Abstract
Meiotic recombination is required for the orderly segregation of chromosomes during meiosis and for providing genetic diversity among offspring. Among mammals, as well as yeast and higher plants, recombination preferentially occurs at highly delimited chromosomal sites 1–2 kb long known as hotspots. Although considerable progress has been made in understanding the roles various proteins play in carrying out the molecular events of the recombination process, relatively little is understood about the factors controlling the location and relative activity of mammalian recombination hotspots. To search for trans-acting factors controlling the positioning of recombination events, we compared the locations of crossovers arising in an 8-Mb segment of a 100-Mb region of mouse Chromosome 1 (Chr 1) when the longer region was heterozygous C57BL/6J (B6) × CAST/EiJ (CAST) and the remainder of the genome was either similarly heterozygous or entirely homozygous B6. The lack of CAST alleles in the remainder of the genome resulted in profound changes in hotspot activity in both females and males. Recombination activity was lost at several hotspots; new, previously undetected hotspots appeared; and still other hotspots remained unaffected, indicating the presence of distant trans-acting gene(s) whose CAST allele(s) activate or suppress the activity of specific hotspots. Testing the activity of three activated hotspots in sperm samples from individual male progeny of two genetic crosses, we identified a single trans-acting regulator of hotspot activity, designated Rcr1, that is located in a 5.30-Mb interval (11.74–17.04 Mb) on Chr 17. Using an Escherichia coli cloning assay to characterize the molecular products of recombination at two of these hotspots, we found that Rcr1 controls the appearance of both crossover and noncrossover gene conversion events, indicating that it likely controls the sites of the double-strand DNA breaks that initiate the recombination process.
Highlights
Meiotic homologous recombination is responsible for generating genetic variety among offspring as well as ensuring accurate chromosome segregation during meiotic cell divisions
Studies in Saccharomyces cerevisiae show that COs and NCOs are the preferred outcomes of two alternative pathways in meiotic recombination, COs being predominantly produced by the Double-Strand Break Repair (DSBR) pathway, and NCOs predominantly produced by the SynthesisDependent Strand-Annealing (SDSA) pathway [4,5]
Assaying the activity of specific hotspots in the sperm of males segregating in genetic crosses, we found that the activity of several hotspots depended on a single Mendelian factor we have designated Recombination regulator 1 (Rcr1) that maps to a 5.30-Mb region on proximal chromosome 17 (Chr 17)
Summary
Meiotic homologous recombination is responsible for generating genetic variety among offspring as well as ensuring accurate chromosome segregation during meiotic cell divisions. The process of recombination is initiated by the formation of DNA double-strand breaks (DSBs) created by the highly conserved topoisomerase IV–like protein SPO11 [1]. These DSBs provide the sites at which chiasmata and crossovers form, events that are necessary for proper chromosome alignment and segregation in Meiosis I. In all organisms, meiotic recombination does not occur at uniform rates along chromosomes. In both yeast and mammals—the most extensively studied cases—recombination rates vary considerably along the length of a chromosome [6,7,8,9,10]. When examined at high resolution, the great majority of recombination, possibly all, occurs in restricted regions, termed hotspots, that are typically 1–2 kb long in humans and mice [11,12]
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