Structure of the Highly Conserved HERC2 Gene and of Multiple Partially Duplicated Paralogs in Human

Abstract

Recombination between chromosome-specific low-copy repeats (duplicons) is an underlying mechanism for several genetic disorders. Recently, a chromosome 15 duplicon was discovered in the common breakpoint regions of Prader-Willi and Angelman syndrome deletions. We identified previously the large HERC2 transcript as an ancestral gene in this duplicon, with ∼11 HERC2-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 ∼250 kb and a CpG island promoter. A processed ribosomal protein L41 pseudogene occurs in intron 2 of HERC2, and putative VNTRs occur in intron 70 (28 copies, ∼76-bp repeat) and 3Ј exon 40 through intron 40 (6 copies, ∼62-bp repeat). Sequence comparisons show that HERC2-containing duplicons have undergone several deletion, inversion, and dispersion events to form complex duplicons in 15q11, 15q13, and 16p11. To further understand the developmental role of HERC2, a highly conserved Drosophila ortholog was characterized, with 70% amino acid sequence identity to human HERC2 over the carboxy-terminal 743 residues. Combined, these studies provide significant insights into the structure of complex duplicons and into the evolutionary pathways of formation, dispersal, and 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.

Structure of Chromosomal Duplicons and their Role in Mediating Human Genomic Disorders

“…4; Amos-Landgraf et al 1999;Ji et al 1999Ji et al , 2000Loftus et al 1999). These data suggest that the processes responsible for transchromosomal and intrachromosomal pericentromeric duplication and for disease-causing rearrangements may be molecularly interrelated.…”

“…The presence of a sequence in SMS-REP that is homologous to one with autonomously replicating activity also suggests a role for open chromatin structure, and/ or DNA replication. Sequences related to those that can promote recombination have been identified in recombination hot spots in CMT1A-REP and 22q11 rearrangements, and VNTRs are found within each copy of the S232 and LCR22 repeats, as well as within the END repeats (Ji et al 2000). (3) In cases in which more than two duplicons exist in the same chromosome region, there are preferences as to which copies are involved in specific rearrangements.…”

“…Nevertheless, the end point of the duplicon 5Ј of HERC2 is unknown. Additional genes are present in the duplicons, including the small MYLE gene (Christian et al 1999), although only four of the seven potential transcripts identified may represent new genes/pseudogenes in the END repeats (discussed in Ji et al 2000). Furthermore, there is evidence that independent duplicons flank the HERC2 (and MYLE)-containing duplicons in 15q11.2 .…”

“…The HERC2-related content of different duplicons is 36.6 kb in the most rearranged/deleted copy in 16p11.2 to an estimated ∼150-200 kb in some of the chromosome 15 duplicons (Ji et al 2000). Nevertheless, the end point of the duplicon 5Ј of HERC2 is unknown.…”

Complete loss of function of the ubiquitin ligase HERC2 causes a severe neurodevelopmental phenotype

“…1 Sequences homologous to the HERC2 gene constitute low-copy repeats associated with breakpoints of chromosomal rearrangements located in 15q11-15q13. 2 HERC2 encodes a 528 kDa E3 ubiquitin ligase, that interacts with E6AP/UBE3A, another ubiquitin ligase, and targets BRCA1 and XPA for degradation. [3][4][5] Until recently, HERC2 mutations were not associated with a human disorder.…”