Profiles

Genomic DNA experiences various types of lesions that can potentially lead to double strand breaks (DSBs). Failure to resolve such insults correctly has implications in cancer. Homologous recombination (HR) is a major pathway for repairing DSBs. HR is essential 1) for life: null mutations in BRCA genes are embryonic lethal; 2) in meiosis, which is initiated by hundreds of DSBs; and 3) in tumorigenesis. The central vision of our lab is to build a fully probabilistic understanding of HR by developing high-throughput single-cell sequencing technologies. Given one’s genotype, our long term goal is to be able to predict: 1) which genome regions are fragile; 2) what (epi)genetic contexts regulate DNA breakage; 3) how mutations and expression levels of DNA repair genes affect repair processes; and 4) what consequences HR and resulting rearrangements have from a single cell to an individual.

The majority of HR events, however, occur between identical sister chromatids and is error-free. Unlike error-prone repair, HR is difficult to track by bulk whole-genome sequencing (WGS). For example, pan-cancer mutation signature studies read “scars” in the genome and by definition miss these error-free events. Rare spontaneous HR in development is even harder to analyze and thus its cell-type variation is poorly understood. The lack of high-throughput global assay for error-free HR hinders our understanding of DNA repair. We developed sci-L3 suite of singel-cell sequencing technologies, which enables linear amplification of single-cell genomes that scales to 1M cells and generalizes to multi-omics, including WGS, targeted-sequencing and DNA/RNA co-assay. Recently, we have expanded sci-L3 to Strand-seq, which provides the first high-throughput global assay for error-free HR.

Our lab will focus on developing a full-fledged HR mapping platform to characterize genome, tissue and evolutionary variation in mitotic HR rates and machinery, and to rapidly generate and test thousands of hypotheses in the space of mutants and/or genetic variants of DNA repair genes. We also aim to develop tools for studying HR in non-model organisms in a scalable manner. We are broadly interested in the following directions:
A. Genome-wide characterization of HR partner choice between homologs and sister chromatids;
B. Systematically investigate cell-type variation on DNA repair pathway usage;
C. Construct dense linkage maps in non-model organisms;
D. New DNA repair gene finding in unculturable microbes.