Genetic Variations of Ultraconserved Elements in the Human Genome.

Ultraconserved elements (UCEs) are among the most popular DNA markers for phylogenomic analysis. In at least three of five placental mammalian genomes (human, dog, cow, mouse, and rat), 2189 UCEs of at least 200 bp in length that are identical have been identified. Most of these regions have not yet been functionally annotated, and their associations with diseases remain largely unknown. This is an important knowledge gap in human genomics with regard to UCE roles in physiologically critical functions, and by extension, their relevance for shared susceptibilities to common complex diseases across several mammalian organisms in the event of their polymorphic variations. In the present study, we remapped the genomic locations of these UCEs to the latest human genome assembly, and examined them for documented polymorphisms in sequenced human genomes. We identified 29,983 polymorphisms within analyzed UCEs, but revealed that a vast majority exhibits very low minor allele frequencies. Notably, only 112 of the identified polymorphisms are associated with a phenotype in the Ensembl genome browser. Through literature analyses, we confirmed associations of 37 (i.e., out of the 112) polymorphisms within 23 UCEs with 25 diseases and phenotypic traits, including, muscular dystrophies, eye diseases, and cancers (e.g., familial adenomatous polyposis). Most reports of UCE polymorphism-disease associations appeared to be not cognizant that their candidate polymorphisms were actually within UCEs. The present study offers strategic directions and knowledge gaps for future computational and experimental work so as to better understand the thus far intriguing and puzzling role(s) of UCEs in mammalian genomes.