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.
Pennacchio LA, Ahituv N, Moses AM, Prabhakar S, Nobrega MA, Shoukry M, Minovitsky S, Dubchak I, Holt A, Lewis KD, Plajzer-Frick I, Akiyama J, De Val S, Afzal V, Black BL, Couronne O, Eisen MB, Visel A, Rubin EM In vivo enhancer analysis of human conserved noncoding sequences, Nature 2006; 444:499-502.
Ahituv N, Kavaslar N, Schackwitz WS, Ustaszewska A, Martin J, Hébert S, Doelle H, Ersoy B, Kryukov G, Schmidt S, Yosef N, Ruppin E, Sharan R, Vaisse C, Sunyaev S, Dent R, Cohen J, McPherson R, Pennacchio LA Medical sequencing at the extremes of human body mass, American Journal of Human Genetics 2007; 80: 779-791.
Ahituv N, Zhu Y, Visel A, Holt A, Afzal V, Pennacchio LA, Rubin EM Deletion of ultraconserved elements yields viable mice, PLoS Biology 2007; 5:e234.
Kim MJ, Skewes-Cox P, Fukushima H, Hesselson S, Yee SW, Ramsey LB, Nguyen L, Eshragh JL, Castro RA, Wen C, Stryke D, Johns SJ, Ferrin TE, Kwok PY, Relling MV, Giacomini KM, Kroetz DL, Ahituv N Functional characterization of liver enhancers regulating drug-associated transporters, Clinical Pharmacology and Therapeutics 2011, 89: 571-578.
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, Josephine EC,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, in press, 2012.
Laurell T^, VanderMeer JE, Wenger AM, Grigelioniene G, Nordenskjold A, Arner M, Bejerano G, Ahituv N^, Nordgren A A novel 13 base pair insertion in the Sonic Hedgehog ZRS limb enhancer causes preaxial polydactyly and triphalangeal thumb, Human Mutation, in press, 2012.
^ co-corresponding author