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.

Keywords: ultraconserved element; human genome; purifying selection; transcriptional enhancer; poison cassette exon; cryptic intron

Figure 1.

Alignment of a representative ultraconserved element (uc.440; nucleotides 20 to 349 of the human sequence shown) in human (H), mouse (M), opossum (O), chicken (C), Xenopus tropicalis (X), zebrafish (Z) and elephant shark (ES). Uc.440 is located in an intron of the zinc finger protein 407 gene ZNF407.

Figure 2.

Ultraconserved elements that flank (a) DACH1 and (b) Iroquois genes act as long‐range transcriptional enhancers. The alignments include sequences from human/mouse/rat (H/M/R), dog (D), chicken (C) and fugu (F). The UCEs shown are a subregion of the corresponding enhancer that was validated in transgenic mice (DACH1) or Xenopus (IrxB cluster) assays. Not drawn to scale.

Figure 3.

Multiplexing of two functions onto a single ultraconserved element. Ultraconserved element uc.221 is an ultraconserved transcriptional enhancer (ei) and also encodes a ncRNA that acts as a coactivator of the Dlx2 transcription factor. Enhancers ei and eii are marked by shaded boxes, whereas exons of the ncRNA Evf‐1 and Evf‐2 are shown by unshaded boxes. The two alternative transcripts of Evf are shown in solid and dotted lines.

Figure 4.

Unproductive splicing of SR genes SRSF3 and SRSF1. UCEs (bold lines above exons) may overlap (a) ‘poison cassette exons’ that contain a premature termination codon (red circle) or (b) cryptic 3′ UTR introns. Two different splice variants are shown (solid and dotted lines) that connect the exons of each gene. In (b), the normal stop codon is marked with a green circle. Not drawn to scale.

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Lee, Alison P, and Venkatesh, B(Apr 2013) Ultraconserved Elements (UCEs) in the Human Genome. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0020842.pub2]