A de Novo Genome Assembly of an Angelman Syndrome Pig ( <i>sus Scrofa Domesticus</i> ) Model to Resolve <i>SNHG14</i>

Pigs (Sus scrofa domesticus) are used as biomedical and preclinical models for their comparable anatomy, physiology, and neurodevelopment to humans. Angelman syndrome is a rare genetic neurodevelopmental disorder, caused by the loss of the maternal Ubiquitin protein ligase E3A (UBE3A) allele, that was recently modelled and characterized in Yorkshire/Landrace pigs. The paternal UBE3A allele is intact but silenced in neurons of the central nervous system by the long non-coding RNA and polycistronic transcription unit Small Nuclear Host Gene 14 (SNHG14). Targeting SNHG14 to reactivate the paternal UBE3A allele is a therapeutic approach for Angelman syndrome currently under investigation. However, the current pig reference genome (Sscrofa11.1) misassembles the highly complex SNHG14 locus, hindering accurate targeting and regulatory studies in this model. Using PacBio HiFi and Hi-C sequencing, we generated a chromosome-level assembly for an Angelman syndrome pig model and fully resolved the SNHG14 locus without gaps. We show that the current pig reference genome contains extensive tandem repeat collapse within SNHG14, misrepresenting both its size and organization. The resolved locus reveals a previously unknown bipartite architecture of SNORD116 tandem repeats, comprising two distinct groups in both sequence and structure. This resolution and genome resource remove the genomic hindrance to SNHG14-focused studies in pigs.