Summary The nonrandom distribution of meiotic recombination shapes patterns of inheritance and genome evolution, but chromosomal features governing this distribution are poorly understood. Formation of the DNA double-strand breaks (DSBs) that initiate recombination results in accumulation of Spo11 protein covalently bound to small DNA fragments. We show here that sequencing these fragments provides a genome-wide DSB map of unprecedented resolution and sensitivity. We use this map to explore the influence of large-scale chromosome structures, chromatin, transcription factors, and local sequence composition on DSB distributions. Our analysis supports the view that the recombination terrain is molded by combinatorial and hierarchical interaction of factors that work on widely different size scales. Mechanistic aspects of DSB formation and early processing steps are also uncovered. This map illuminates the occurrence of DSBs in repetitive DNA elements, repair of which can lead to chromosomal rearrangements. We discuss implications for evolutionary dynamics of recombination hotspots.

Meiotic recombination, which promotes proper homologous chromosome segregation at the first meiotic division, normally occurs between allelic sequences on homologues. However, recombination can also take place between non-allelic DNA segments that share high sequence identity. Such non-allelic homologous recombination (NAHR) can markedly alter genome architecture during gametogenesis by generating chromosomal rearrangements. Indeed, NAHRmediated deletions, duplications, inversions and other alterations have been implicated in numerous human genetic disorders. Studies in yeast have revealed insights into the molecular mechanisms of meiotic NAHR as well as the cellular strategies that limit NAHR.Gametes are the products of a meiotic programme in which diploid germ cells undergo one round of DNA replication followed by two successive rounds of cell division. During this process, gametes acquire chromosomes comprising new assortments of parental alleles. Subsequent fusion of two gametes during sexual reproduction results in the reconstitution of a diploid genome, yielding offspring that are genetically distinct from their parents.In most sexually reproducing organisms, homologous recombination lies at the heart of meiosis by promoting proper segregation of HOMOLOGOUS CHROMOSOMES (also referred to as homologues) (reviewed in REF. 1 ). Prior to the first meiotic division, recombination begins when DNA double-strand breaks (DSBs) are deliberately introduced into each chromosome. The DSBs are then repaired by genetic exchange with allelic sequences, resulting in physical linkages between pairs of homologues. These connections ensure that homologues orient correctly on the meiotic spindle and migrate to opposite spindle poles. Meiotic recombination thus promotes genetic stability and faithful transmission of the genome by limiting the repair of each DSB primarily to DNA sequences at the allelic position on the homologue and ensuring the accurate distribution of chromosomes to gametes.Errors in meiotic recombination can affect genome stability during gametogenesis. Research spanning several decades has shown that chromosome non-disjunction (that is, missegregation) in meiosis results in constitutive ANEUPLOIDY, which can lead to spontaneous abortion or congenital birth defects (reviewed in REF. 2 ). More recent work has uncovered a second process that influences genome stability in the germline: aberrant meiotic Correspondence to S.K. s-keeney@ski.mskcc.org. 4 These authors contributed equally to this work. NIH Public Access Author ManuscriptNat Rev Mol Cell Biol. Author manuscript; available in PMC 2011 April 11. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript recombination between non-allelic DNA segments that share high sequence similarity. This process is known as non-allelic homologous recombination (NAHR); the synonymous term ectopic recombination' is more prevalent in older literature and in yeast studies. NAHR is a more recent, mechanistically evocative term and is used in this...

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Fission yeast Rec12 (Spo11 homolog) initiates meiotic recombination by forming developmentally programmed DNA double-strand breaks (DSBs). DSB distributions influence patterns of heredity and genome evolution, but the basis of the highly nonrandom choice of Rec12 cleavage sites is poorly understood, largely because available maps are of relatively low resolution and sensitivity. Here, we determined DSBs genome-wide at near-nucleotide resolution by sequencing the oligonucleotides attached to Rec12 following DNA cleavage. The single oligonucleotide size class allowed us to deeply sample all break events. We find strong evidence across the genome for differential DSB repair accounting for crossover invariance (constant cM/kb in spite of DSB hotspots). Surprisingly, about half of all crossovers occur in regions where DSBs occur at low frequency and are widely dispersed in location from cell to cell. These previously undetected, low-level DSBs thus play an outsized and crucial role in meiosis. We further find that the influence of underlying nucleotide sequence and chromosomal architecture differs in multiple ways from that in budding yeast. DSBs are not strongly restricted to nucleosome-depleted regions, as they are in budding yeast, but are nevertheless spatially influenced by chromatin structure. Our analyses demonstrate that evolutionarily fluid factors contribute to crossover initiation and regulation.