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Norman Arnheim

Distinguished Professor of Biological Sciences, Molecular Biology and Biochemistry, and Ester Dornsife Chair in Biological Sciences

Contact Information
E-mail: arnheim@usc.edu
Phone: (213) 740-7675
Office: RRI 319C

 

Education

Ph.D. Genetics, University of California, Berkeley, 1/1965
M.S. Biology, University of Rochester, 1/1962
B.A. Biology, University of Rochester, 1/1960
 

Description of Research

Summary Statement of Research Interests

A major interest of our lab is mutation in the human germline. We are using single molecule PCR analysis to study the patterns of mutational change that occur at human disease loci. Our studies on human mutation focus on loci that exhibit the paternal age effect. An example is the locus that codes for the FGFR3 protein. Mutations in this protein cause achondroplasia, the most common form of dwarfism. We are also studying Apert syndrome due to mutations in the FGFR2 gene. It has been known for a long time that older men are more likely to have children with these mutations. The basic premise of the paternal age effect is that as men age, they produce more sperm carrying a de novo mutation. Attempts to use sperm DNA to test this assumption were made for the first time only within the last few years. We are interested in two major features of the paternal age effect; 1) the reason for the fact that mutations that exhibit the paternal age effect occur only in males and 2) why the mutation frequency is 100-1000 times greater for these mutations than the average nucleotide site. We are focusing on the role that germline selection may play in increasing the frequency of these genetic conditions beyond the level of mutation events that give rise to a nucleotide substitution.
 

Research Specialties

Aging and Development Biology, Biochemistry, Molecular Biology
 

Affiliations with Research Centers, Labs, and Other Institutions

Department of Biological Sciences, http://www.usc.edu/dept/LAS/biosci/
 

Publications

Journal Article

Shinde, D. N., Elmer, D. P., Calabrese, P., Boulanger, J., Arnheim, N., Tiemann-Boege,Shinde, I. ,., Elmer, D. P., Calabrese, P., Boulanger, J., Arnheim, N., Tiemann-Boege,Shinde, I. ,., Elmer, D. P., Calabrese, P., Boulanger, J., Arnheim, N., Tiemann-Boege, I. (2013). New evidence for positive selection helps explain the paternal age effect observed in achondroplasia. Human molecular genetics. Vol. 22 (20), pp. 4117-26. PubMed Web Address
Yoon, S. R., Choi, S. K., Eboreime, J., Gelb, B. D., Calabrese, P., Arnheim,Yoon, N. ,., Choi, S. K., Eboreime, J., Gelb, B. D., Calabrese, P., Arnheim,Yoon, N. ,., Choi, S. K., Eboreime, J., Gelb, B. D., Calabrese, P., Arnheim, N. (2013). Age-Dependent Germline Mosaicism of the Most Common Noonan Syndrome Mutation Shows the Signature of Germline Selection. American journal of human genetics. PubMed Web Address
Choi, S. K., Yoon, S. R., Calabrese, P., Arnheim,Choi, N. ,., Yoon, S. R., Calabrese, P., Arnheim,Choi, N. ,., Yoon, S. R., Calabrese, P., Arnheim, N. (2012). Positive selection for new disease mutations in the human germline: evidence from the heritable cancer syndrome multiple endocrine neoplasia type 2B. PLoS genetics. Vol. 8 (2), pp. e1002420. PubMed Web Address
Yoon, S. R., Qin, J., Glaser, R. L., Wang Jabs, E., Wexler, N. S., Sokol, R., Arnheim, N., Calabrese, P. (2009). The ups and downs of mutation frequencies during aging can account for the apert syndrome paternal age effect. PLoS Genet. Vol. 5 (72009/07/14), pp. e1000558.
Arnheim, N., Calabrese, P. (2009). Understanding what determines the frequency and pattern of human germline mutations. Nat Rev Genet. Vol. 10 (72009/06/03), pp. 478-88.
Tiemann-Boege, I., Curtis, C., Shinde, D. N., Goodman, D. B., Tavare, S., Arnheim, N. (2009). Product length, dye choice, and detection chemistry in the bead-emulsion amplification of millions of single DNA molecules in parallel. Anal Chem. Vol. 81 (142009/07/16), pp. 5770-6.
Qin, J., Subramanian, J., Arnheim,Qin, N. ,., Subramanian, J., Arnheim, N. (2009). Detection of meiotic DNA breaks in mouse testicular germ cells. Methods in molecular biology (Clifton, N.J.). Vol. 557, pp. 165-81. PubMed Web Address
Choi, S. K., Yoon, S. R., Calabrese, P., Arnheim, N. (2008). A germ-line-selective advantage rather than an increased mutation rate can explain some unexpectedly common human disease mutations. Proc Natl Acad Sci U S A. Vol. 105 (292008/07/18), pp. 10143-8.
Qin, J., Calabrese, P., Tiemann-Boege, I., Shinde, D. N., Yoon, S. R., Gelfand, D., Bauer, K., Arnheim,Qin, N. ,., Calabrese, P., Tiemann-Boege, I., Shinde, D. N., Yoon, S. R., Gelfand, D., Bauer, K., Arnheim, N. (2007). The molecular anatomy of spontaneous germline mutations in human testes. PLoS biology. Vol. 5 (9), pp. e224. PubMed Web Address
Shelbourne, P. F., Keller-McGandy, C., Bi, W. L., Yoon, S. R., Dubeau, L., Veitch, N. J., Vonsattel, J. P., Wexler, N. S., US-Venezuela, G. r., Arnheim, N., Augood,Shelbourne, S. J., Keller-McGandy, C., Bi, W. L., Yoon, S. R., Dubeau, L., Veitch, N. J., Vonsattel, J. P., Wexler, N. S., US-Venezuela, G. r., Arnheim, N., Augood, S. J. (2007). Triplet repeat mutation length gains correlate with cell-type specific vulnerability in Huntington disease brain. Human molecular genetics. Vol. 16 (10), pp. 1133-42. PubMed Web Address
Clark, V. J., Ptak, S. E., Tiemann, I., Qian, Y., Coop, G., Stone, A. C., Przeworski, M., Arnheim, N., Di,Clark, A. ,., Ptak, S. E., Tiemann, I., Qian, Y., Coop, G., Stone, A. C., Przeworski, M., Arnheim, N., Di, A. (2007). Combining sperm typing and linkage disequilibrium analyses reveals differences in selective pressures or recombination rates across human populations. Genetics. Vol. 175 (2), pp. 795-804. PubMed Web Address
., .. (2007). Clark V, Ptak SE, Tiemann-Boege I, Gian Y, Coop G, Stone AC, Przeworski M, Arnheim N, Di Rienzo A. (2007) Combining sperm typing and LD analyses reveals differences in selective pressures or recombination rates across human populations. Genetics. 175(2):795-804.
., .. (2007). Shelbourne, PF, Keller-McGandy, C, Bi, WL, Yoon, SR, Dubeau, L, Veitch, NJ, Vonsattel, JP, Wexler, NX and the Venezuela Huntington Disease Project, Arnheim, N, Augood, SJ. (2007) Triplet repeat mutation length gains correlate with cell-type specific vulnerability in Huntington disease brain. Human Molecular Genetics. 16(10):1133-1142.
Arnheim, N., Calabrese, P., Tiemann-Boege,Arnheim, I. ,., Calabrese, P., Tiemann-Boege, I. (2007). Mammalian meiotic recombination hot spots. Annual review of genetics. Vol. 41, pp. 369-99. PubMed Web Address
Tiemann-Boege, I., Calabrese, P., Cochran, D. M., Sokol, R., Arnheim,Tiemann-Boege, N. ,., Calabrese, P., Cochran, D. M., Sokol, R., Arnheim, N. (2006). High-resolution recombination patterns in a region of human chromosome 21 measured by sperm typing. PLoS genetics. Vol. 2 (5), pp. e70. PubMed Web Address
Wesoly, J., Agarwal, S., Sigurdsson, S., Bussen, W., Van, S., Qin, J., van, H., van, J., Wassenaar, E., Baarends, W. M., Ghazvini, M., Tafel, A. A., Heath, H., Galjart, N., Essers, J., Grootegoed, J. A., Arnheim, N., Bezzubova, O., Buerstedde, J. M., Sung, P., Kanaar,Wesoly, R. ,., Agarwal, S., Sigurdsson, S., Bussen, W., Van, S., Qin, J., van, H., van, J., Wassenaar, E., Baarends, W. M., Ghazvini, M., Tafel, A. A., Heath, H., Galjart, N., Essers, J., Grootegoed, J. A., Arnheim, N., Bezzubova, O., Buerstedde, J. M., Sung, P., Kanaar, R. (2006). Differential contributions of mammalian Rad54 paralogs to recombination, DNA damage repair, and meiosis. Molecular and cellular biology. Vol. 26 (3), pp. 976-89. PubMed Web Address
., .. (2006). Wyrobek AJ, Eskenazi B, Young S, Arnheim N, Tiemann-Boege I, Jabs EW, Glaser RL, Pearson FS, Evenson D. (2006) Advancing age has differential effects on DNA damage, chromatin integrity, gene mutations, and aneuploidies in sperm. Proc Natl Acad Sci U S A. 103(25):9601-6.
., .. (2006). Wesoly J, Agarwal S, Sigurdsson S, Bussen W, Van Komen S, Qin J, van Steeg, H, van Benthem J, Wassenaar E, Baarends WM, Ghazvini M, Tafel AA, Heath H, Galjart N, Essers J, Grootegoed JA, Arnheim N, Bezzubova O, Buerstedde JM, Sung P, Kanaar R. (2006) Differential contributions of Mammalian rad54 paralogs to recombination, DNA damage repair, and meiosis. Mol Cell Biol. 26(3):976-89.
., .. (2006). Tiemann-Boege, I. Calabrese, P., Cochran, D.C., Sokol, R.Z., Arnheim, N. (2006) High Resolution Recombination Patterns in a Region of Human Chromosome 21 Measured by Sperm Typing. PLoS Genetics 2(5): e70.
Chen, P. C., Dudley, S., Hagen, W., Dizon, D., Paxton, L., Reichow, D., Yoon, S. R., Yang, K., Arnheim, N., Liskay, R. M., Lipkin,Chen, S. M., Dudley, S., Hagen, W., Dizon, D., Paxton, L., Reichow, D., Yoon, S. R., Yang, K., Arnheim, N., Liskay, R. M., Lipkin, S. M. (2005). Contributions by MutL homologues Mlh3 and Pms2 to DNA mismatch repair and tumor suppression in the mouse. Cancer research. Vol. 65 (19), pp. 8662-70. PubMed Web Address
Subramanian, J., Vijayakumar, S., Tomkinson, A. E., Arnheim,Subramanian, N. ,., Vijayakumar, S., Tomkinson, A. E., Arnheim, N. (2005). Genetic instability induced by overexpression of DNA ligase I in budding yeast. Genetics. Vol. 171 (2), pp. 427-41. PubMed Web Address
., .. (2005). Subramanian, J., Vijayakumar, S., Tomkinson, A. and Arnheim, N. (2005) Genetic Instability Induced by Overexpression of DNA ligase I in Budding Yeast. Genetics. 171(2):427-41. Genetics. Vol. 171(2), pp. 427-41.
., .. (2005). Chen PC, Dudley S, Hagen W, Dizon D, Paxton L, Reichow D, Yoon SR, Yang K, Arnheim N, Liskay RM, Lipkin SM.. (2005) Contributions by MutL Homologs Mlh3 and Pms2 to DNA Mismatch Repair and Tumor Suppression in the Mouse. Cancer Research, 65(19):8662-70.
Wexler, N. S., Lorimer, J., Porter, J., Gomez, F., Moskowitz, C., Shackell, E., Marder, K., Penchaszadeh, G., Roberts, S. A., Gayán, J., Brocklebank, D., Cherny, S. S., Cardon, L. R., Gray, J., Dlouhy, S. R., Wiktorski, S., Hodes, M. E., Conneally, P. M., Penney, J. B., Gusella, J., Cha, J. H., Irizarry, M., Rosas, D., Hersch, S., Hollingsworth, Z., MacDonald, M., Young, A. B., Andresen, J. M., Housman, D. E., De, M. M., Bonilla, E., Stillings, T., Negrette, A., Snodgrass, S. R., Martinez-Jaurrieta, M. D., Ramos-Arroyo, M. A., Bickham, J., Ramos, J. S., Marshall, F., Shoulson, I., Rey, G. J., Feigin, A., Arnheim, N., Acevedo-Cruz, A., Acosta, L., Alvir, J., Fischbeck, K., Thompson, L. M., Young, A., Dure, L., O'Brien, C. J., Paulsen, J., Brickman, A., Krch, D., Peery, S., Hogarth, P., Higgins, J. r., Landwehrmeyer, B., U.S.-Venezuela,Wexler, P. r., Lorimer, J., Porter, J., Gomez, F., Moskowitz, C., Shackell, E., Marder, K., Penchaszadeh, G., Roberts, S. A., Gayán, J., Brocklebank, D., Cherny, S. S., Cardon, L. R., Gray, J., Dlouhy, S. R., Wiktorski, S., Hodes, M. E., Conneally, P. M., Penney, J. B., Gusella, J., Cha, J. H., Irizarry, M., Rosas, D., Hersch, S., Hollingsworth, Z., MacDonald, M., Young, A. B., Andresen, J. M., Housman, D. E., De, M. M., Bonilla, E., Stillings, T., Negrette, A., Snodgrass, S. R., Martinez-Jaurrieta, M. D., Ramos-Arroyo, M. A., Bickham, J., Ramo, J. S. (2004). Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease age of onset. Proceedings of the National Academy of Sciences of the United States of America. Vol. 101 (10), pp. 3498-503. PubMed Web Address
Qin, J., Richardson, L. L., Jasin, M., Handel, M. A., Arnheim, N. (2004). Mouse strains with an active H2-Ea meiotic recombination hot spot exhibit increased levels of H2-Ea-specific DNA breaks in testicular germ cells. Molecular and cellular biology. Vol. 24 (4), pp. 1655-66. PubMed Web Address
Brohede, J., Arnheim, N., Ellegren, H. (2004). Single-molecule analysis of the hypermutable tetranucleotide repeat locus D21S1245 through sperm genotyping: a heterogeneous pattern of mutation but no clear male age effect. Molecular biology and evolution. Vol. 21 (1), pp. 58-64. PubMed Web Address
., .. (2004). Brohede, J., Arnheim, N. and Ellegren, H. (2004) Single molecule analysis of the hypermutable tetranucleotide repeat locus D21S1245 through sperm genotyping: a heterogeneous pattern of mutation but no clear male age effect. Molecular Biology and Evolution: 21:58-64.
Yoon, S. R., Dubeau, L., de, M., Wexler, N. S., Arnheim, N. (2003). Huntington disease expansion mutations in humans can occur before meiosis is completed. Proceedings of the National Academy of Sciences of the United States of America. Vol. 100 (15), pp. 8834-8. PubMed Web Address
Arnheim, N., Calabrese, P., Nordborg, M. (2003). Hot and cold spots of recombination in the human genome: the reason we should find them and how this can be achieved. American journal of human genetics. Vol. 73 (1), pp. 5-16. PubMed Web Address
Shinde, D., Lai, Y., Sun, F., Arnheim, N. (2003). Taq DNA polymerase slippage mutation rates measured by PCR and quasi-likelihood analysis: (CA/GT)n and (A/T)n microsatellites. Nucleic acids research. Vol. 31 (3), pp. 974-80. PubMed Web Address
., .. (2003). Shinde, D., Lai, Y., Sun, F. and Arnheim, N. (2003) Taq DNA polymerase slippage mutation rates measured by PCR and quasi-likelihood analysis: (CA/GT)(n) and (A/T)(n) microsatellites. Nucleic Acids Res. 31(3):974-80.
., .. (2003). Nenguke, T., Aladjem, M.I., Gusella, J.F., Wexler, N.S. and the Venezuela HD Project and Arnheim, N. (2003) Candidate DNA replication initiation regions at human trinucleotide repeat disease loci. Human Molecular Genetics, 12:1021-1028.
., .. (2003). Arnheim, N., Calabrese, P. and Nordborg, N. (2003) Hot and cold spots of recombination in the Human genome: the reason we should find them and how this can be achieved. Am. J. Hum. Genet 73: 5-16.
., .. (2003). Yoon, S-R., Dubeau, L., de Young, M., Wexler, N.S. and Arnheim, N. (2003) Huntington disease expansion mutations in humans can occur before meiosis is completed. Proc. Natl. Acad. Sci. 100:8834-8.
Lai, Y., Shinde, D., Arnheim, N., Sun, F. (2003). The mutation process of microsatellites during the polymerase chain reaction. Journal of computational biology : a journal of computational molecular cell biology. Vol. 10 (2), pp. 143-55. PubMed Web Address
Lien, S., Szyda, J., Leeflang, E. P., Hubert, R., Zhang, L., Schmitt, K., Arnheim,Lien, N. ,., Szyda, J., Leeflang, E. P., Hubert, R., Zhang, L., Schmitt, K., Arnheim, N. (2002). Single-sperm typing. Current protocols in human genetics / editorial board, Jonathan L. Haines ... [et al.]. Vol. Chapter 1, pp. Unit 1.6. PubMed Web Address
., .. (2002). Tiemann-Boege I, Navidi W, Grewal R, Cohn D, Eskenazi B, Wyrobek AJ, Arnheim N. The observed human sperm mutation frequency cannot explain the achondroplasia paternal age effect. Proc Natl Acad Sci U S A. [ 2002 ] Nov 12;99(23):14952-7.
 

Honors and Awards

American Association for the Advancement of Science Fellow, Fellow, 12/1/2012-  
USC Endowed Chair, Ester Dornsife Chair in Biological Sciences, 1998-  
USC Distinguished Professor, Distinguished Professor of Biological Sciences, Molecular Biology, and Biochemistry, 2001  
 
 
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