Sequence Determinants of Meiotic Recombination Hotspots

Niagara University, Niagara University NY

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Meiotic recombination is a fundamental biological process common to virtually all sexually reproducing organisms. This process creates new allelic combinations and thus, increases the genetic diversity within a species; furthermore, it is essential, in most cases, for the proper segregation of chromosomes, which ensures against aneuploid progeny. Our long term goal is to understand the mechanism and regulation of meiotic recombination. One of the most striking, but least-well understood aspects, of meiotic recombination is that it does not occur at uniform frequency throughout the genome. Rather there are discrete sites (hotspots) at which recombination events preferentially occur. Recently, we showed that a specific nucleotide sequence, 5'-ATGACGTCA-3,' is associated with a subset of recombination hotspots in the fission yeast Schizosaccharomyces pombe. This hotspot sequence motif is likely to be just one example among a diverse group of short nucleotide sequences that determine the location of meiotic recombination hotspots. The goals of this proposal are: 1) to find additional sequence-defined hotspots of recombination. To this end, we are performing a screen that will allow us to rapidly sift through very large numbers of unique sequences and identify hotspot motifs. This screen should reveal the majority, or perhaps all, sequence-defined hotspots. 2) After identification of hotspot sequence motifs, we will survey the S. pombe genome for those sequences and determine whether they are sites of meiotic DNA breakage, a hallmark of recombination hotspots. Where appropriate, these motifs will be mutated to confirm that DNA breakage and/or hotspot activity results from the specific sequence at those sites. 3) Since recombination hotspots are frequently binding sites for transcription factors, and these factors are frequently conserved between organisms, we will test whether hotspot sequence motifs discovered in S. pombe are also active in the distantly related budding yeast Saccharomyces cerevisiae. Sequences that are active in both organisms may be widely conserved among eukaryotes, including man. [unreadable] [unreadable] [unreadable]