Norman Arnheim

Summary Statement of Research Interests

A major interest of our lab is the process that produces germline disease mutations each generation at frequencies far above the known normal human mutation rate (100-1,000 times greater). These mutations: 1) are Recurrent and always take place at the same nucleotide site, 2) result in a gain of function so the disease is inherited as an Autosomal dominant, 3) almost always occur in the male germline and 4) are more likely to be transmitted to the man’s children as he ages-the Paternal age effect. We use the acronym RAMP for such mutations. We studied many different RAMP mutations in four different genes. Among these genes are receptor tyrosine kinases and a non-receptor tyrosine phosphatase, all of which are known in the mouse to be important for spermatogonial stem cell (SSC) proliferation and survival. We found that the unusually high RAMP mutation frequency was not because the mutated DNA base was unusually susceptible to the mutation process. Instead, our data suggest that, in a normal man, any SSC that experiences a rare RAMP mutation is also provided with a selective advantage over his un-mutated brother SSC. This results in an ever-increasing proportion of RAMP mutation-carrying sperm as the man ages. We are currently using transgenic mice to compare the proliferation of mutant and non-mutant SSC in the testis. Our goal is to understand the mechanism of SSC selection and why the mutant SSC do not form tumors but continue to make sperm.
Another main interest is developing new technologies that can solve the fundamental conflict between detecting rare mutations in very small samples of DNA and the inherent problem of the artifactual mutations that accompany the standard detection methods.

Research Specialties

Aging and Development Biology, Biochemistry, Molecular Biology

Journal Article

• Arnheim, N., Calabrese, P. (2016). Frequency of Human Disease Mutations and Spermatogoinal Stem Cell Function. Springer. (The Biology of Mammalian Spermatogonia)
• Eboreime, J., Choi, S. K., Yoon, S. R., Arnheim, N., Calabrese, P. (2016). Estimating Exceptionally Rare Germline and Somatic Mutation Frequencies via Next Generation Sequencing. PloS one. Vol. 11 (6), pp. e0158340. PubMed Web Address
• Arnheim, N., Calabrese, P. (2016). Germline Stem Cell Competition, Mutation Hot Spots, Genetic Disorders, and Older Fathers. Annual review of genomics and human genetics. PubMed Web Address
• 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.

• American Association for the Advancement of Science Fellow, Fellow, 12/01/2012 –
• USC Endowed Chair, Ester Dornsife Chair in Biological Sciences, 1998 – 05/15/2018
• USC Distinguished Professor, Distinguished Professor of Biological Sciences, Molecular Biology, and Biochemistry, 2001