Proper pairing and recombination are essential for human reproduction, and lesions in this process can result in a variety of disorders. During meiosis, homologous chromosomes undergo paring and generate crossovers in order to reciprocally exchange genetic material. Meiotic recombination is regulated by both genetic and epigenetic factors. While a great deal is known about genetic factors, relatively little is known about epigenetic factors. Further, there is evidence that transposable elements (TEs) (the primary target of epigenetic silencing in both plants and mammals) can influence recombination both genetically, by inducing double-strand breaks, and epigenetically, by introducing new methylated sequences near genes. In both plants and mammals, DNA methylation is a key component of epigenetic regulation. In plants, mutations that alter global levels of DNA methylation are known to effect recombination frequency. Interestingly, these mutations can also result in the activation of TEs, which may also increase recombination and that are also a target of de novo methylation once they have inserted into new locations and are re-silenced. Our long-term goal is to identify novel genetic and epigenetic factors that can influence meiotic recombination to better understand this fundamental process. The overall objective of this proposal is to determine how TEs effect recombination, either due to double-strand breaks they introduce when they are active, or due to DNA methylation they bring to genes once they are epigentically silenced. Because mutations that alter DNA methylation in mammals are lethal or sterile, we will do these experiments in maize, an organism that has been a model for understanding recombination for decades. Based on our preliminary data, our central hypotheses are that removal of DNA methylation introduced by silenced transposons and/or the presence of active transposons without DNA methylation can alter the frequency of recombination. To test these hypotheses, we propose three specific aims: 1) Determine the effects of the mop1 (mediator of paramutation 1) mutation on meiotic recombination in euchromatic and heterochromatic regions. 2) Compare the effects of the mop1 mutation on meiotic recombination during female and male meiosis. 3) Determine the effects of active Mutator (Mu) TEs on the frequency of meiotic recombination in mop1 mutants. By examination of epigenetic (Aims 1, 2 and 3) and genetic (Aim 3) effects of TEs on meiosis, the expected outcomes include dissection of the causes of location-specific and sex-specific recombination changes in DNA methylation mutants, and the determination of the effects of silenced and active TEs on meiotic recombination. The results will have an important positive impact because this project will advance our understanding of how DNA methylation and active TEs influence meiotic recombination in higher eukaryotes. Importantly, this project provides plentiful opportunities for undergraduate students to participate in research on classical genetics and epigenetics, to learn cutting edge technologies in comparative genomics and bioinformatics, and to enhance the research environment at Miami University.

Public Health Relevance

Genetic recombination reshuffles genes and prevents segregation errors that cause pregnancy failure, congenital disorders and several other genetic diseases. Understanding the factors that influence meiotic recombination in higher eukaryotes will help to minimize these diseases. Because many aspects of meiosis are shared between animals and plants and methylation mutants in mammals cannot produce progeny, we will use maize as a model for epigenetic factors that mediate recombination in higher eukaryotes.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Academic Research Enhancement Awards (AREA) (R15)
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Molecular Genetics B Study Section (MGB)
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Gindhart, Joseph G
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Miami University Oxford
Schools of Arts and Sciences
United States
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