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Education:
BA 1960 Biology - University of Rochester, New York
MS 1962 Biology - University of Rochester, New York
PhD 1965 Genetics - University of California, Berkeley
Postdoctoral Research Fellowship:
1965 - 1968 University of California, Berkeley
Started at USC: 1985 Research Topics: DNA Replication, Repair, Modification, DNA & RNA, Human/Mammalian Genetics
Research Description A major interest of our lab is recombination and mutation in the human germline and the relation between these processes and human genetic disease. We are using single molecule PCR analysis to study the patterns of mutational change that occur at loci containing repeated DNA sequences. For example, a number of human genetic diseases are caused by the mutational expansion in the number of trinucleotide repeats at specific loci. Among these diseases is Huntington's disease (HD). In every case, the presence of the HD is associated with an expansion in the number of repeats in the gene over that found in the normal individuals. By studying sperm from normal individuals and patients with HD we can estimate the mutation frequency of trinucleotide repeat expansion mutation and determine the size distribution of these mutations. Based on this information we are trying to determine the stage of gamete formation when these expansions take place. Another project aims to discover whether brain cells carrying an expanded HD gene can undergo further expansions and whether such an increase might affect the severity of the disease. We are also interested in understanding the factors that determine why some human chromosome regions undergo genetic recombination at a much higher frequency than others. This project is important to the attempts to map disease gene loci using so called "association mapping" with single nucleotide polymorphisms (SNPs). In order to gain information on the distribution of recombination events at very high resolution we developed a method of allele-specific PCR that can detect rare recombinants in a pooled sample of sperm DNA. This will allow quantitation of human recombination frequencies over intervals of between 1,000 and 10,000 base pairs. In addition to studying allelic recombination between homologous chromosomes we are also studying recombination between human repeated sequences on the same or different chromosomes (ectopic recombination). Ectopic recombination events are known to lead to chromosomal abnormalities that cause genetic disease. Allele specific PCR using sperm DNA will allows us to localize the sites of recombination between the repeated sequences, the frequency of these events and how DNA sequence differences between the repeats affect the frequency.
10 Selected Publications:
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Qin J,Subramanian J,Arnheim N - Detection of meiotic DNA breaks in mouse testicular germ cells. - Methods Mol Biol [2009] ;557():165-81 PubMed
Tiemann-Boege I,Curtis C,Shinde DN,Goodman DB,Tavaré S,Arnheim N - Product length, dye choice, and detection chemistry in the bead-emulsion amplification of millions of single DNA molecules in parallel. - Anal Chem [2009] Jul 15;81(14):5770-6 PubMed
Yoon SR,Qin J,Glaser RL,Wang Jabs E,Wexler NS,Sokol R,Arnheim N,Calabrese P - The ups and downs of mutation frequencies during aging can account for the apert syndrome paternal age effect. - PLoS Genet [2009] Jul;5(7):e1000558 PubMed
Arnheim N,Calabrese P - Understanding what determines the frequency and pattern of human germline mutations. - Nat Rev Genet [2009] Jun 2;(): PubMed
Choi SK,Yoon SR,Calabrese P,Arnheim N - 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 [2008] Jul 22;105(29):10143-8 PubMed
Lien S,Szyda J,Leeflang EP,Hubert R,Zhang L,Schmitt K,Arnheim N - Single-sperm typing. - Curr Protoc Hum Genet [2002] May;Chapter 1():Unit 1.6 PubMed
Arnheim N,Calabrese P,Tiemann-Boege I - Mammalian meiotic recombination hot spots. - Annu Rev Genet [2007] ;41():369-99 PubMed
Qin J,Calabrese P,Tiemann-Boege I,Shinde DN,Yoon SR,Gelfand D,Bauer K,Arnheim N - The molecular anatomy of spontaneous germline mutations in human testes. - PLoS Biol [2007] Sep;5(9):e224 PubMed
Shelbourne PF,Keller-McGandy C,Bi WL,Yoon SR,Dubeau L,Veitch NJ,Vonsattel JP,Wexler NS,US-Venezuela Collaborative Research Group,Arnheim N,Augood SJ - Triplet repeat mutation length gains correlate with cell-type specific vulnerability in Huntington disease brain. - Hum Mol Genet [2007] May 15;16(10):1133-42 PubMed
Clark VJ,Ptak SE,Tiemann I,Qian Y,Coop G,Stone AC,Przeworski M,Arnheim N,Di Rienzo A - Combining sperm typing and linkage disequilibrium analyses reveals differences in selective pressures or recombination rates across human populations. - Genetics [2007] Feb;175(2):795-804 PubMed
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