data from 32 human dermal fibroblast lines, identifying hundreds of differentially expressed genes between cells from different somatic clones. These genes are frequently enriched for cell cycle and proliferation pathways, indicating a key role for cell division genes in non-neutral somatic evolution.

Single-cell RNA-sequencing of differentiating iPS cells reveals dynamic genetic effects on gene expression

“…5; Methods). Exploiting that each cell line's genotype acts as a unique barcode, we demultiplexed the pooled cell populations, enabling identification of the cell line of origin for each cell (similar to 8,9 ; Methods). At each time point, cells from between 104 and 112 donors were captured, with each donor being represented by an average of 286 cells (after QC, Supplementary Fig.…”

Single-cell transcriptomics identifies an effectorness gradient shaping the response of CD4+ T cells to cytokines

“…A list of common genetic variants was collected, defined as any SNP included in gnomAD 64 with a minor allele frequency higher than 1% in the Non-Finish European (NFE) population. Next, cellSNP Cardelino v0.99) 65 was used to generate pileups at these SNPs, resulting in one VCF file per sample. This information was then used by Cardelino 65 (v0.99) to infer which cells belong to the same individual.…”

sigfit: flexible Bayesian inference of mutational signatures

“…We have also illustrated the flexibility and ease-of-use of the publicationquality visualisation routines included in the package. Moreover, the usefulness of the functionalities in sigfit has been recently evidenced by its adoption by other research groups (24)(25)(26).…”