Jay A.Tischfield Professor Rutgers University Department of Genetics Life Sciences Building. Room 136 Piscataway. NJ 08854 (732) 445-1027 FAX - 1147 jay@biology.rutgers.edu

Medical and human genetics: the genetics of somatic cells. mouse models for human diseases and genes for complex human genetic disorders

Our primary research interests include studies of both somatically heritable and transient genetic changes in somatic cells that predispose to disease in humans. In addition. we are engaged in several large projects whose ultimate goal is the identification of genes that have major contributions to complex oligogenic disorders.

Loss of heterozygosity (LOH) for tumor suppressor genes in somatic cells frequently results in a recessive cellular phenotype that leads to cancer. We have studied the frequency and mechanisms of LOH in human heterozygotes and produced a heterozygous mouse model for investigation of LOH in different genetic backgrounds and after exposure to environmental agents. We have discovered that the major mechanisms for LOH in normal cells are mitotic recombination. followed by point mutation. Thus. we are investigating genes (e.g.. Tp53. Mlh1. Msh2) and environmental agents that may affect these processes. The mouse is an excellent model for this research due to the availability of many "knockouts" for genes that might affect LOH and our ability to deliver environmental agents. such as chemicals and radiation. in a precise manner.

Our group has also produced a knockout mouse model for APRT deficiency. which produces a human genetic disease (dihydroxyadenine urolithiasis) characterized by severe kidney stones and. in rare cases. chronic renal failure. We are comparing gene expression in mice with and without kidney stones in order to identify genes that are involved in early and late pathological changes. Thus far. the expression of several known and novel genes has been shown to increase or decrease with stone disease. We are investigating the expression of these genes in specific kidney cell types and correlating it with pathologic changes. Such studies may produce new targets for early pharmacologic intervention in the progression of kidney stone disease.

We are collaborating in several large. multidisciplinary projects whose goal is the identification and characterization of genes that make major contributions to complex human diseases such as alcoholism. opiate addiction. autism. schizophrenia and bipolar disorder. We are collecting blood and producing cell lines and DNA from large numbers of individuals in families with a high incidence of a specific disorder in an effort to find such genes.

Selected Publications

Barrera-Oro J, Liu TY, Gorden E, Kucherlapati R, Shao C, Tischfield JA. (2008) Role of the mismatch repair gene, Msh6, in suppressing genome instability and radiation-induced mutations. Mutat Res. 642(1-2):74-9.

Bierut LJ, Stitzel JA, Wang JC, Hinrichs AL, Grucza RA, Xuei X, Saccone NL, Saccone SF, Bertelsen S, Fox L, Horton WJ, Breslau N, Budde J, Cloninger CR, Dick DM, Foroud T, Hatsukami D, Hesselbrock V, Johnson EO, Kramer J, Kuperman S, Madden PA, Mayo K, Nurnberger J Jr, Pomerleau O, Porjesz B, Reyes O, Schuckit M, Swan G, Tischfield JA, Edenberg HJ, Rice JP, Goate AM. (2008) Variants in nicotinic receptors and risk for nicotine dependence. Am J Psychiatry. Jun 2. [Epub ahead of print]

Liang L, Deng L, Nguyen SC, Zhao X, Maulion CD, Shao C, Tischfield JA. (2008) Human DNA ligases I and III, but not ligase IV, are required for microhomology-mediated end joining of DNA double-strand breaks. Nucleic Acids Res. 36(10):3297-310.

Foroud T, Wetherill LF, Kramer J, Tischfield JA, Nurnberger JI Jr, Schuckit MA, Xuei X, Edenberg HJ. (2008) The tachykinin receptor 3 is associated with alcohol and cocaine dependence. Alcohol Clin Exp Res. 32(6):1023-30.

Edenberg HJ, Wang J, Tian H, Pochareddy S, Xuei X, Wetherill L, Goate A, Hinrichs T, Kuperman S, Nurnberger JI Jr, Schuckit M, Tischfield JA, Foroud T. (2008) A regulatory variation in OPRK1, the gene encoding the kappa-opioid receptor, is associated with alcohol dependence. Hum Mol Genet. 17(12):1783-9.

Dick DM, Aliev F, Wang JC, Saccone S, Hinrichs A, Bertelsen S, Budde J, Saccone N, Foroud T, Nurnberger J Jr, Xuei X, Conneally PM, Schuckit M, Almasy L, Crowe R, Kuperman S, Kramer J, Tischfield JA, Hesselbrock V, Edenberg HJ, Porjesz B, Rice JP, Bierut L, Goate A. (2008) A Systematic single nucleotide polymorphism screen to fine-map alcohol dependence genes on chromosome 7 identifies association with a novel susceptibility gene ACN9. Biol Psychiatry. 63(11):1047-53.

Edenberg HJ, Xuei X, Wetherill LF, Bierut L, Bucholz K, Dick DM, Hesselbrock V, Kuperman S, Porjesz B, Schuckit MA, Tischfield JA, Almasy LA, Nurnberger JI Jr, Foroud T. (2008)
Association of NFKB1, which encodes a subunit of the transcription factor NF-kappaB, with alcohol dependence. Hum Mol Genet. 17(7):963-70.

Liang L, Deng L, Mendonca MS, Chen Y, Zheng B, Stambrook PJ, Shao C, Tischfield JA. (2007) X-rays induce distinct patterns of somatic mutation in fetal versus adult hematopoietic cells. DNA Repair (Amst). 6(9):1380-5.

Liang L, Mendonca MS, Deng L, Nguyen SC, Shao C, Tischfield JA. (2007) Reduced apoptosis and increased deletion mutations at Aprt locus in vivo in mice exposed to repeated ionizing radiation. Cancer Res. 67(5):1910-7.

Bahassi el M, Penner CG, Robbins SB, Tichy E, Feliciano E, Yin M, Liang L, Deng L, Tischfield JA, Stambrook PJ. (2007) The breast cancer susceptibility allele CHEK2*1100delC promotes genomic instability in a knock-in mouse model. Mutat Res. 616(1-2):201-9.

Hinrichs AL. Wang JC. Bufe B. Kwon JM. Budde J. Allen R. Bertelsen S. Evans W. Dick D. Rice J. Foroud T. Nurnberger J. Tischfield JA. Kuperman S. Crowe R. Hesselbrock V. Schuckit M. Almasy L. Porjesz B. Edenberg HJ. Begleiter H. Meyerhof W. Bierut LJ. Goate AM. (2006) Functional variant in a bitter-taste receptor (hTAS2R16) influences risk of alcohol dependence. Am J Hum Genet. 78(1):103-11.

Buyske S. Bates ME. Gharani N. Matise TC. Tischfield JA. Manowitz P. (2006) Cognitive traits link to human chromosomal regions. Behav Genet. 36(1):65-76.

Vernon HJ. Osborne C. Tzortzaki EG. Yang M. Chen J. Rittling SR. Denhardt DT. Buyske S. Bledsoe SB. Evan AP. Fairbanks L. Simmonds HA. Tischfield JA. Sahota A. (2005) Aprt/Opn double knockout mice: osteopontin is a modifier of kidney stone disease severity. Kidney Int. 68(3):938-47.

Liang L. Deng L. Chen Y. Li GC. Shao C. Tischfield JA. (2005) Modulation of DNA end joining by nuclear proteins. J Biol Chem. 280(36):31442-9.

Shao C. Deng L. Chen Y. Kucherlapati R. Stambrook PJ. Tischfield JA. (2004) Mlh1 mediates tissue-specific regulation of mitotic recombination. Oncogene. 23(56):9017-24.

Jones. K.A.. Porjesz. B.. Almasy. L.. Bierut. L.. Goate. A.. Wang. J.C.. Dick. D.M.. Hinrichs. A.. Kwon. J.. Rice. J.P.. Rohrbaugh. J.. Stock. H.. Wu. W.. Bauer. L.O.. Chorlian. D.B.. Crowe. R.R.. Edenberg. H.J.. Foroud. T.. Hesselbrock. V.. Kuperman. S.. Nurnberger. J. Jr. O'Connor. S.J.. Schuckit. M.A.. Stimus. A.T.. Tischfield. J.A.. Reich. T.. Begleiter. H. (2004). Linkage and linkage disequilibrium of evoked EEG oscillations with CHRM2 receptor gene polymorphisms: Implications for human brain dynamics and cognition. Int J Psychophysiol 53:75-90.

Wang J.C. Hinrichs A.L. Stock H. Budde J. Allen R. Bertelsen S. Kwon JM. Wu W. Dick D.M. Rice J. Jones K. Nurnberger J.I Jr. Tischfield J. Porjesz B. Edenberg HJ. Hesselbrock V. Crowe R. Schuckit M. Begleiter H. Reich T. Goate AM. Bierut L.J. (2004). Evidence of common and specific genetic effects: association of the muscarinic acetylcholine receptor M2 (CHRM2) gene with alcohol dependence and major depressive syndrome. Hum Mol Genet. 13:1903-11.

Shao C. Deng L. Chen Y. Kucherlapati R. Stambrook PJ (2004). Tischfield JA. Mlh1 mediates tissue-specific regulation of mitotic recombination. Oncogene 23:9017-24.

Tzortzaki. E.G.. Yang. M.. Glass. D.. Deng. L.. Evan. A.P.. Bledsoe. S.B.. Stambrook. P.J.. Sahota. A.. Tischfield. J.A. (2003). Impaired expression of an organic cation transporter. IMPT1. in a knockout mouse model for kidney stone disease. Urol Res. 31:257-261.

Tischfield. J.A.. Shao. C. (2003). Somatic recombination redux. Nature Genet. 33:5-6.

Bierut LJ. Saccone NL. Rice JP. Goate A. Foroud T. Edenberg H. Almasy L. Conneally PM. Crowe R. Hesselbrock V. Li TK. Nurnberger J Jr. Porjesz B. Schuckit MA. Tischfield J. Begleiter H. Reich T. (2002). Defining alcohol-related phenotypes in humans. The Collaborative Study on the Genetics of Alcoholism. Alcohol Res Health. 26:208-13.

Wang. L.. Raikwar. N.. Yang. M.. Deng. L.. McAteer. J.A.. Stambrook. P.J.. Sahota. A.. and Tischfield. J.A. (2002). Induction of alpha-catenin. integrin alpha3. integrin beta6. and PDGF-B by 2,8-dihydroxyadenine crystals in cultured kidney epithelial cells. Exp Nephrol. 10:365-73.

Liang. L.. Shao. C.. Deng. L.. Mendoca. M.S.. Stambrook. P. J.. and Tischfield. J.A. (2002). Radiation-induced genetic instability in vivo depends on p53 status. Mutation Res. 502:69-80.

Stambrook. P.J.. and Tischfield. J.A.Mutation in Stem Cells: The Good. The Bad and The Ugly. Scientific World 1:89-91.

Shao. C.. Yin. M.. Deng. L.. Liskay. R.M.. Stambrook. P.J.. Doetschman. T.C. and Tischfield. J.A. (2002). Loss of heterozygosity and point mutation at Aprt locus in T cells and fibroblasts of Pms2 mice. Oncogene 21:2840-5.

Tzortzaki EG. Glass D. Yang M. Evan AP. Bledsoe SB. Stambrook PJ. Sahota A. Tischfield JA. (2002). Gender- and age-dependent changes in kidney androgen protein mRNA expression in a knockout mouse model for nephrolithiasis. J Histochem Cytochem 50:1663-1670.

Porjesz. B.. Almasy. L.. Edenberg. H.J.. Wang. K.. Chorlian. D.B.. Foroud. T.. Goate. A.. Rice. J.P.. O'Connor. S.J.. Rohrbaugh. J.. Kuperman. S.. Bauer L.O.. Crowe. R.R.. Schuckit. M.A.. Hesselbrock. V.. Conneally. P.M.. Tischfield. J.A.. Li. T-K. Reich. T.. and Begleiter. H. (2002). Linkage Disequilibrium between the Beta Frequency of the Human EEG and a GABA_A receptor gene locus. Proc Natl Acad Sci USA 99:3729-3733.

Cervantes. R.B.. Stringer. J.R.. Shao. C.. Tischfield. J.A.. Stambrook. P.J. (2002). Embryonic stem cells and somatic cells differ in mutation frequency and type. Proc Natl Acad Sci USA 99:3586-3590.

Evan. A.P.. Bledsoe. S.. Connors. B.A.. Deng. L.. Shao. C.. Liang. L.. Fineberg. N.. Grynpass. M.D.. Stambrook. P.J.. Sahota. A. and Tischfield. J.A. (2001). Sequential analysis of 2,8-dihydroxyadenine renal stone formation in a knockout mouse model for adenine phosphoribosyltransferase deficiency. Kidney International 60:910-923.

Shao. C.. Stambrook. P.J.. and Tischfield. J.A. (2001). Mitotic recombination is suppressed by chromosomal divergence in hybrids of distantly related mouse strains. Nature Genetics 28:169-172.

Sahota. A.S.. Tischfield. J.A.. Kamatani. N.. Simmonds. A.H. (2001). Adenine phosphoribosyltransferase deficiency and 2,8-Dihydroxyadenine lithiasis. The Metabolic & Molecular Bases of Inherited Disease. Scriver. C.R.. Beaudet. A.L.. Sly. W.S. and Valle. D. eds. DMcGraw-Hill Publishers pp. 2571-2584.

Deng. L.. Yang. M.. Frund. S.. Wessel. T.. De Abreu. R.A.. Tischfield. J.A.. and Sahota. A. (2001). 2,8- Dihydroxyadenine urolithiasis in a patient with considerable residual adenine phosphoribosyltransferase activity in cell extracts but with mutations in both copies of APRT. Mol Genet Metab. 72:260-264.