Does the Pachytene Checkpoint, a Feature of Meiosis, Filter Out Mistakes in Double-Strand DNA Break Repair and as a...

This essay aims to explain two biological puzzles: why eukaryotic transcription units are composed of short segments of coding DNA interspersed with long stretches of non-coding (intron) DNA, and the near ubiquity of sexual reproduction. As is well known, alternative splicing of its coding sequences enables one transcription unit to produce multiple variants of each encoded protein. Additionally, padding transcription units with non-coding DNA (often many thousands of base pairs long) provides a readily evolvable way to set how soon in a cell cycle the various mRNAs will begin being expressed and the total amount of mRNA that each transcription unit can make during a cell cycle. This regulation complements control via the transcriptional promoter and facilitates the creation of complex eukaryotic cell types, tissues, and organisms. However, it also makes eukaryotes exceedingly vulnerable to double-strand DNA breaks, which end-joining break repair pathways can repair incorrectly. Transcription units cover such a large fraction of the genome that any mis-repair producing a reorganized chromosome has a high probability of destroying a gene. During meiosis, the synaptonemal complex aligns homologous chromosome pairs and the pachytene checkpoint detects, selectively arrests, and in many organisms actively destroys gamete-producing cells with chromosomes that cannot adequately synapse; this creates a filter favoring transmission to the next generation of chromosomes that retain the parental organization, while selectively culling those with interrupted transcription units. This same meiotic checkpoint, reacting to accidental chromosomal reorganizations inflicted by error-prone break repair, can, as a side effect, provide a mechanism for the formation of new species in sympatry. It has been a long-standing puzzle how something as seemingly maladaptive as hybrid sterility between such new species can arise. I suggest that this paradox is resolved by understanding the adaptive importance of the pachytene checkpoint, as outlined above.