The goals of the proposed research are to investigate the frequency, properties, and factors which affect meiotic and mitotic gene conversion in the germline of mice. Gene conversion is the non-reciprocal recombination of genetic information. One manifestation of this process is non-Mendelian segregation of alleles. The result can have profound effects upon genome evolution and diversification. The frequency and mechanism of meiotic gene conversion has been extensively studied in fungi, where one can obtain and score all the products of a single meiosis. Similar experiments are not feasible in mammals. In fact, evidence that meiotic gene conversion actually occurs in mammals is circumstantial. The experiments described in this proposal circumvent the technical and logistical problems which have heretofore limited the study of mammalian gene conversion: generating large numbers of progeny and simple detection of a conversion event. We have designed and tested a system to score populations of murine male gametes for contrived conversion events. The occurrence of a planned event results in correction of a mutated reporter gene and synthesis of histochemically detectable reporter activity in spermatids. Modifications of this strategy will allow a quantitative analysis of both meiotic and mitotic intra- and interchromosomal gene conversion in the germ line. In addition, we intend to investigate the size of gene conversions and the influence of gene structure parameters upon the frequency of these processes. Gene duplication is a central process for evolutionary change and adaptation. Gene conversion significantly influences gene families created through duplication. These experiments will be instrumental for assessing the evolutionary and functional ramifications of gene conversion upon the divergence of related genes.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM045415-05
Application #
2183159
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1992-02-01
Project End
1996-01-31
Budget Start
1995-02-01
Budget End
1996-01-31
Support Year
5
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
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McNairn, Adrian J; Rinaldi, Vera D; Schimenti, John C (2017) Repair of Meiotic DNA Breaks and Homolog Pairing in Mouse Meiosis Requires a Minichromosome Maintenance (MCM) Paralog. Genetics 205:529-537
Rinaldi, Vera D; Hsieh, Kristin; Munroe, Robert et al. (2017) Pharmacological Inhibition of the DNA Damage Checkpoint Prevents Radiation-Induced Oocyte Death. Genetics 206:1823-1828
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Singh, Priti; Schimenti, John C; Bolcun-Filas, Ewelina (2015) A mouse geneticist's practical guide to CRISPR applications. Genetics 199:1-15
Luo, Yunhai; Hartford, Suzanne A; Zeng, Ruizhu et al. (2014) Hypersensitivity of primordial germ cells to compromised replication-associated DNA repair involves ATM-p53-p21 signaling. PLoS Genet 10:e1004471
Bolcun-Filas, Ewelina; Rinaldi, Vera D; White, Michelle E et al. (2014) Reversal of female infertility by Chk2 ablation reveals the oocyte DNA damage checkpoint pathway. Science 343:533-6
Handel, Mary Ann; Eppig, John J; Schimenti, John C (2014) Applying ""gold standards"" to in-vitro-derived germ cells. Cell 157:1257-61
Qiao, Huanyu; Prasada Rao, H B D; Yang, Ye et al. (2014) Antagonistic roles of ubiquitin ligase HEI10 and SUMO ligase RNF212 regulate meiotic recombination. Nat Genet 46:194-9
Schimenti, Kerry J; Feuer, Sky K; Griffin, Laurie B et al. (2013) AKAP9 is essential for spermatogenesis and sertoli cell maturation in mice. Genetics 194:447-57

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