Ultraconserved element
An ultraconserved element (UCE) is a region of the genome that is shared between evolutionarily distant taxa and shows little or no variation between those taxa. These regions and regions adjacent to them (flanking DNA) are useful for tracing the evolutionary history of groups of organisms.{{cite journal |last1=Faircloth |first1=BC |last2=McCormack |first2=JE |last3=Crawford |first3=NG |last4=Harvey |first4=MG |last5=Brumfield |first5=RT |last6=Glenn |first6=TC |title=Ultraconserved elements anchor thousands of genetic markers spanning multiple evolutionary timescales|journal=Systematic Biology |date=October 2012 |volume=61 |issue=5 |pages=717-26 |doi=10.1093/sysbio/sys004 |pmid=22232343}}{{cite journal |last1=Zhang |first1=Y. Miles |last2=Williams |first2=Jason L. |last3=Lucky |first3=Andrea |title=Understanding UCEs: A Comprehensive Primer on Using Ultraconserved Elements for Arthropod Phylogenomics |journal=Insect Systematics and Diversity |date=3 September 2019 |volume=3 |issue=5 |doi=10.1093/isd/ixz016|doi-access=free }} Another term for ultraconserved element is ultraconserved region (UCR).
The term "ultraconserved element" 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.{{cite journal | vauthors = Reneker J, Lyons E, Conant GC, Pires JC, Freeling M, Shyu CR, Korkin D | title = Long identical multispecies elements in plant and animal genomes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 19 | pages = E1183–E1191 | date = May 2012 | pmid = 22496592 | pmc = 3358895 | doi = 10.1073/pnas.1121356109 | doi-access = free }}{{cite journal |vauthors=Bejerano G, Pheasant M, Makunin I, Stephen S, Kent WJ, Mattick JS, Haussler D |date=May 2004 |title=Ultraconserved elements in the human genome |journal=Science |volume=304 |issue=5675 |pages=1321–1325 |bibcode=2004Sci...304.1321B |citeseerx=10.1.1.380.9305 |doi=10.1126/science.1098119 |pmid=15131266 |s2cid=2790337}} 481 of these segments have been identified in the human genome. If ribosomal DNA (rDNA regions) are excluded, these range in size from 200 bp to 781 bp. UCEs are found on all human chromosomes except for 21 and Y.
Since its creation, this term's usage has broadened to include more evolutionarily distant species or shorter segments, for example 100 bp instead of 200 bp. By some definitions, segments need not be syntenic between species. Human UCEs also show high conservation with more evolutionarily distant species, such as chicken and fugu. Out of 481 identified human UCEs, approximately 97% align with high identity to the chicken genome, though only 4% of the human genome can be reliably aligned to the chicken genome. 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. Despite often being noncoding DNA,{{cite journal | vauthors = Katzman S, Kern AD, Bejerano G, Fewell G, Fulton L, Wilson RK, Salama SR, Haussler D | display-authors = 6 | title = Human genome ultraconserved elements are ultraselected | journal = Science | volume = 317 | issue = 5840 | pages = 915 | date = August 2007 | pmid = 17702936 | doi = 10.1126/science.1142430 | s2cid = 35322654 | bibcode = 2007Sci...317..915K }} some ultraconserved elements have been found to be transcriptionally active, producing non-coding RNA molecules.{{cite journal | vauthors = Calin GA, Liu CG, Ferracin M, Hyslop T, Spizzo R, Sevignani C, Fabbri M, Cimmino A, Lee EJ, Wojcik SE, Shimizu M, Tili E, Rossi S, Taccioli C, Pichiorri F, Liu X, Zupo S, Herlea V, Gramantieri L, Lanza G, Alder H, Rassenti L, Volinia S, Schmittgen TD, Kipps TJ, Negrini M, Croce CM | display-authors = 6 | title = Ultraconserved regions encoding ncRNAs are altered in human leukemias and carcinomas | journal = Cancer Cell | volume = 12 | issue = 3 | pages = 215–229 | date = September 2007 | pmid = 17785203 | doi = 10.1016/j.ccr.2007.07.027 | doi-access = free }}
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.{{cite journal | vauthors = Sathirapongsasuti JF, Sathira N, Suzuki Y, Huttenhower C, Sugano S | title = Ultraconserved cDNA segments in the human transcriptome exhibit resistance to folding and implicate function in translation and alternative splicing | journal = Nucleic Acids Research | volume = 39 | issue = 6 | pages = 1967–1979 | date = March 2011 | pmid = 21062826 | pmc = 3064809 | doi = 10.1093/nar/gkq949 }} 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. Many studies have examined the validity of each hypothesis. The probability of finding ultraconserved elements by chance (under neutral evolution) has been estimated at less than 10−22 in 2.9 billion bases. 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. This fold change difference in mutation rates was consistent between humans, chimpanzees, and chickens. Ultraconserved 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.{{cite journal | vauthors = Habic A, Mattick JS, Calin GA, Krese R, Konc J, Kunej T | title = Genetic Variations of Ultraconserved Elements in the Human Genome | journal = Omics | volume = 23 | issue = 11 | pages = 549–559 | date = November 2019 | pmid = 31689173 | pmc = 6857462 | doi = 10.1089/omi.2019.0156 }} However, affected phenotypes were only caused by 112 of these polymorphisms, most of which were located in coding regions of the UCEs. 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.{{cite journal | vauthors = Ahituv N, Zhu Y, Visel A, Holt A, Afzal V, Pennacchio LA, Rubin EM | title = Deletion of ultraconserved elements yields viable mice | journal = PLOS Biology | volume = 5 | issue = 9 | pages = e234 | date = September 2007 | pmid = 17803355 | pmc = 1964772 | doi = 10.1371/journal.pbio.0050234 | doi-access = free }} Affected mice were fertile and targeted screens of the nearby coding genes showed no altered phenotype. A separate mouse study demonstrated that ultraconserved 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.{{cite journal | vauthors = Snetkova V, Ypsilanti AR, Akiyama JA, Mannion BJ, Plajzer-Frick I, Novak CS, Harrington AN, Pham QT, Kato M, Zhu Y, Godoy J, Meky E, Hunter RD, Shi M, Kvon EZ, Afzal V, Tran S, Rubenstein JL, Visel A, Pennacchio LA, Dickel DE | display-authors = 6 | title = Ultraconserved enhancer function does not require perfect sequence conservation | journal = Nature Genetics | volume = 53 | issue = 4 | pages = 521–528 | date = April 2021 | pmid = 33782603 | pmc = 8038972 | doi = 10.1038/s41588-021-00812-3 }} Computational analysis of human ultraconserved noncoding elements (UCNEs) found that the regions are enriched for A-T sequences and are generally GC poor.{{cite journal | vauthors = Fedorova L, Mulyar OA, Lim J, Fedorov A | title = Nucleotide Composition of Ultra-Conserved Elements Shows Excess of GpC and Depletion of GG and CC Dinucleotides | journal = Genes | volume = 13 | issue = 11 | pages = 2053 | date = November 2022 | pmid = 36360290 | pmc = 9690913 | doi = 10.3390/genes13112053 | doi-access = free }} However, the UNCEs were found to be enriched for CpG, or highly methylated. 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.
Function
Often, ultraconserved elements are located near transcriptional regulators or developmental genes performing functions such as gene enhancing and splicing regulation.{{cite journal |display-authors=6 |vauthors=Saygin D, Tabib T, Bittar HE, Valenzi E, Sembrat J, Chan SY, Rojas M, Lafyatis R |date=January 2005 |title=Transcriptional profiling of lung cell populations in idiopathic pulmonary arterial hypertension |journal=Pulmonary Circulation |volume=10 |issue=1 |pages=e19 |doi=10.1371/journal.pbio.0030019 |pmc=544543 |pmid=32166015 |doi-access=free }} {{open access}} A study comparing ultraconserved elements between humans and the Japanese puffer fish Takifugu rubripes proposed an importance in vertebrate development.{{cite journal |display-authors=6 |vauthors=Woolfe A, Goodson M, Goode DK, Snell P, McEwen GK, Vavouri T, Smith SF, North P, Callaway H, Kelly K, Walter K, Abnizova I, Gilks W, Edwards YJ, Cooke JE, Elgar G |date=January 2005 |title=Highly conserved non-coding sequences are associated with vertebrate development |journal=PLOS Biology |volume=3 |issue=1 |pages=e7 |doi=10.1371/journal.pbio.0030007 |pmc=526512 |pmid=15630479 |doi-access=free }} {{open access}} Double-knockouts of UCEs near the ARX gene in mice caused a shrunken hippocampus in the brain, though the effect was not lethal.Elizabeth Pennisi (2017) [https://www.science.org/doi/10.1126/science.356.6341.892 Mysterious unchanging DNA finds a purpose in life], Science 02 Jun 2017] Some UCEs are not transcribed, and are referred to as ultraconserved noncoding elements. However, many UCRs in humans are extensively transcribed. A small number of those which are transcribed, known as transcribed UCEs (T-UCEs), have been connected with human carcinomas and leukemias. For example, TUC338 is strongly upregulated in human hepatocellular carcinoma cells.{{cite journal | vauthors = Braconi C, Valeri N, Kogure T, Gasparini P, Huang N, Nuovo GJ, Terracciano L, Croce CM, Patel T | display-authors = 6 | title = Expression and functional role of a transcribed noncoding RNA with an ultraconserved element in hepatocellular carcinoma | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 2 | pages = 786–791 | date = January 2011 | pmid = 21187392 | pmc = 3021052 | doi = 10.1073/pnas.1011098108 | doi-access = free | bibcode = 2011PNAS..108..786B }} 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.{{cite journal |vauthors=McCole RB, Fonseka CY, Koren A, Wu CT |date=October 2014 |title=Abnormal dosage of ultraconserved elements is highly disfavored in healthy cells but not cancer cells |journal=PLOS Genetics |volume=10 |issue=10 |pages=e1004646 |doi=10.1371/journal.pgen.1004646 |pmc=4207606 |pmid=25340765 |doi-access=free }}{{cite journal |vauthors=Derti A, Roth FP, Church GM, Wu CT |date=October 2006 |title=Mammalian ultraconserved elements are strongly depleted among segmental duplications and copy number variants |journal=Nature Genetics |volume=38 |issue=10 |pages=1216–1220 |doi=10.1038/ng1888 |pmid=16998490 |s2cid=10671674}}{{cite journal |vauthors=Chiang CW, Derti A, Schwartz D, Chou MF, Hirschhorn JN, Wu CT |date=December 2008 |title=Ultraconserved elements: analyses of dosage sensitivity, motifs and boundaries |journal=Genetics |volume=180 |issue=4 |pages=2277–2293 |doi=10.1534/genetics.108.096537 |pmc=2600958 |pmid=18957701}}
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.{{cite journal | vauthors = Pereira Zambalde E, Mathias C, Rodrigues AC, de Souza Fonseca Ribeiro EM, Fiori Gradia D, Calin GA, Carvalho de Oliveira J | title = Highlighting transcribed ultraconserved regions in human diseases | journal = Wiley Interdisciplinary Reviews. RNA | volume = 11 | issue = 2 | pages = e1567 | date = March 2020 | pmid = 31489780 | doi = 10.1002/wrna.1567 | s2cid = 201844414 }} The tables below highlight transcripts and polymorphisms within UCRs that have been shown to contribute to human diseases. 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.{{cite journal |display-authors=6 |vauthors=De Grassi A, Segala C, Iannelli F, Volorio S, Bertario L, Radice P, Bernard L, Ciccarelli FD |date=January 2010 |title=Ultradeep sequencing of a human ultraconserved region reveals somatic and constitutional genomic instability |journal=PLOS Biology |volume=8 |issue=1 |pages=e1000275 |doi=10.1371/journal.pbio.1000275 |pmc=2794366 |pmid=20052272 |veditors=Hastie N |doi-access=free }}
= Phenotype-associated polymorphisms within ultraconserved elements =
See also
References
{{reflist|30em}}
External links
- http://ultraconserved.org/