Interference-mediated synaptonemal complex formation with embedded crossover designation

Abstract

Biological systems exhibit complex patterns at length scales ranging from the molecular to the organismic. Along chromosomes, events often occur stochastically at different positions in different nuclei but nonetheless tend to be relatively evenly spaced. Examples include replication origin firings, formation of chromatin loops along chromosome axes and, during meiosis, localization of crossover recombination sites ("crossover interference"). We present evidence in the fungus Sordaria macrospora that crossover interference is part of a broader pattern that includes synaptonemal complex (SC) nucleation. This pattern comprises relatively evenly spaced SC nucleation sites, among which a subset are crossover sites that show a classical interference distribution. This pattern ensures that SC forms regularly along the entire length of the chromosome as required for the maintenance of homolog pairing while concomitantly having crossover interactions locally embedded within the SC structure as required for both DNA recombination and structural events of chiasma formation. This pattern can be explained by a threshold-based designation and spreading interference process. This model can be generalized to give diverse types of related and/or partially overlapping patterns, in two or more dimensions, for any type of object.spatial patterning | synapsis initiation site | recombination/synapsis | crossover designation M eiosis is the specialized cellular cycle that yields haploid gametes for sexual reproduction. A central feature of the meiotic program is recombination (1, 2). DNA/DNA recombination interactions, initiated by programmed double-strand breaks (DSBs), mediate the recognition and juxtaposition (pairing) of homologous chromosomes. A minority subset of these interactions matures into reciprocal crossover recombination products (COs); the remaining majority matures primarily into interhomolog non-crossover products (NCOs). COs promote genetic diversity but also are required for the segregation of homologous chromosomes (homologs) via their role in creating chiasmata (3).A nearly universal feature of meiosis is that COs occur along a particular chromosome at different positions in different meiotic nuclei. Nonetheless, along any given chromosome, COs tend to be evenly spaced. This pattern results from the reduced possibility that a second cross-over will occur if a crossover has occurred nearby. The existence of such a pattern was identified more than a century ago as the genetic phenomenon of CO interference (4, 5). In this phenomenon, occurrence of a CO in one genetic interval is accompanied by a reduced probability that another CO will occur along the same chromosome in a nearby interval. This effect implies the existence of communication along chromosomes, with an event at one position triggering occurrence of an "interference signal" that spreads outward, inhibiting occurrence of subsequent events nearby.A second central feature of the meiotic program is the synaptonemal complex (SC). This prominent structure link...

Meiotic Recombination: The Essence of Heredity

“…Given that chromosome pairing and synapsis requires recombination in most organisms, including budding yeast (but not Drosophila or Caenorhabditis elegans), detected SEIs must be preceded by less stable nascent strand-pairing intermediates ( presumably D-loops) that are not readily detected by current approaches. The timing of SEI formation reflects the interdependence between the initiation of synapsis and the initial differentiation of crossover and noncrossover pathways, with SEIs being the earliest detectable crossover-specific joint molecules (see below) (Hunter and Kleckner 2001;Borner et al 2004;Reynolds et al 2013;Zhang et al 2014a). Along the crossover pathway, SEIs give rise to dHJs, which must be resolved exclusively into crossovers, in contrast to the equal mixture of crossovers and noncrossovers originally envisioned by the DSBR model (Allers and Lichten 2001a;Clyne et al 2003;Zakharyevich et al 2012).…”

“…However, the processes that ensure that a crossover outcome is triggered for at least one DSB site per chromosome pair (the obligatory crossover) remain unknown. Evidence from a variety of organisms indicates that the patterning processes that designate crossover sites occur before and independently of synapsis (Page and Hawley 2001;Borner et al 2004;Fung et al 2004;Higgins et al 2005;Zhang et al 2014a). These data rule out the idea that bidirectional polymerization of synaptonemal complex is the major mode of interference signaling (King and Mortimer 1990).…”

“…In a number of organisms, the initial differentiation of crossover and noncrossover pathways is temporally and functionally coupled to the onset of synapsis (Bojko 1985;Zickler et al 1992;Hunter and Kleckner 2001;Borner et al 2004;Fung et al 2004;Reynolds et al 2013;Zhang et al 2014a). Moreover, in budding yeast, there appears to be a 1:1 correlation between designated crossover sites (marked by crossover-specific markers) and initiation sites for polymerization of synaptonamal complex (Fung et al 2004;Henderson and Keeney 2004).…”

“…Moreover, in budding yeast, there appears to be a 1:1 correlation between designated crossover sites (marked by crossover-specific markers) and initiation sites for polymerization of synaptonamal complex (Fung et al 2004;Henderson and Keeney 2004). In other organisms, these sites are also correlated, but synaptonemal complex-initiation sites outnumber crossover sites (Zickler et al 1992;Zickler and Kleckner 1999;Brown et al 2005;Gruhn et al 2013;Zhang et al 2014a).…”

Questions and Assays

“…Accordingly, joint studies with the Zickler laboratory provide evidence that a single patterning process explains both crossover interference and the spacing of SC nucleations (Zhang et al 2014a).…”