Strange Company: CCDC200, RNU2-1, and ERVK13 Retroviruses

Background/Objectives: The human RNU2-1 locus combines a variable tandem array of U2 small nuclear RNA (snRNA) genes, retroviral sequences, and extensive linkage with BRCA1. How these features evolved and whether they are functionally related remain unclear. We characterize the structure and variation in this genomic region. Methods: We investigated RNU2-1 and flanking sequences by comparing the T2T-CHM13 assembly with 466 publicly available phased haplotype assemblies, from which we recovered 453 RNU2-1 arrays containing 10,256 U2-1 snRNA genes in total, and by estimating array length from long-read depth from a further 876 individuals. Results: The array is flanked by complex repetitive sequences, including three ERVK13 endogenous retroviruses and sequences predicted to form secondary structures near CCDC200. Although most U2 snRNA genes encode the canonical sequence, some haplotypes contain substantial proportions of variants. Sequence variation is lowest in the region that is most constrained in the single-copy paralogue RNU2-2, suggesting purifying selection on individual copies. Array size and variant composition are associated with extended haplotypes encompassing BRCA1, with larger arrays and more variant genes on certain haplotypes. Conclusions: RNU2-1 is a structurally complex, evolutionarily dynamic locus in which tandem gene amplification, sequence homogenization, and long-range linkage shape patterns of genetic variation. The association between array properties and BRCA1 haplotypes provides a framework for investigating the evolutionary forces acting on this region. The conserved features of its retroviral remnants and the distribution of variation among U2 snRNA gene copies also motivate further investigation of their potential functional significance.