An ultra-conserved element (UCE) was originally defined as a genome segment longer than 200 base pairs (bp) that is absolutely conserved, with no insertions or deletions and 100% identity, between orthologous regions of the human, rat, and mouse genomes.[1][2] 481 ultra-conserved elements have been identified in the human genome.[1][2] If ribosomal DNA (rDNA regions) are excluded, these range in size from 200 bp to 781 bp.[2] UCRs are found on all chromosomes except for 21 and Y.[3] A database collecting genomic information about ultra-conserved elements (UCbase) is available at http://ucbase.unimore.it.[4]

Since its creation, this term's usage has broadened to include more evolutionary distant species or shorter segments, for example 100 bp instead of 200 bp.[1][2] By some definitions, segments need not be syntenic between species.[1] Human UCEs also show high conservation with more evolutionarily distant species, such as chicken and fugu.[2] Out of 481 identified human UCEs, approximately 97% align with high identity to the chicken genome, though only 4% of human genome can only be reliably aligned to the chicken genome.[2] Similarly, the same sequences in the fugu genome have 68% identity to human UCEs, despite the human genome only reliably aligning to 1.8% of the fugu genome.[2] Despite often being noncoding DNA,[5] some ultra-conserved elements have been found to be transcriptionally active, producing non-coding RNA molecules.[6]

Evolution

Researchers originally assumed that perfect conservation of these long stretches of DNA implied evolutionary importance, as these regions appear to have experienced strong negative (purifying) selection for 300-400 million years.[2][5][7] More recently, this assumption has been replaced by two main hypotheses: that UCEs are created through a reduced negative selection rate, or through reduced mutation rates, also known as a “cold spot” of evolution.[1][2] Many studies have examined the validity of each hypothesis. The probability of finding ultra-conserved elements by chance (under neutral evolution) has been estimated at less than 10−22 in 2.9 billion bases.[2] In support of the cold spot hypothesis, UCEs were found to be mutating 20 fold less than expected under conservative models for neutral mutation rates.[2] This fold change difference in mutation rates was consistent between humans, chimpanzees, and chickens.[2] Ultra-conserved elements are not exempt from mutations, as exemplified by the presence of 29,983 polymorphisms in the UCE regions of the human genome assembly GRCh38.[8] However, affected phenotypes were only caused by 112 of these polymorphisms, most of which were located in coding regions of the UCEs.[8] A study performed in mice determined that deleting UCEs from the genome did not create obvious deleterious phenotypes, despite deletion of UCEs in proximity to promoters and protein coding genes.[9] Affected mice were fertile and targeted screens of the nearby coding genes showed no altered phenotype.[9] A separate mouse study demonstrated that ultra-conserved enhancers were robust to mutagenesis, concluding that perfect conservation of UCE sequences is not required for their function, which would suggest another reason for the sequence consistency besides evolutionary importance.[10] Computational analysis of human ultra-conserved noncoding elements (UCNEs) found that the regions are enriched for A-T sequences and are generally GC poor.[11] However, the UNCEs were found to be enriched for CpG, or highly methylated.[11] This may indicate that there is some change to DNA structure in these regions favoring their precise retention, but this possibility has not been validated through testing.[11]

Function

Often, ultra-conserved elements are located near transcriptional regulators or developmental genes performing functions such as gene enhancing and splicing regulation.[1][2][12] A study comparing ultra-conserved elements between humans and the Japanese puffer fish Takifugu rubripes proposed an importance in vertebrate development.[13] Double-knockouts of UCEs near the ARX gene in mice caused a shrunken hippocampus in the brain, though the effect was not lethal.[14] Some UCEs are not transcribed, and are referred to as ultra-conserved noncoding elements.[11] However, many UCRs in humans are extensively transcribed.[6] A small number of those which are transcribed, known as transcribed UTRs (T-UTRs), have been connected with human carcinomas and leukemias.[6] For example, TUC338 is strongly upregulated in human hepatocellular carcinoma cells.[15] Indeed, UCEs are often affected by copy number variation in cancer cells much more than in healthy contexts, suggesting that altering the copy number of T-UCEs may be deleterious.[16][17][18]

Role in Human Disease

Research has demonstrated that T-UCRs have a tissue-specific expression, and a differential expression profile between tumors and other diseases.[3] The tables below highlight transcripts and polymorphisms within UCRs that have been shown to contribute to human diseases.[3][8] For example, UCRs tend to accumulate less mutations than flanking segments, in both neoplastic and non-neoplastic samples from persons with hereditary non-polyposis colorectal cancer.[19]

Regulation Mechanisms of Disease Related Ultra-conserved Element Transcripts

miR/methylation/transcript factor associated with T-UCRs Disease References
miR-24-1/uc.160 Leukemia Calin et al., 2007 [6]
miR-130b/uc.63 Prostate CA Sekino et al., 2017 [20]
miR-153/uc.416 Colorectal and renal CA Goto et al., 2016;[21] Sekino et al., 2017[20]
miR-155/uc.160 Gastric CA Calin et al., 2007;[6] Pang et al., 2018[22]
miR-155/uc346A Leukemia Calin et al., 2007 [6]
mir-195/uc.283 Bladder CA Liz et al., 2014 [23]
miR-195, miR-4668/uc.372 Lipid metabolism Guo et al., 2018 [24]
mir-195/uc.173 Gastrointestinal tract Xiao et al., 2018[25]
miR-214/uc.276 Colorectal CA Wojcik et al., 2010[26]
miR-291a-3p/uc.173 Nervous system Nan et al., 2016 [27]
miR-29b/uc.173 Gastrointestinal tract J. Y. Wang et al., 2018 [28]
miR-339-3p, miR-663b-3p, miR-95-5p/uc.339 Lung CA Vannini et al., 2017[29]
miR-596/uc.8 Bladder CA Olivieri et al., 2016 [30]
DNA methylation/uc.160, uc.283, and uc.346 Colorectal CA Kottorou et al., 2018 [31]
DNA methylation/uc.158 + A, uc.160+, uc.241 + A, uc.283 + A, uc.346 + A Gastric CA Goto et al., 2016;[21] Lujambio et al., 2010 [20]
Transcription factor SP1/uc.138 (TRA2β4) Colorectal CA Kajita et al., 2016 [32]
Transcription factor YY1/uc.8 Bladder CA Terreri et al., 2016 [33]

Phenotype-Associated Polymorphisms within Ultra-conserved Elements

Polymorphism name Associated phenotype description Source
rs17105335 Amyotrophic lateral sclerosis Cronin et al. (2008)[34]
rs2020906 Lynch syndrome Hansen et al. (2014)[35]
rs10496382 Height Chiang et al. (2012)[36]
rs13382811 Severe myopia Khor et al. (2013)[37]
rs104893634 Vertical talus congenital Dobbs et al. (2006);[38] Shrimpton et al. (2004)[38]
rs2307121 Central corneal thickness Lu et al. (2013)[39]
rs587777277 Bosch-Boonstra-Schaaf optic atrophy syndrome Bosch et al. (2014)[40]
rs587777275 Bosch-Boonstra-Schaaf optic atrophy syndrome Bosch et al. (2014)[40]
rs587777274 Bosch-Boonstra-Schaaf optic atrophy syndrome Bosch et al. (2014)[40]
rs387906239 Familial adenomatous polyposis 1 attenuated Soravia et al. (1999)[41]
rs3797704 No association with breast cancer Chang et al. (2016)[42]
rs387906232 Familial adenomatous polyposis 1 Fodde et al. (1992)[43]
rs387906237 Familial adenomatous polyposis 1 attenuated Curia et al. (1998)[44]
rs121434591 Distal myopathy Senderek et al. (2009)[12]
rs587777300 Amyotrophic lateral sclerosis 21 Johnson et al. (2014)[45]
rs863223403 Au-Kline syndrome Au et al. (2015)[46]
rs121917900 Cockayne syndrome B Mallery et al. (1998)[47]
rs75462234 Papillorenal syndrome Schimmenti et al. (1999)[48]
rs77453353 Renal coloboma syndrome Amiel et al. (2000)[49]
rs76675173 Papillorenal syndrome Schimmenti et al. (1997)[50]
rs587777708 Focal segmental glomerulosclerosis 7 Barua et al. (2014)[51]
rs11190870 Adolescent idiopathic scoliosis, no association with breast cancer Chettier et al. (2015);[52] Gao et al. (2013);[53] Grauers et al. (2015);[54] Jiang et al. (2013);[55] Londono et al. (2014);[56] Miyake et al. (2013);[57] Shen et al. (2011);[58] Takahashi et al. (2011)[59]
rs724159963 Peroxisomal fatty acyl-CoA reductase 1 disorder Buchert et al. (2014)[60]
rs16932455 Capecitabine sensitivity O’Donnell et al. (2012)[61]
rs997295 Motion sickness; BMI De et al. (2015);[62] Guo et al. (2013);[63] Hromatka et al.[64]
rs587777373 Congenital heart defects multiple types 4 Al Turki et al. (2014)[65]
rs398123839 Duchenne muscular dystrophy Hofstra et al. (2004);[66] Roberts et al. (1992)[67]
rs863224976 Becker muscular dystrophy Tuffery-Giraud et al. (2005)[68]
rs132630295 Spastic paraplegia 2 X-linked Gorman et al. (2007)[69]
rs132630287 Spastic paraplegia 2 X-linked Saugier-Veber et al. (1994)[70]
rs132630292 Pelizaeus/Merzbacher disease atypical Hodes et al. (1997)[71]
rs137852350 Mental retardation X-linked 94 Wu et al. (2007)[72]
rs122459149 Emery-Dreifuss muscular dystrophy 6 X-linked Gueneau et al. (2009);[73] Knoblauch et al. (2010)[74]
rs122458141 Myopathy X-linked with postural muscle atrophy Schoser et al. (2009);[75] Windpassinger et al. (2008)[76]
rs786200914 Myopathy X-linked with postural muscle atrophy Schoser et al. (2009)[75]
rs267606811 Myopathy X-linked with postural muscle atrophy Windpassinger et al. (2008)[76]
rs62621672 Rett syndrome (nonpathogenic variant) Zahorakova et al. (2007)[77]

See also

References

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