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Ultra-conserved element

January 26, 2023

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 syntetic 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strong negative (purifying) selection for 300-400 million years.[2][5][7] More recently, this assumption has been replaced by two main hypotheses: that UCEs are created through a reduced negative selection rate, or through reduced mutation rates, also known as a “cold spot” of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)[39]
rs2307121 Central corneal thickness Lu et al. (2013)[40]
rs587777277 Bosch-Boonstra-Schaaf optic atrophy syndrome Bosch et al. (2014)[41]
rs587777275 Bosch-Boonstra-Schaaf optic atrophy syndrome Bosch et al. (2014)[41]
rs587777274 Bosch-Boonstra-Schaaf optic atrophy syndrome Bosch et al. (2014)[41]
rs387906239 Familial adenomatous polyposis 1 attenuated Soravia et al. (1999)[42]
rs3797704 No association with breast cancer Chang et al. (2016)[43]
rs387906232 Familial adenomatous polyposis 1 Fodde et al. (1992)[44]
rs387906237 Familial adenomatous polyposis 1 attenuated Curia et al. (1998)[45]
rs121434591 Distal myopathy Senderek et al. (2009)[12]
rs587777300 Amyotrophic lateral sclerosis 21 Johnson et al. (2014)[46]
rs863223403 Au-Kline syndrome Au et al. (2015)[47]
rs121917900 Cockayne syndrome B Mallery et al. (1998)[48]
rs75462234 Papillorenal syndrome Schimmenti et al. (1999)[49]
rs77453353 Renal coloboma syndrome Amiel et al. (2000)[50]
rs76675173 Papillorenal syndrome Schimmenti et al. (1997)[51]
rs587777708 Focal segmental glomerulosclerosis 7 Barua et al. (2014)[52]
rs11190870 Adolescent idiopathic scoliosis, no association with breast cancer Chettier et al. (2015);[53] Gao et al. (2013);[54] Grauers et al. (2015);[55] Jiang et al. (2013);[56] Londono et al. (2014);[57] Miyake et al. (2013);[58] Shen et al. (2011);[59] Takahashi et al. (2011)[60]
rs724159963 Peroxisomal fatty acyl-CoA reductase 1 disorder Buchert et al. (2014)[61]
rs16932455 Capecitabine sensitivity O’Donnell et al. (2012)[62]
rs997295 Motion sickness; BMI De et al. (2015);[63] Guo et al. (2013);[64] Hromatka et al.[65]
rs587777373 Congenital heart defects multiple types 4 Al Turki et al. (2014)[66]
rs398123839 Duchenne muscular dystrophy Hofstra et al. (2004);[67] Roberts et al. (1992)[68]
rs863224976 Becker muscular dystrophy Tuffery-Giraud et al. (2005)[69]
rs132630295 Spastic paraplegia 2 X-linked Gorman et al. (2007)[70]
rs132630287 Spastic paraplegia 2 X-linked Saugier-Veber et al. (1994)[71]
rs132630292 Pelizaeus/Merzbacher disease atypical Hodes et al. (1997)[72]
rs137852350 Mental retardation X-linked 94 Wu et al. (2007)[73]
rs122459149 Emery-Dreifuss muscular dystrophy 6 X-linked Gueneau et al. (2009);[74] Knoblauch et al. (2010)[75]
rs122458141 Myopathy X-linked with postural muscle atrophy Schoser et al. (2009);[76] Windpassinger et al. (2008)[77]
rs786200914 Myopathy X-linked with postural muscle atrophy Schoser et al. (2009)[76]
rs267606811 Myopathy X-linked with postural muscle atrophy Windpassinger et al. (2008)[77]
rs62621672 Rett syndrome (nonpathogenic variant) Zahorakova et al. (2007)[78]

See also

References

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January 26, 2023
ultra, conserved, element, ultra, conserved, element, originally, defined, genome, segment, longer, than, base, pairs, that, absolutely, conserved, with, insertions, deletions, identity, between, orthologous, regions, human, mouse, genomes, ultra, conserved, e. 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 syntetic 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 Contents 1 Evolution 2 Function 3 Role in Human Disease 3 1 Regulation Mechanisms of Disease Related Ultra conserved Element Transcripts 3 2 Phenotype Associated Polymorphisms within Ultra conserved Elements 4 See also 5 ReferencesEvolution EditResearchers 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 EditOften 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 EditResearch 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 Edit miR methylation transcript factor associated with T UCRs Disease ReferencesmiR 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 TRA2b4 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 Edit Polymorphism name Associated phenotype description Sourcers17105335 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 39 rs2307121 Central corneal thickness Lu et al 2013 40 rs587777277 Bosch Boonstra Schaaf optic atrophy syndrome Bosch et al 2014 41 rs587777275 Bosch Boonstra Schaaf optic atrophy syndrome Bosch et al 2014 41 rs587777274 Bosch Boonstra Schaaf optic atrophy syndrome Bosch et al 2014 41 rs387906239 Familial adenomatous polyposis 1 attenuated Soravia et al 1999 42 rs3797704 No association with breast cancer Chang et al 2016 43 rs387906232 Familial adenomatous polyposis 1 Fodde et al 1992 44 rs387906237 Familial adenomatous polyposis 1 attenuated Curia et al 1998 45 rs121434591 Distal myopathy Senderek et al 2009 12 rs587777300 Amyotrophic lateral sclerosis 21 Johnson et al 2014 46 rs863223403 Au Kline syndrome Au et al 2015 47 rs121917900 Cockayne syndrome B Mallery et al 1998 48 rs75462234 Papillorenal syndrome Schimmenti et al 1999 49 rs77453353 Renal coloboma syndrome Amiel et al 2000 50 rs76675173 Papillorenal syndrome Schimmenti et al 1997 51 rs587777708 Focal segmental glomerulosclerosis 7 Barua et al 2014 52 rs11190870 Adolescent idiopathic scoliosis no association with breast cancer Chettier et al 2015 53 Gao et al 2013 54 Grauers et al 2015 55 Jiang et al 2013 56 Londono et al 2014 57 Miyake et al 2013 58 Shen et al 2011 59 Takahashi et al 2011 60 rs724159963 Peroxisomal fatty acyl CoA reductase 1 disorder Buchert et al 2014 61 rs16932455 Capecitabine sensitivity O Donnell et al 2012 62 rs997295 Motion sickness BMI De et al 2015 63 Guo et al 2013 64 Hromatka et al 65 rs587777373 Congenital heart defects multiple types 4 Al Turki et al 2014 66 rs398123839 Duchenne muscular dystrophy Hofstra et al 2004 67 Roberts et al 1992 68 rs863224976 Becker muscular dystrophy Tuffery Giraud et al 2005 69 rs132630295 Spastic paraplegia 2 X linked Gorman et al 2007 70 rs132630287 Spastic paraplegia 2 X linked Saugier Veber et al 1994 71 rs132630292 Pelizaeus Merzbacher disease atypical Hodes et al 1997 72 rs137852350 Mental retardation X linked 94 Wu et al 2007 73 rs122459149 Emery Dreifuss muscular dystrophy 6 X linked Gueneau et al 2009 74 Knoblauch et al 2010 75 rs122458141 Myopathy X linked with postural muscle atrophy Schoser et al 2009 76 Windpassinger et al 2008 77 rs786200914 Myopathy X linked with postural muscle atrophy Schoser et al 2009 76 rs267606811 Myopathy X linked with postural muscle atrophy Windpassinger et al 2008 77 rs62621672 Rett syndrome nonpathogenic variant Zahorakova et al 2007 78 See also EditHuman accelerated regions SyntenyReferences Edit a b c d e f Reneker J Lyons E Conant GC Pires JC Freeling M Shyu CR Korkin D May 2012 Long identical multispecies elements in plant and animal genomes Proceedings of the National Academy of Sciences of the United States of America 109 19 E1183 E1191 doi 10 1073 pnas 1121356109 PMC 3358895 PMID 22496592 a b c d e f g h i j k l m Bejerano G Pheasant M Makunin I Stephen S Kent WJ Mattick JS Haussler D May 2004 Ultraconserved elements in the human genome Science 304 5675 1321 1325 Bibcode 2004Sci 304 1321B CiteSeerX 10 1 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