**7. NCO recombination likely occurs by synthesis-dependent strand annealing**

Molecular models of meiotic recombination have evolved over the years as relevant evidence accumulated. The model that has been most influential in recent decades has been the Double-Strand Break Repair model (Szostak et al. 1983). By this model, during each recombination event two Holliday Junctions (HJs) are formed and resolved (see Figure 1). Thus the Double-Strand Break Repair model can also be referred to as the Double Holliday Junction (DHJ) model. The DHJ model was considered to provide an explanation for both CO and NCO types of recombination events. However, Allers & Lichten (2001) showed that, although CO recombinants are likely formed by a pathway involving resolution of Holliday junctions, NCO recombinants arise by a different pathway that acts earlier in meiosis. Allers & Lichten (2001), McMahill et al. (2007) and Andersen & Sekelsky (2010) have presented evidence that NCO recombinants are generated during meiosis by an HRR repair process referred to as "Synthesis-Dependent Strand Annealing" or "SDSA" (see Figure 1). During SDSA the invading strand from a chromosome with a DSB is displaced from the D-loop structure of an intact chromosome and its newly synthesized sequence anneals to the other side of the break on the chromosome with the original DSB. This process can accurately

SDSA.

DNA repair.

**proper chromosome segregation** 

Meiosis as an Evolutionary Adaptation for DNA Repair 365

Although the SDSA model starts with a DSB, it would also be applicable to other types of double-strand damages such as interstrand-crosslinks, or a single-strand damage (e.g. an altered base) opposite a break in the other strand. In principle, both of these types of doublestrand damages could be converted by nucleases to a DSB that would then be subject to

**8. The role of Spo11 in promoting accurate DNA repair can also facilitate** 

In the budding yeast *S. cerevisiae,* synapsis (pairing of homologous chromosomes) and synaptonemal complex formation depend on Spo11, a nuclease related to type II topoismerases. Spo11 induces DSBs leading to HRR events of the CO type that form the physical association between homologs (chiasmata) needed for synaptonemal complex formation and proper disjunction of non-sister homologs at the first meiotic division. On the basis of these properties of Spo11, it is sometimes assumed that the primary function of meiotic recombination is to promote synapsis. However, as reviewed by Barzel & Kupiec (2008), this theme cannot be generalized, as synapsis occurs independently of Spo11 induced recombination in the nematode worm *C. elegans* and the fruitfly *D. melanogaster*. In *C. elegans,* synapsis between homologs occurs normally in a *spo-11* mutant (Dernburg et al., 1998). The *D. melanogaster* gene *mei-W68* encodes a *spo11* homolog (McKim & Hayashi-Hagihara, 1998). In *D. melanogaster* females, meiotic chromosome synapsis occurs in the absence of *mei-W68* mediated CO recombination (McKim et al., 1998). Electron microscopy of oocytes from females homozygous for *mei-W68* mutations that eliminated meiotic recombination revealed normal synaptonemal complex formation. In *D. melanogaster* females, meiotic recombination does not appear to be necessary for synapsis. Since the role of Spo11 is of substantial interest in current discussions of the adaptive significance of meiotic recombination, we offer a speculation on its possible role consistent with the DNA repair hypothesis. As shown in Figure 1, both the DHJ and SDSA models for HRR start with a DSB. During meiosis in *S. cerevisiae*, DSBs are formed by a process that usually depends on Spo11. In *S. pombe*, Spo11 homolog Rec12 generates meiotic recombinants and meiosis specific DSBs. In *C. elegans*, a Spo11 homolog seems to have a similar role. We propose that DNA damages of various types are converted to DSBs, a "common currency," in order to initiate their recombinational repair (see also H. Bernstein et al., 1988). Spo11 appears to be employed in this process. Our reasoning is based on the precedents of the well-established pathways of nucleotide excision repair and base excision repair. In nucleotide excision repair, the initial steps of the pathway involve recognition of a wide variety of bulky damages followed by their removal to generate a single-strand gap, the "common currency" which is then repaired by a gap filling process. In base excision repair, a variety of altered bases are recognized by a corresponding variety of DNA glycosylases that generate an intermediate apurinic/apyrimidinic site, the "common currency" for further repair. On this reasoning, formation of DSBs by a Spo11-dependent process is part of an overall DNA repair sequence. In those species where the resolution of meiotic HRR by CO recombination is beneficial in promoting proper chromosome segregation at the first meiotic division, we think this benefit arose secondarily to the primary benefit of accurate

repair DNA DSBs by copying the information lost in the damaged homolog from the other intact homolog without the need for physical exchange of DNA. This process contributes little to genetic variation since the arms of the chromosomes flanking the recombination event remain in the parental position.

Youds et al. (2010) presented evidence that the RTEL-1 protein of *C. elegans* physically dissociates strand invasion events, thereby promoting NCO repair by SDSA (Figure 1). HRR events initiated by DSBs consequently divide into two subsets, a larger subset which undergoes SDSA forming NCO recombinants, and a smaller subset which undergo DHJ repair and form CO recombinants. Perhaps SDSA is the preferred mode of HRR for unprogrammed double-strand damages, and DHJ repair is used primarily for programmed DSBs to promote proper chromosome segregation.

Fig. 1. Current models of meiotic recombination are initiated by a double-strand break or gap, followed by pairing with an homologous chromosome and strand invasion to initiate the recombinational repair process. Repair of the gap can lead to crossover (CO) or noncrossover (NCO) of the flanking regions. CO recombination is thought to occur by the Double Holliday Junction (DHJ) model, illustrated on the right, above. NCO recombinants are thought to occur primarily by the Synthesis Dependent Strand Annealing (SDSA) model, illustrated on the left, above. Most recombination events appear to be the SDSA type.

repair DNA DSBs by copying the information lost in the damaged homolog from the other intact homolog without the need for physical exchange of DNA. This process contributes little to genetic variation since the arms of the chromosomes flanking the recombination

Youds et al. (2010) presented evidence that the RTEL-1 protein of *C. elegans* physically dissociates strand invasion events, thereby promoting NCO repair by SDSA (Figure 1). HRR events initiated by DSBs consequently divide into two subsets, a larger subset which undergoes SDSA forming NCO recombinants, and a smaller subset which undergo DHJ repair and form CO recombinants. Perhaps SDSA is the preferred mode of HRR for unprogrammed double-strand damages, and DHJ repair is used primarily for programmed

Fig. 1. Current models of meiotic recombination are initiated by a double-strand break or gap, followed by pairing with an homologous chromosome and strand invasion to initiate the recombinational repair process. Repair of the gap can lead to crossover (CO) or noncrossover (NCO) of the flanking regions. CO recombination is thought to occur by the Double Holliday Junction (DHJ) model, illustrated on the right, above. NCO recombinants are thought to occur primarily by the Synthesis Dependent Strand Annealing (SDSA) model,

illustrated on the left, above. Most recombination events appear to be the SDSA type.

event remain in the parental position.

DSBs to promote proper chromosome segregation.

Although the SDSA model starts with a DSB, it would also be applicable to other types of double-strand damages such as interstrand-crosslinks, or a single-strand damage (e.g. an altered base) opposite a break in the other strand. In principle, both of these types of doublestrand damages could be converted by nucleases to a DSB that would then be subject to SDSA.
