Research in our laboratory focuses on understanding the role of regulatory sequences in human biology and disease. Through a combination of comparative genomic strategies, regulatory element analysis, human patient samples, massively parallel sequencing and mouse and fish genetic engineering technologies, we are working to elucidate mechanisms whereby genetic variation within these sequences lead to changes in human phenotypes. The research focuses on three clinically relevant phenotypic categories. The first is monogenic disease, using limb malformations, the second most common form of human congenital abnormalities (prevalence of 1 in every 500 births), as a model. The second is complex disease, analyzing how nucleotide changes in regulatory sequences contribute to obesity, autism and epilepsy. The third is pharmacogenomics, characterizing how genetic differences in regulatory sequences, with a focus on regions surrounding membrane transport proteins, lead to clinical variation in response to drugs. In addition, by developing methods that allow massively parallel testing of thousands of sequences for regulatory activity, we are attempting to gain a better understanding of the functional properties of regulatory elements.
Patwardhan RP, Hiatt JB, Witten DM, Kim MJ, Smith RP, May D, Lee C, Andrie JM, Lee S, Cooper GM, Ahituv N^, Pennacchio LA^, Shendure J^ Massively parallel functional dissection of mammalian enhancers in vivo, Nature Biotechnology 2012, 30: 265-270.
Birnbaum RY, Clowney EJ, Agamy O, Kim MJ, Zhao J, Yamanaka T, Pappalardo Z, Clarke SL, Wenger AM, Nguyen L, Gurrieri F, Everman DB, Schwartz CE, Birk OS, Bejerano G, Lomvardas S, Ahituv N. Coding exons function as tissue-specific enhancers of nearby genes. Genome Research, 2012, 22: 1059-1068.
Birnbaum RY, Everman DB, Murphy KK, Gurrieri F, Schwartz CE, Ahituv N. Functional characterization of tissue-specific enhancers in the DLX5/6 locus, Human Molecular Genetics, 2012, 21: 4930-4938.
Oksenberg N., Stevnison L, Wall J, Ahituv N. Function and regulation of AUTS2, a gene implicated in autism and human evolution, PLoS Genetics, 2013: e1003221.
Smith RP, Riesenfeld SJ, Holloway AK, Li Q, Murhpy KK, Feliciano NM, Orecchia L, Oksenberg N, Pollard KS^, Ahituv N^. A compact, in vivo screen of all 6-mers reveals drivers of tissue-specific expression and guides synthetic regulatory element design, Genome Biology, 2013, In press.
Smith RP, Taher L, Patwardhan R, Kim MJ, Inoue F, Shendure J^, Ovcharenko I^, Ahituv N^. Massively parallel decoding of mammalian regulatory sequences supports a flexible organizational model, Nature Genetics, 2013, In press.
^ co-corresponding author