Meiotic pairing through barcode-like satellite DNA repeats

During meiosis, chromosomes must find, pair, and synapse with their homologous partners in the crowded milieu of the nucleus1. Although homology detection is generally attributed to recombination, pairing and synapsis can occur in its absence2-10, suggesting alternate mechanisms that discriminate between homologous and non-homologous chromosomes. In many eukaryotes, tandem repeats known as satellite DNA facilitate inter-chromosomal associations11. Notably, their non-uniform distribution across chromosomes gives rise to homologue-specific satellite DNA barcodes12-14, which have been speculated to enable meiotic pairing15-18. However, satellite DNA function remains actively debated since these repeats cannot be manipulated in most model organisms. Here, we use satellite DNA deletion, duplication, and translocation strains that are unique to Drosophila to demonstrate that repeat mismatches perturb meiotic pairing, particularly at centromeres and pericentromeres. In the absence of satellite DNA homology, pairing is antagonized by the HORMAD protein, Mad2, while a Pachytene checkpoint 2 (Pch2)-dependent meiotic delay restores pairing. Remarkably, pairing defects are also observed in the progeny of D. melanogaster natural populations that have diverged in their satellite DNA content. Finally, compromised meiotic pairing is strongly correlated with mid-oogenesis cell death, a quality control mechanism that likely culls defective oocytes to prevent chromosome mis-segregation and aneuploidy. These findings resolve a long-standing debate on satellite DNA functionality by demonstrating a barcode-like role in homology detection. We propose that this repeat-based pairing mechanism exerts an underappreciated selective pressure, constraining the divergence of rapidly evolving satellite DNA within interbreeding natural populations.