Abstract

This proposal seeks to study fundamental questions concerning mutation and recombination events that lead to human disease.
One aim i s to determine whether expansions of the CAT/CTG tracts found in Huntington disease patients occur in germline mitotic cells or following the initiation of meiosis. Studies are also proposed to examine whether the proximity or orientation of a CAG/CTG tract relative to an origin of DNA replication influences expansion size or frequency and whether this accounts for the marked inter-locus variation in expansion mutation susceptibility. Two other aims also focus on mutation.
One aim will examine human sperm to determine whether the mutation that causes achondroplasia, the most common cause of dwarfism, increases with the age of the father as predicted by population studies. Another will examine the role played by members of the MutL DNA repair protein family on mononucleotide repeat slippage mutations. In humans this kind of mutation has been shown to inactivate important genes in many tumors from patients with the a familial colon cancer (HNPCC). The last aim seeks to directly measure the effects of sequence length and sequence similarity on the frequency of unequal recombination between repeated sequences in the human genome. Such events have been shown to lead to a variety of human disease syndromes.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM036745-19
Application #
6725464
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Anderson, Richard A
Project Start
1985-09-01
Project End
2006-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
19
Fiscal Year
2004
Total Cost
$806,973
Indirect Cost

  Institution

Name
University of Southern California
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089

  Publications

Eboreime, Jordan; Choi, Soo-Kung; Yoon, Song-Ro et al. (2016) Estimating Exceptionally Rare Germline and Somatic Mutation Frequencies via Next Generation Sequencing. PLoS One 11:e0158340
Arnheim, Norman; Calabrese, Peter (2016) Germline Stem Cell Competition, Mutation Hot Spots, Genetic Disorders, and Older Fathers. Annu Rev Genomics Hum Genet 17:219-43
Fischer, Jared M; Calabrese, Peter P; Miller, Ashleigh J et al. (2016) Single cell lineage tracing reveals a role for Tgf?R2 in intestinal stem cell dynamics and differentiation. Proc Natl Acad Sci U S A 113:12192-12197
Yoon, Song-Ro; Choi, Soo-Kung; Eboreime, Jordan et al. (2013) Age-dependent germline mosaicism of the most common noonan syndrome mutation shows the signature of germline selection. Am J Hum Genet 92:917-26
Shinde, Deepali N; Elmer, Dominik P; Calabrese, Peter et al. (2013) New evidence for positive selection helps explain the paternal age effect observed in achondroplasia. Hum Mol Genet 22:4117-26
Choi, Soo-Kyung; Yoon, Song-Ro; Calabrese, Peter et al. (2012) Positive selection for new disease mutations in the human germline: evidence from the heritable cancer syndrome multiple endocrine neoplasia type 2B. PLoS Genet 8:e1002420
Qin, Jian; Subramanian, Jaichandar; Arnheim, Norman (2009) Detection of meiotic DNA breaks in mouse testicular germ cells. Methods Mol Biol 557:165-81
Yoon, Song-Ro; Qin, Jian; Glaser, Rivka L et al. (2009) The ups and downs of mutation frequencies during aging can account for the Apert syndrome paternal age effect. PLoS Genet 5:e1000558
Arnheim, Norman; Calabrese, Peter (2009) Understanding what determines the frequency and pattern of human germline mutations. Nat Rev Genet 10:478-88
Tiemann-Boege, Irene; Curtis, Christina; Shinde, Deepali N et al. (2009) Product length, dye choice, and detection chemistry in the bead-emulsion amplification of millions of single DNA molecules in parallel. Anal Chem 81:5770-6

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