Ultraconserved Elements ( UCEs ) in the Human Genome

Abstract

Ultraconserved elements (UCEs) are deoxyribonucleic acid sequences of at least 200 base pairs in length and perfectly conserved in human, mouse and rat genomes. Exonic UCEs are significantly associated with splicing regulator genes, whereas nonexonic UCEs are significantly associated with transcriptional regulator genes. UCEs are highly conserved among all jawed vertebrates, with primitive instances having originated in the ancestral vertebrate genome and subsequently constrained in jawed vertebrates. UCEs are under extreme purifying selection and are implicated in functions such as transcriptional enhancers, exons of noncoding ribonucleic acid transcripts, alternatively spliced ‘poison cassette exons’ and cryptic introns that regulate the expression of certain classes of proteins. UCEs may have maintained their perfect identity over a long period of evolution due to the layering of multiple functions on the same element and increased selective constraint. Key Concepts: Human genome contains ultraconserved elements (UCEs) that are 200 bp or longer and 100% identical in mouse and rat genomes. The majority of UCEs were present in the last common ancestor of jawed vertebrates. UCEs have experienced high purifying selection, possibly due to the ‘multiplexing’ of multiple functions on the same element. UCEs are depleted among segmental duplications and copy number variants in the human genome. UCEs may be protein‐coding sequence, transcriptional enhancers, exons of noncoding RNA, alternatively spliced ‘poison cassette exons’ and/or adjacent flanking sequence of cryptic introns. The majority of UCEs are transcribed as either protein‐coding transcripts or ncRNA transcripts. A fraction of transcribed UCEs are aberrantly expressed in human cancers. Several single nucleotide polymorphisms (SNPs) in UCEs are associated with increased risk to human diseases.

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“…UCEs are areas of the genome phylogenetically conserved across diverged taxa (Bejerano et al, 2004). Their high level of sequence conservation is thought to be maintained by strong purifying selection (Lee & Venkatesh, 2013). Some polymorphisms in UCEs are associated with genetic diseases or phenotypic traits (Habic et al, 2019), with UCEs being linked to enhancers in early development in both mammals (Visel et al, 2008) and flies (Warnefors et al, 2016).…”