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The Need for an Anti-Anti-Crossover Activity

During mitotic DSB repair, helicases act to prevent crossovers. During meiotic DSB repair, crossovers must be generated to promote chromosome segregation. However, these anti-crossover helicases are present and active, so there needs to be some mechanism to block their activities: an anti-anti-crossover. In many eukaryotes, the anti-anti-crossover activity is provided by the Msh4-Msh5 heterodimer (for review, see Lynn 2007).

Curiously, Drosophila doesn't have Msh4 or Msh5. Other dipteran insects have them, so Drosophila must have lost them (Schurkok 2010). Did some other proteins take over this job? We think the answer is yes - a group of MCM-related proteins evolved quickly to acquire an anti-anti-crossover function in meiosis.

REC (MCM8) is a mei-MCM

Mutations in the recombination defective (rec) gene were isolated by Rhoda Grell (1978) based on a severe decrease in meiotic crossing over (Grell 1978). We cloned the gene and found that it encodes the Drosophila ortholog of MCM8. Eukaryotic genomes were known to encode six paralogous mini-chromosome maintenance proteins, MCM2-MCM7, believed to function as a heterohexamer or heterododecamer. These MCMs are essential for initiation of DNA replication, and may function as the replicative helicase. MCM8 and MCM9 are found in arthropods and vertebrates. This has led some authors to make the erroneous claim that MCM8 and MCM9 are only found in "higher eukaryotes". However, our phylogenetic analysis showed that there are orthologs of MCM8 and MCM9 in plants and many protists), suggesting that they arose early in eukaryotic evolution, but were lost from some lineages. Some curious observations: every species we analyzed has either MCM8 and MCM9, or neither...except Drosophila: all 12 sequenced genomes have MCM8 (REC) but not MCM9. Also, REC always has the longest branch length in pylograms, suggesting it has evolved rapidly (see figure below).

H. Blanton, S.J. Radford, H. Kearney, S. McMahan, J. Ibrahim, and J. Sekelsky (2005) REC, Drosophila MCM8, drives formation of meiotic crossovers. PLoS Genetics 1: e40.

MCM phylogeny
MEI-217 and MEI218: An Ancient MCM-related Protein

rec belongs to a class of genes called "pre-condition", because their products were thought to be required for establishing conditions necessary for crossovers to form (Baker & Carpenter 1972). If we restrict the definition to include only null phenotypes, then the only other genes in this class are mei-217 and mei-218. MEI-217 and MEI-218 are translated as overlapping ORFs from the same transcript (Liu 2000). In some Drosophila species' genomes they are annotated as a single fusion protein, but our own analysis suggests they are separate polypeptides in the entire Drosophila genus. They were originally pioneer proteins; in a standard BLAST with MEI-217 you find all the Drosophila orthologs, but nothing else - not even other Dipeteran insects. However, our analysis indicates that MEI-217 and MEI-218 are two halves of a highly divergent MCM-like protein that has evolved very rapidly.