ABSTRACT
Short Tandem Repeats (STRs) are highly mutable genomic elements composed of repetitive short motifs, widely distributed within the human genome, and as such are the most promising source for somatic genomic variations. We present an affordable and scalable cell lineage reconstruction platform that combines customizable duplex Molecular Inversion Probes (MIPs), high throughput targeted sequencing and tailored analysis, all integrated in a bioinformatics Database Management System (DBMS). By applying this platform to a benchmark of ex vivo lineage samples, we demonstrate efficient acquisition of tens of thousands of targets in single-cell whole-genome amplified DNA and the discovery of lineage relations among these cells with superior accuracy. We then reconstruct a cell lineage tree of healthy and metastatic cells from a melanoma patient, supporting the hypothesis of clonal metastases and demonstrating that a naïve panel targeting STR somatic mutations in single cells can outperform a cancer specific SNP panel in reconstruction accuracy.