We develop genome-scale technologies to comprehensively identify sequence variants, resolve genomic structures, and dissect their functional impacts with respect to molecular and cellular phenotypes.

1. Haplotype-resolved sequencing. We have developed new sequencing methods to experimentally resolve the haplotype phase of variants, which is almost entirely discarded during conventional short-read sequencing. We have leveraged phased genome sequencing to resolve the structures of normal and cancer genomes, and to enable the first non-invasive whole-genome sequencing of a human fetus. We are now pursuing refinements to this approach as well as novel applications in basic and clinical genomics.

2. Dissecting sequence-function relationships using saturation mutagenesis. With the availability of commodity genome sequencing, the rate-limiting step in genetic research is shifting from variation discovery to functional interpretation. We are developing new experimental approaches to measure the functional impacts of many mutant alleles in massively multiplexed tissue culture models using deep sequencing as a “read-out”.