Ultraconserved Elements in the Human Genome

Abstract

There are 481 segments longer than 200 bp that are absolutely conserved (100% identity with no insertions or deletions) between orthologous regions of the human, rat and mouse genomes. Nearly all of these segments are also conserved in the chicken and dog genomes, with an average of 95% and 99% identity, respectively. Many are also significantly conserved in fish. These ultraconserved elements of the human genome are most often located either overlapping exons in genes involved in RNA processing or in introns or nearby genes involved in regulation of transcription and development. Along with more than 5,000 sequences of over 100bp that are absolutely conserved among the three sequenced mammals, these represent a class of genetic elements whose functions and evolutionary origins are yet to be determined, but which are more highly conserved between these species than proteins, and appear to be essential for the ontogeny of mammals and other vertebrates.Although only about 1.2% of the human genome appears to code for protein (1-3), it has been estimated that as much as 5% is more conserved than expected from neutral evolution since the split with rodents, and hence may be under negative or "purifying" selection (4-6). Several studies have found specific non-coding segments in the human genome that appear to be under selection, using a threshold for conservation of 70% or 80% identity with mouse over more than 100bp (7-13). A study of these elements on human chromosome 21 found that those that were very highly conserved in multiple species contained significant numbers of non-coding elements (13). Similar results were found comparing the human, mouse and rat (14, 15) in a study of the 1.8 Mb CFTR region (16,17), and in a functional study of the SIM2 locus in a number of mammalian species (18). We determined the longest segments of the human genome that are maximally conserved with orthologous segments in rodents: those showing 100% identity and with no insertions or deletions in their alignment with mouse and rat. Exclusive of ribosomal RNA regions, there are 481 such segments longer than 200bp that we call ultraconserved elements (table S1). They are widely distributed in the genome (on all chromosomes except chromosomes 21 and Y), and are often found in clusters (Fig. 1). The probability is less than 10 -22 of finding even one such element in 2.9 billion bases under a simple model of neutral evolution with independent substitutions at each site, using the slowest neutral substitution rate that is observed for any 1 Mb region of the genome (supporting text, section S1). Nearly all of these elements also exhibited extremely high levels of conservation with orthologous regions in the chicken genome (467/481 = 97% of the elements aligning at an average of 95.7% identity, 29 at 100% identity), and about two-thirds of them with the fugu genome as well (324/481 = 67.3% of the elements aligning at an average of 76.8% identity), despite the fact that only about 4% of the human genome can be reliably aligned to the chicken ...

Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor

“…Interestingly NFAT5 exon 5 is one of the 111 'ultraconserved elements' identified in human protein-coding genes (Bejerano et al, 2004;McGlincy and Smith, 2008). It has been reported that many ultraconserved elements are associated with exons inducing NMD ( (Bejerano et al, 2004;McGlincy and Smith, 2008). In this context, the ddx5/ddx17 effect on NFAT5 expression was observed in different human cell lines (Figure 4) as well as in a mouse cell line (Supplementary Figure S4).…”

“…Indeed, ddx5 and ddx17 favored the inclusion of the NFAT5 exon 5, which generated unproductive transcripts that were not translated ( Figure 6). Interestingly NFAT5 exon 5 is one of the 111 'ultraconserved elements' identified in human protein-coding genes (Bejerano et al, 2004;McGlincy and Smith, 2008). It has been reported that many ultraconserved elements are associated with exons inducing NMD ( (Bejerano et al, 2004;McGlincy and Smith, 2008).…”

Mapping of conserved RNA secondary structures predicts thousands of functional noncoding RNAs in the human genome

“…42 detected regions are contained within one of the different cDNA collections. 38 overlap with one of the 481 "ultraconserved elements" (segments longer than 200 base pairs that are identical between human, mouse and rat genomes) reported by Bejerano et al 30 . A few of these can be unambiguously identified as structural RNAs because of the substitution pattern in the fish and chicken sequences.…”

Radial chromatin positioning is shaped by local gene density, not by gene expression

“…The existence of transcriptionally highly active genes also in the gene-poor environment of the nuclear periphery argues for an impact of other factors such as the switching of replication timing, ultra-conserved DNA elements (Bejerano et al 2004), and local chromatin unfolding in addition to the influence of local gene density. Finally, the observation of gene-dense chromatin confirmed in a variety of different cell types and species so far does not implicate that such an arrangement is mandatory and does not exclude the existence of specific cell types with an opposite nuclear distribution.…”