Areas of Interest
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”.
Adey A*, Burton JN*, Kitzman JO*, Hiatt JB, Lewis AP, Martin BK, Qiu R, Lee C, Shendure J. The haplotype-resolved genome and epigenome of the aneuploid HeLa cancer cell line. Nature. 2013 Aug 8;500(7461):207-11. [*equal contributors]
Kitzman JO, Snyder MW, Ventura M, Lewis AP, Qiu R, Simmons LE, Gammill HS, Rubens CE, Santillan DA, Murray JC, Tabor HK, Bamshad MJ, Eichler EE, Shendure J. Noninvasive whole-genome sequencing of a human fetus. Sci Transl Med. 2012 Jun 6;4(137).
Kitzman JO, Mackenzie AP, Adey A, Hiatt JB, Patwardhan RP, Sudmant PH, Ng SB, Alkan C, Qiu R, Eichler EE, Shendure J. Haplotype-resolved genome sequencing of a Gujarati Indian individual. Nat Biotechnol. 2011 Jan;29(1):59-63.
Adey A, Morrison HG, Asan, Xun X, Kitzman JO, Turner EH, Stackhouse B, MacKenzie AP, Caruccio NC, Zhang X, Shendure J. Rapid, low-input, low-bias construction of shotgun fragment libraries by high-density in vitro transposition. Genome Biol. 2010;11(12):R119.
Sudmant PH*, Kitzman JO*, Antonacci F, Alkan C, Malig M, Tsalenko A, Sampas N, Bruhn L, Shendure J; 1000 Genomes Project, Eichler EE. Diversity of human copy number variation and multicopy genes. Science. 2010 Oct 29;330(6004):641-6. [*equal contributors]