Structure of the highly conserved HERC2 gene and of multiple partially duplicated paralogs in human

Recombination between chromosome-specific low-copy repeats (duplicons) is a n underlying mechanism for several genetic disorders. Recently, a chromosom e 15 duplicon was discovered in the common breakpoint regions of Prader-Wil li and Angelman syndrome deletions. We identified previously the large HERC 2 transcript as an ancestral gene in this duplicon, with similar to 11 HERC 2-containing duplicons, and demonstrated that recessive mutations in mouse Herc2 lead to a developmental syndrome, juvenile development and fertility 2 (jdf2). We have now constructed and sequenced a genomic contig of HERC2, revealing a total of 93 exons spanning similar to 250 kb and a CpG island p romoter. A processed ribosomal protein L41 pseudogene occurs in intron 2 of HERC2, and putative VNTRs occur in intron 70 (28 copies, similar to 76-bp repeat) and 3' exon 40 through intron 40 (6 copies, similar to 62-bp repeat ). Sequence comparisons show that HERC2-containing duplicons have undergone several deletion, inversion, and dispersion events to form complex duplico ns in 15q11, 15q13, and 16p11. To further understand the developmental role of HERC2, a highly conserved Drosophila ortholog was characterized, with 7 0% amino acid sequence identity to human HERC2 over the carboxy-terminal 74 3 residues. Combined, these studies provide significant insights into the s tructure of complex duplicons and into the evolutionary pathways of formati on, dispersal, acid genomic instability of duplicons. Our results establish that some genes not only have a protein coding function but can also play a structural role in the genome.