Perspective PCH’ing Together an Understanding of Crossover Control Drew Thacker1,2, Scott Keeney1,2,3* 1 Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America, 2 Weill Graduate School of Medical Sciences, Cornell University, New York, New York, United States of America, 3 Howard Hughes Medical Institute, New York, New York, United States of America Meiosis is a specialized form of cell division involving one round of chromosome replication followed by two rounds of segregation, thereby producing daughter cells with half the genomic equivalent of the progenitor. In most organisms, double- strand breaks (DSBs) are introduced into the genome following premeiotic S-phase. These breaks are repaired almost exclusively from the homologous chromosome via repair pathways that yield either a crossover or non-crossover recombination product [1,2]. Of particular importance are the crossovers, which tether homologous chro- mosomes and ensure accurate segregation at the first meiotic division (MI) [3]. Chromo- somes that fail to cross over have signifi- cantly higher rates of non-disjunction at MI, which produces aneuploid gametes, causing miscarriages and birth defects in humans. It should be no surprise then that most eukaryotes possess a sophisticated mecha- nism to control meiotic recombination. Consider the situation in an individual mouse meiocyte. More than 200 DSBs are made; however, only a subset of these precursors are repaired as crossovers, while the rest are repaired as non- crossovers (Figure 1) [4]. Thus, central to the ‘‘crossover control’’ mechanism is a decision to direct a given DSB to either a crossover or non-crossover fate [5]. This process ensures that each homolog pair receives at least one crossover (often referred to as the obligate crossover), and also regulates the spatial distribution of crossovers along chromosomes such that, if a chromosome receives two or more crossovers, they tend to occur further apart than expected by chance (referred to as crossover interference) (Figure 1B) [6]. Furthermore, it has been shown that when the number of DSBs is reduced, crossovers tend to be maintained at the expense of non-crossovers (a phenomenon called crossover homeostasis) [7,8]. It has been proposed that the obligate crossover, crossover interference, and crossover ho- meostasis are all manifestations of a single or closely related set of molecular process- es, but this hypothesis remains to be rigorously tested [7,9,10]. Almost a century after the first obser- vation of crossover control [11], we still know very little about the underlying mechanism(s). Most of the proteins that have been shown to influence crossover control in budding yeast appear to func- tion downstream of the crossover/non- crossover decision. One such class of proteins, commonly referred to as ZMMs (Zip1/2/3/4, Msh4/5, Mer3), is specifi- cally required for the repair of DSBs into crossovers that exhibit interference [2]. Deletion of any of the ZMM genes causes accumulation of intermediates in the crossover pathway and subsequent pro- phase arrest [12]. Two articles in this issue of PLoS Genetics identify a role for the Pachytene Check- point gene, PCH2, in crossover control in Saccharomyces cerevisiae [13,14]. PCH2, which encodes a putative AAA+-ATPase, was initially identified in yeast as a checkpoint factor due to suppression of a zip1D arrest in a pch2D mutant. This and other observations led to the hypothesis that Pch2 helps monitor chromosome synapsis during meiotic prophase [15,16]. However, studies in yeast, flies, and mice revealed that Pch2 is not just a checkpoint factor, but that it is also required for chromosome axis organization and DSB repair [17,18,19]. Interestingly, PCH2 is widely conserved in organisms that construct a synaptonemal complex and exhibit crossover interference, but is absent from organisms such as Schizosaccharomyces pombe that do not exhibit these features [15]. This observation sug- gested that Pch2 might also function in crossover control. Recent analysis in yeast demonstrated a small reduction in cross- over numbers in pch2 mutants at the HIS4LEU2 recombination hotspot [19], but data available at the time did not allow evaluation of crossing over genome-wide and also did not address whether crossover control was normal. In studies published in this issue of PLoS Genetics, the Alani and Bo¨rner groups [13,14] have examined these issues in detail. When crossover frequencies were measured across several genetic intervals on chromosomes III, VII, and VIII, Zanders et al. [13] and Joshi et al. [14] observed either no difference or an increase (de- pending on the interval) in pch2D strains. Importantly, these analyses demonstrated that the crossovers formed in pch2D mu- tants show reduced interference. Recent studies have indicated that de- creased crossover interference is associated with a concomitant decrease in crossover homeostasis [8]. To investigate this relation- ship, both Zanders et al. and Joshi et al. measured spore viability of pch2D strains carrying various hypomorphic alleles of the topoisomerase-like protein, Spo11. These hypomorphic alleles decrease the number of DSBs [20]. If crossover homeostasis and crossover interference are separate manifes- tations of a common crossover control mechanism, then an interference-defective mutant would also be expected to show defects in homeostasis, and thus a decrease in DSBs in such a mutant should result in fewer crossovers that are randomly distrib- uted throughout the genome. Such a scenario would in turn be expected to result in an increase in the frequency of chromo- some pairs without a crossover, causing reduced spore viability because of MI non- Citation: Thacker D, Keeney S (2009) PCH’ing Together an Understanding of Crossover Control. PLoS Genet 5(7): e1000576. doi:10.1371/journal.pgen.1000576 Editor: Gregory P. Copenhaver, The University of North Carolina at Chapel Hill, United States of America Published July 24, 2009 Copyright: 2009 Thacker, Keeney. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: Work from the authors’ lab is supported in part by NIH R01 grants GM58673 (to SK) and HD40916 and HD53855 (to SK and M. Jasin). The funders had no role in the preparation of the article. Competing Interests: The authors have declared that no competing interests exist. * E-mail: s-keeney@ski.mskcc.org PLoS Genetics | www.plosgenetics.org 1 July 2009 | Volume 5 | Issue 7 | e1000576