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==Evolution==
==Evolution==
Perfect conservation of these long stretches of DNA is thought to imply [[evolution]]ary importance as these regions appear to have experienced strong [[Negative selection (natural selection)|negative (purifying) selection]] for 300-400 million years.<ref name="Sci04" /><ref name="Kat07" /><ref>{{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 Res. |volume=39 |issue=6 |pages=1967–79 |year=2011 |pmid=21062826 |pmc=3064809 |doi=10.1093/nar/gkq949 }}</ref> UCEs are hypothesized to be created through a reduced negative selection rate, a reduced mutation rate, also called a “cold spot” of evolution, or a combination of these two factors.<ref name="Sci04" /> Many studies have examined the validity of each hypothesis. The probability of finding ultra-conserved elements by chance (under [[Neutral theory of molecular evolution|neutral evolution]]) has been estimated at less than 10<sup>−22</sup> in 2.9 billion bases.<ref name="Sci04" /> 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.<ref name="Sci04" /> This fold change difference in mutation rates was consistent between humans, chimpanzees, and chickens.<ref name="Sci04" /> 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]].<ref name=":1">{{Cite journal |last=Habic |first=Anamarija |last2=Mattick |first2=John S. |last3=Calin |first3=George Adrian |last4=Krese |first4=Rok |last5=Konc |first5=Janez |last6=Kunej |first6=Tanja |date=2019-11-01 |title=Genetic Variations of Ultraconserved Elements in the Human Genome |url=https://www.liebertpub.com/doi/10.1089/omi.2019.0156 |journal=OMICS: A Journal of Integrative Biology |volume=23 |issue=11 |pages=549–559 |doi=10.1089/omi.2019.0156 |pmc=6857462 |pmid=31689173}}</ref> However, affected phenotypes were only caused by 112 of these [[Polymorphism (biology)|polymorphisms]], most of which were located in coding regions of the UCEs.<ref name=":1" /> 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<ref name=":2">{{Cite journal |last=Ahituv |first=Nadav |last2=Zhu |first2=Yiwen |last3=Visel |first3=Axel |last4=Holt |first4=Amy |last5=Afzal |first5=Veena |last6=Pennacchio |first6=Len A. |last7=Rubin |first7=Edward M. |date=2007-09-04 |title=Deletion of Ultraconserved Elements Yields Viable Mice |url=https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.0050234 |journal=PLOS Biology |language=en |volume=5 |issue=9 |pages=e234 |doi=10.1371/journal.pbio.0050234 |issn=1545-7885 |pmc=1964772 |pmid=17803355}}</ref>. Affected mice were fertile and targeted screens of the nearby coding genes showed no altered phenotype.<ref name=":2" /> 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.<ref>{{Cite journal |last=Snetkova |first=Valentina |last2=Ypsilanti |first2=Athena R. |last3=Akiyama |first3=Jennifer A. |last4=Mannion |first4=Brandon J. |last5=Plajzer-Frick |first5=Ingrid |last6=Novak |first6=Catherine S. |last7=Harrington |first7=Anne N. |last8=Pham |first8=Quan T. |last9=Kato |first9=Momoe |last10=Zhu |first10=Yiwen |last11=Godoy |first11=Janeth |last12=Meky |first12=Eman |last13=Hunter |first13=Riana D. |last14=Shi |first14=Marie |last15=Kvon |first15=Evgeny Z. |date=2021 |title=Ultraconserved enhancer function does not require perfect sequence conservation |url=https://www.nature.com/articles/s41588-021-00812-3 |journal=Nature Genetics |language=en |volume=53 |issue=4 |pages=521–528 |doi=10.1038/s41588-021-00812-3 |issn=1546-1718 |pmc=8038972 |pmid=33782603}}</ref> Computational analysis of human [[ultra-conserved noncoding elements]] (UCNEs) found that the regions are enriched for A-T sequences and are generally GC poor.<ref name=":3">{{Cite journal |last=Fedorova |first=Larisa |last2=Mulyar |first2=Oleh A. |last3=Lim |first3=Jan |last4=Fedorov |first4=Alexei |date=2022 |title=Nucleotide Composition of Ultra-Conserved Elements Shows Excess of GpC and Depletion of GG and CC Dinucleotides |url=https://www.mdpi.com/2073-4425/13/11/2053 |journal=Genes |language=en |volume=13 |issue=11 |pages=2053 |doi=10.3390/genes13112053 |issn=2073-4425 |pmc=9690913 |pmid=36360290}}</ref> However, the UNCEs were found to be enriched for [[CpG site|CpG]], or highly [[Methylation|methylated]].<ref name=":3" /> This may indicate that there is some change to DNA structure in these regions, but this possibility has not been validated through testing.<ref name=":3" />
Perfect conservation of these long stretches of DNA is thought to imply [[evolution]]ary importance as these regions appear to have experienced strong [[Negative selection (natural selection)|negative (purifying) selection]] for 300-400 million years.<ref name="Sci04" /><ref name="Kat07" /><ref>{{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 Res. |volume=39 |issue=6 |pages=1967–79 |year=2011 |pmid=21062826 |pmc=3064809 |doi=10.1093/nar/gkq949 }}</ref> UCEs are hypothesized to be created through a reduced negative selection rate, a reduced mutation rate, also called a “cold spot” of evolution, or a combination of these two factors.<ref name="Sci04" /> Many studies have examined the validity of each hypothesis. The probability of finding ultra-conserved elements by chance (under [[Neutral theory of molecular evolution|neutral evolution]]) has been estimated at less than 10<sup>−22</sup> in 2.9 billion bases.<ref name="Sci04" /> 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.<ref name="Sci04" /> This fold change difference in mutation rates was consistent between humans, chimpanzees, and chickens.<ref name="Sci04" /> 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]].<ref name=":1">{{Cite journal |last=Habic |first=Anamarija |last2=Mattick |first2=John S. |last3=Calin |first3=George Adrian |last4=Krese |first4=Rok |last5=Konc |first5=Janez |last6=Kunej |first6=Tanja |date=2019-11-01 |title=Genetic Variations of Ultraconserved Elements in the Human Genome |url=https://www.liebertpub.com/doi/10.1089/omi.2019.0156 |journal=OMICS: A Journal of Integrative Biology |volume=23 |issue=11 |pages=549–559 |doi=10.1089/omi.2019.0156 |pmc=6857462 |pmid=31689173}}</ref> However, affected phenotypes were only caused by 112 of these [[Polymorphism (biology)|polymorphisms]], most of which were located in coding regions of the UCEs.<ref name=":1" /> 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<ref name=":2">{{Cite journal |last=Ahituv |first=Nadav |last2=Zhu |first2=Yiwen |last3=Visel |first3=Axel |last4=Holt |first4=Amy |last5=Afzal |first5=Veena |last6=Pennacchio |first6=Len A. |last7=Rubin |first7=Edward M. |date=2007-09-04 |title=Deletion of Ultraconserved Elements Yields Viable Mice |url=https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.0050234 |journal=PLOS Biology |language=en |volume=5 |issue=9 |pages=e234 |doi=10.1371/journal.pbio.0050234 |issn=1545-7885 |pmc=1964772 |pmid=17803355}}</ref>. Affected mice were fertile and targeted screens of the nearby coding genes showed no altered phenotype.<ref name=":2" /> 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.<ref name=":23">{{Cite journal |last=Snetkova |first=Valentina |last2=Ypsilanti |first2=Athena R. |last3=Akiyama |first3=Jennifer A. |last4=Mannion |first4=Brandon J. |last5=Plajzer-Frick |first5=Ingrid |last6=Novak |first6=Catherine S. |last7=Harrington |first7=Anne N. |last8=Pham |first8=Quan T. |last9=Kato |first9=Momoe |last10=Zhu |first10=Yiwen |last11=Godoy |first11=Janeth |last12=Meky |first12=Eman |last13=Hunter |first13=Riana D. |last14=Shi |first14=Marie |last15=Kvon |first15=Evgeny Z. |date=2021 |title=Ultraconserved enhancer function does not require perfect sequence conservation |url=https://www.nature.com/articles/s41588-021-00812-3 |journal=Nature Genetics |language=en |volume=53 |issue=4 |pages=521–528 |doi=10.1038/s41588-021-00812-3 |issn=1546-1718 |pmc=8038972 |pmid=33782603}}</ref> Computational analysis of human [[ultra-conserved noncoding elements]] (UCNEs) found that the regions are enriched for A-T sequences and are generally GC poor.<ref name=":3">{{Cite journal |last=Fedorova |first=Larisa |last2=Mulyar |first2=Oleh A. |last3=Lim |first3=Jan |last4=Fedorov |first4=Alexei |date=2022 |title=Nucleotide Composition of Ultra-Conserved Elements Shows Excess of GpC and Depletion of GG and CC Dinucleotides |url=https://www.mdpi.com/2073-4425/13/11/2053 |journal=Genes |language=en |volume=13 |issue=11 |pages=2053 |doi=10.3390/genes13112053 |issn=2073-4425 |pmc=9690913 |pmid=36360290}}</ref> However, the UNCEs were found to be enriched for [[CpG site|CpG]], or highly [[Methylation|methylated]].<ref name=":3" /> This may indicate that there is some change to DNA structure in these regions, but this possibility has not been validated through testing.<ref name=":3" />


==Functions==
==Functions==
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|miR-155/uc.160
|miR-155/uc.160
|Gastric CA
|Gastric CA
|Calin et al., 2007 <ref name=":02" />; Pang et al., 2018<ref name=":24">{{Cite journal |last=Pang |first=Wenjing |last2=Su |first2=Jiaojiao |last3=Wang |first3=Yalei |last4=Feng |first4=Hui |last5=Dai |first5=Xin |last6=Yuan |first6=Yaozong |last7=Chen |first7=Xi |last8=Yao |first8=Weiyan |date=2015-10 |title=Pancreatic cancer‐secreted miR‐155 implicates in the conversion from normal fibroblasts to cancer‐associated fibroblasts |url=https://onlinelibrary.wiley.com/doi/10.1111/cas.12747 |journal=Cancer Science |language=en |volume=106 |issue=10 |pages=1362–1369 |doi=10.1111/cas.12747 |issn=1347-9032 |pmc=PMC4638007 |pmid=26195069}}</ref>
|Calin et al., 2007 <ref name=":02" />; Pang et al., 2018 (4)
|-
|-
|miR-155/uc346A
|miR-155/uc346A
Line 97: Line 97:
|rs17105335
|rs17105335
|Amyotrophic lateral sclerosis
|Amyotrophic lateral sclerosis
|Cronin et al. (2008)<ref>{{Cite journal |last=Cronin |first=S. |last2=Berger |first2=S. |last3=Ding |first3=J. |last4=Schymick |first4=J. C |last5=Washecka |first5=N. |last6=Hernandez |first6=D. G. |last7=Greenway |first7=M. J. |last8=Bradley |first8=D. G. |last9=Traynor |first9=B. J. |last10=Hardiman |first10=O. |date=2007-11-16 |title=A genome-wide association study of sporadic ALS in a homogenous Irish population |url=https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddm361 |journal=Human Molecular Genetics |language=en |volume=17 |issue=5 |pages=768–774 |doi=10.1093/hmg/ddm361 |issn=0964-6906}}</ref>
|Cronin et al. (2008)<ref name=":25">{{Cite journal |last=Cronin |first=S. |last2=Berger |first2=S. |last3=Ding |first3=J. |last4=Schymick |first4=J. C |last5=Washecka |first5=N. |last6=Hernandez |first6=D. G. |last7=Greenway |first7=M. J. |last8=Bradley |first8=D. G. |last9=Traynor |first9=B. J. |last10=Hardiman |first10=O. |date=2007-11-16 |title=A genome-wide association study of sporadic ALS in a homogenous Irish population |url=https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddm361 |journal=Human Molecular Genetics |language=en |volume=17 |issue=5 |pages=768–774 |doi=10.1093/hmg/ddm361 |issn=0964-6906}}</ref>
|-
|-
|rs2020906
|rs2020906
Line 193: Line 193:
|rs997295
|rs997295
|Motion sickness; BMI
|Motion sickness; BMI
|De et al. (2015)<ref>{{Cite journal |last=De |first=Rishika |last2=Verma |first2=Shefali S. |last3=Drenos |first3=Fotios |last4=Holzinger |first4=Emily R. |last5=Holmes |first5=Michael V. |last6=Hall |first6=Molly A. |last7=Crosslin |first7=David R. |last8=Carrell |first8=David S. |last9=Hakonarson |first9=Hakon |last10=Jarvik |first10=Gail |last11=Larson |first11=Eric |last12=Pacheco |first12=Jennifer A. |last13=Rasmussen-Torvik |first13=Laura J. |last14=Moore |first14=Carrie B. |last15=Asselbergs |first15=Folkert W. |date=2015-06 |title=Identifying gene-gene interactions that are highly associated with Body Mass Index using Quantitative Multifactor Dimensionality Reduction (QMDR) |url=http://biodatamining.biomedcentral.com/articles/10.1186/s13040-015-0074-0 |journal=BioData Mining |language=en |volume=8 |issue=1 |pages=41 |doi=10.1186/s13040-015-0074-0 |issn=1756-0381 |pmc=PMC4678717 |pmid=26674805}}</ref>; Guo et al. (2013)<ref>{{Cite journal |last=Guo |first=Yiran |last2=Lanktree |first2=Matthew B. |last3=Taylor |first3=Kira C. |last4=Hakonarson |first4=Hakon |last5=Lange |first5=Leslie A. |last6=Keating |first6=Brendan J. |last7=The IBC 50K SNP array BMI Consortium |date=2013-01-01 |title=Gene-centric meta-analyses of 108 912 individuals confirm known body mass index loci and reveal three novel signals |url=https://academic.oup.com/hmg/article/22/1/184/614868 |journal=Human Molecular Genetics |language=en |volume=22 |issue=1 |pages=184–201 |doi=10.1093/hmg/dds396 |issn=1460-2083 |pmc=PMC3522401 |pmid=23001569}}</ref>; Hromatka et al. (2015)
|De et al. (2015); Guo et al. (2013); Hromatka et al. (2015)
|-
|-
|rs587777373
|rs587777373
Line 247: Line 247:
*[[Human accelerated regions]]
*[[Human accelerated regions]]
*[[Synteny]]
*[[Synteny]]

== Bibliography ==
This is where you will compile the bibliography for your Wikipedia assignment. Add the name and/or notes about what each source covers, then use the "Cite" button to generate the citation for that source.

* Pereira Zambalde (2019). Highlighting transcribed ultraconserved regions in human diseases.<ref name=":17" />
** This is a peer-reviewed scientific journal, so it should be a reliable source. It covers the topic in some depth, so it's helpful in establishing notability.
* De Grass (2010). Ultradeep sequencing of a human ultraconserved region reveals somatic and constitutional genomic instability. PLoS Biolog<ref name=":18" />
** This is a peer-reviewed scientific journal, so it should be a reliable source. It covers the topic in some depth, so it's helpful in establishing notability.
* Ferdin J (2013). HINCUTs in cancer: Hypoxia-induced noncoding ultraconserved transcripts. Cell Death Differ.<ref name=":16" />
** This is a peer-reviewed scientific journal, so it should be a reliable source for a specific fact. Since it only dedicates a few sentences to the topic, it can't be used to establish notability.
* Habic, A., Mattick, (2019). Genetic variations of ultraconserved elements in the human genome. ''OMICS: A Journal of Integrative Biology''<ref name=":1" />
** This is a peer-reviewed scientific journal, so it should be a reliable source. It covers the topic in some depth, so it's helpful in establishing notability.
* Calin, G. A. (2007). Ultraconserved regions encoding ncRNAs are altered in human leukemias and carcinomas. Cancer Cell.<ref name="Cal07" />
** This is a peer-reviewed scientific journal, so it should be a reliable source for a specific fact. Since it only dedicates a few sentences to the topic, it can't be used to establish notability.
* Sekino, Y (2017). Transcribed ultraconserved region Uc.63+ promotes resistance to docetaxel through regulation of androgen receptor signaling in prostate cancer. Oncotarget<ref name=":12" />
** This is a peer-reviewed scientific journal, so it should be a reliable source for a specific fact. Since it only dedicates a few sentences to the topic, it can't be used to establish notability.
* Goto, K. (2016). The transcribed-ultraconserved regions in prostate and gastric cancer: DNA hypermethylation and microRNA-associated regulation. Oncogene. <ref name=":22" />
** This is a peer-reviewed scientific journal, so it should be a reliable source for a specific fact. Since it only dedicates a few sentences to the topic, it can't be used to establish notability.
* Pang, L. (2018). Transcribed ultraconserved noncoding RNA uc.160 acts as a negative regulator in gastric cancer. American Journal of Translational Research.<ref name=":24" />
** This is a peer-reviewed scientific journal, so it should be a reliable source for a specific fact. Since it only dedicates a few sentences to the topic, it can't be used to establish notability.
* Liz, J. (2014). Regulation of pri-miRNA processing by a long noncoding RNA transcribed from an ultraconserved region. Molecular Cell.<ref name=":32" />
** This is a peer-reviewed scientific journal, so it should be a reliable source for a specific fact. Since it only dedicates a few sentences to the topic, it can't be used to establish notability.
* Guo, J. (2018). Ultraconserved element uc.372 drives hepatic lipid accumulation by suppressing miR-195/miR4668 maturation. Nature Communications.<ref name=":4" />
** This is a peer-reviewed scientific journal, so it should be a reliable source for a specific fact. Since it only dedicates a few sentences to the topic, it can't be used to establish notability.
* Xiao, L. (2018). Long noncoding RNA uc.173 promotes renewal of the intestinal mucosa by inducing degradation of microRNA 195. Gastroenterology.<ref name=":5" />
** This is a peer-reviewed scientific journal, so it should be a reliable source for a specific fact. Since it only dedicates a few sentences to the topic, it can't be used to establish notability.
* Wojcik, S. E. (2010). Non-codingRNA sequence variations in human chronic lymphocytic leukemia and colorectal cancer. Carcinogenesis.<ref name=":6" />
** This is a peer-reviewed scientific journal, so it should be a reliable source for a specific fact. Since it only dedicates a few sentences to the topic, it can't be used to establish notability.
* Nan, A. (2016). A transcribed ultraconserved noncoding RNA, Uc.173, is a key molecule for the inhibition of lead-induced neuronal apoptosis. Oncotarget.<ref>{{Cite journal |last=Nan |first=Aruo |last2=Zhou |first2=Xinke |last3=Chen |first3=Lijian |last4=Liu |first4=Meiling |last5=Zhang |first5=Nan |last6=Zhang |first6=Li |last7=Luo |first7=Yuanwei |last8=Liu |first8=Zhenzhong |last9=Dai |first9=Lijun |last10=Jiang |first10=Yiguo |date=2016-01-05 |title=A transcribed ultraconserved noncoding RNA, Uc.173, is a key molecule for the inhibition of lead-induced neuronal apoptosis |url=https://www.oncotarget.com/lookup/doi/10.18632/oncotarget.6590 |journal=Oncotarget |language=en |volume=7 |issue=1 |pages=112–124 |doi=10.18632/oncotarget.6590 |issn=1949-2553 |pmc=PMC4807986 |pmid=26683706}}</ref>
** This is a peer-reviewed scientific journal, so it should be a reliable source for a specific fact. Since it only dedicates a few sentences to the topic, it can't be used to establish notability.
* Wang, J. Y. (2018). Regulation of intestinal epithelial barrier function by long noncoding RNA. Molecular and Cellular Biology.<ref name=":8" />
** This is a peer-reviewed scientific journal, so it should be a reliable source for a specific fact. Since it only dedicates a few sentences to the topic, it can't be used to establish notability.
* Vannini, I. (2017). Transcribed ultraconserved region 339 promotes carcinogenesis by modulating tumor suppressor microRNAs. Nature Communications.<ref name=":9" />
** This is a peer-reviewed scientific journal, so it should be a reliable source for a specific fact. Since it only dedicates a few sentences to the topic, it can't be used to establish notability.
* Olivieri, M. (2016). Long non-coding RNA containing ultraconserved genomic region 8 promotes bladder cancer tumorigenesis. Oncotarget.<ref name=":10" />
** This is a peer-reviewed scientific journal, so it should be a reliable source for a specific fact. Since it only dedicates a few sentences to the topic, it can't be used to establish notability.
* Kottorou, A. E. (2018). Deregulation of methylation of transcribed-ultra conserved regions in colorectal cancer and their value for detection of adenomas and adenocarcinomas. Oncotarget.<ref name=":11" />
** This is a peer-reviewed scientific journal, so it should be a reliable source for a specific fact. Since it only dedicates a few sentences to the topic, it can't be used to establish notability.
* Lujambio, A. (2010). CpG Island hypermethylation-associated silencing of non-coding RNAs transcribed from ultraconserved regions in human cancer. Oncogene.<ref>{{Cite journal |last=Lujambio |first=A |last2=Portela |first2=A |last3=Liz |first3=J |last4=Melo |first4=S A |last5=Rossi |first5=S |last6=Spizzo |first6=R |last7=Croce |first7=C M |last8=Calin |first8=G A |last9=Esteller |first9=M |date=2010-12-02 |title=CpG island hypermethylation-associated silencing of non-coding RNAs transcribed from ultraconserved regions in human cancer |url=https://www.nature.com/articles/onc2010361 |journal=Oncogene |language=en |volume=29 |issue=48 |pages=6390–6401 |doi=10.1038/onc.2010.361 |issn=0950-9232 |pmc=PMC3007676 |pmid=20802525}}</ref>
** This is a peer-reviewed scientific journal, so it should be a reliable source for a specific fact. Since it only dedicates a few sentences to the topic, it can't be used to establish notability.
* Kajita, K. (2016). Ultraconserved region-containing transformer 2β4 controls senescence of colon cancer cells. Oncogene.<ref name=":13" />
** This is a peer-reviewed scientific journal, so it should be a reliable source for a specific fact. Since it only dedicates a few sentences to the topic, it can't be used to establish notability.
* Terreri, S. (2016). New cross-talk layer between ultraconserved non-coding RNAs, microRNAs and polycomb protein YY1 in bladder cancer. Genes (Basel).<ref name=":14" />
** This is a peer-reviewed scientific journal, so it should be a reliable source for a specific fact. Since it only dedicates a few sentences to the topic, it can't be used to establish notability.
* Snetkova, V. (2021) Ultraconserved enhancer function does not require perfect sequence conservation. Nature Genetics<ref name=":23" />
** This is a peer reviewed scientific journal. It is entirely focused on the topic of UCEs, so it can establish notability.
* Cronin S (2008). A genome-wide association study of sporadic ALS in a homogenous Irish population. Hum Mol Genet 17, 768–774<ref name=":25" />
* Hansen MF, Neckmann U, Lavik LAS, et al. (2014). A massive parallel sequencing workflow for diagnostic genetic testing of mismatch repair genes. Mol Genet Genomic Med 2, 186–200.


== References ==
== References ==

Revision as of 04:56, 8 December 2022

An ultra-conserved element (UCE) is a region of DNA that is identical in at least two different species.[1] One of the first studies of UCEs showed that certain human DNA sequences of length 200 nucleotides or greater were entirely conserved (identical nucleic acid sequence) in human, rats, and mice.[2] 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,[3] some ultra-conserved elements have been found to be transcriptionally active, giving non-coding RNA molecules.[4]

Evolution

Perfect conservation of these long stretches of DNA is thought to imply evolutionary importance as these regions appear to have experienced strong negative (purifying) selection for 300-400 million years.[2][3][5] UCEs are hypothesized to be created through a reduced negative selection rate, a reduced mutation rate, also called a “cold spot” of evolution, or a combination of these two factors.[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.[6] However, affected phenotypes were only caused by 112 of these polymorphisms, most of which were located in coding regions of the UCEs.[6] 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[7]. Affected mice were fertile and targeted screens of the nearby coding genes showed no altered phenotype.[7] 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.[8] Computational analysis of human ultra-conserved noncoding elements (UCNEs) found that the regions are enriched for A-T sequences and are generally GC poor.[9] However, the UNCEs were found to be enriched for CpG, or highly methylated.[9] This may indicate that there is some change to DNA structure in these regions, but this possibility has not been validated through testing.[9]

Functions

481 ultra-conserved elements have been identified in the human genome.[1][2] A database collecting genomic information about ultra-conserved elements (UCbase) that share 100% identity among human, mouse and rat is available at http://ucbase.unimore.it.[10] A small number of those which are transcribed have been connected with human carcinomas and leukemias.[4] For example, TUC338 is strongly upregulated in human hepatocellular carcinoma cells.[11] Indeed, UCEs are often affected by copy number variation in cancer cells,[12] much more than in healthy contexts,[12][13][14] suggesting that altering the copy number of ultraconserved elements may be deleterious and associated with cancer. A study comparing ultra-conserved elements between humans and the Japanese puffer fish Takifugu rubripes proposed an importance in vertebrate development.[15] Several ultra-conserved elements are located near transcriptional regulators or developmental genes.[2][16] Other functions include enhancing and splicing regulation.[1] Double-knockouts of UCEs near the ARX gene in mice caused a shrunken hippocampus in the brain.[17] The knockout effects are not lethal in laboratory mice, but could be in the wild.

Role in Disease

UCEs are categorically conserved among orthologous regions of several species’ genomes[18]. A large fraction of UCEs have been found to be transcriptionally active and involved in multiple human cancers[19]. The transcription of several UCEs is upregulated by hypoxia[20]. Research has demonstrated that T-UCRs have a tissue-specific expression, and a differential expression profile between tumors and other diseases[21]. In genomic instability conditions ultraconserved elements do not accumulate mutations in somatic cells[21]. UCRs tend to accumulate less mutations than flanking segments, in both neoplastic and non-neoplastic samples from persons with hereditary non-polyposis colorectal cancer[22]. There are 481 UCRs if excluding ribosomal DNA (rDNA regions) these range in size from 200 bp to 781 bp. UCRs were found on all chromosomes except for 21 and Y[21]. Genome-wide profiling reveals extensive transcription of UCRs in normal human tissues. Therefore, these regions are also named transcribed UCRs (T-UCRs). The T-UCRs are associated with several types of disease the majority being cancer related. Some of these are chronic lymphocytic leukemia (CLL), colorectal carcinoma (CRC), and hepatocellular carcinoma (HCC). UCE polymorphisms currently is not associated with diseases or phenotypic traits, but 112 are annotated as phenotype associated in the Ensembl genome browser[18].

TABLE 1 Regulation mechanisms of ultraconserved regions (UCRs) transcripts related to disease[21]:

miR/methylation/transcript factor associated with T-UCRs Disease References
miR-24-1/uc.160 Leukemia Calin et al., 2007 [19]
miR-130b/uc.63 Prostate CA Sekino et al., 2017 [23]
miR-153/uc.416 Colorectal and renal CA Goto et al., 2016 [24]; Sekino et al., 2017[23]
miR-155/uc.160 Gastric CA Calin et al., 2007 [19]; Pang et al., 2018[25]
miR-155/uc346A Leukemia Calin et al., 2007 [19]
mir-195/uc.283 Bladder CA Liz et al., 2014 [26]
miR-195, miR-4668/uc.372 Lipid metabolism Guo et al., 2018 [27]
mir-195/uc.173 Gastrointestinal tract Xiao et al., 2018[28]
miR-214/uc.276 Colorectal CA Wojcik et al., 2010[29]
miR-291a-3p/uc.173 Nervous system Nan et al., 2016 [30]
miR-29b/uc.173 Gastrointestinal tract J. Y. Wang et al., 2018 [31]
miR-339-3p, miR-663b-3p, miR-95-5p/uc.339 Lung CA Vannini et al., 2017[32]
miR-596/uc.8 Bladder CA Olivieri et al., 2016 [33]
DNA methylation/uc.160, uc.283, and uc.346 Colorectal CA Kottorou et al., 2018 [34]
DNA methylation/uc.158 + A, uc.160+, uc.241 + A, uc.283 + A, uc.346 + A Gastric CA Goto et al., 2016 [24]; Lujambio et al., 2010 [23]
Transcription factor SP1/uc.138 (TRA2β4) Colorectal CA Kajita et al., 2016 [35]
Transcription factor YY1/uc.8 Bladder CA Terreri et al., 2016 [36]

Table 2. An Overview of Phenotype-Associated Polymorphisms Within Ultraconserved Elements for Which Literature References Have Been Found[6]:

Polymorphism name Associated phenotype description Source
rs17105335 Amyotrophic lateral sclerosis Cronin et al. (2008)[37]
rs2020906 Lynch syndrome Hansen et al. (2014)[38]
rs10496382 Height Chiang et al. (2012)[39]
rs13382811 Severe myopia Khor et al. (2013)[40]
rs104893634 Vertical talus congenital Dobbs et al. (2006)[41]; Shrimpton et al. (2004)[42]
rs2307121 Central corneal thickness Lu et al. (2013)[43]
rs587777277 Bosch-Boonstra-Schaaf optic atrophy syndrome Bosch et al. (2014)[44]
rs587777275 Bosch-Boonstra-Schaaf optic atrophy syndrome Bosch et al. (2014)[44]
rs587777274 Bosch-Boonstra-Schaaf optic atrophy syndrome Bosch et al. (2014)[44]
rs387906239 Familial adenomatous polyposis 1 attenuated Soravia et al. (1999)[45]
rs3797704 No association with breast cancer Chang et al. (2016)[46]
rs387906232 Familial adenomatous polyposis 1 Fodde et al. (1992)[47]
rs387906237 Familial adenomatous polyposis 1 attenuated Curia et al. (1998)[48]
rs121434591 Distal myopathy Senderek et al. (2009)[49]
rs587777300 Amyotrophic lateral sclerosis 21 Johnson et al. (2014)[50]
rs863223403 Au-Kline syndrome Au et al. (2015)[51]
rs121917900 Cockayne syndrome B Mallery et al. (1998)[52]
rs75462234 Papillorenal syndrome Schimmenti et al. (1999)[53]
rs77453353 Renal coloboma syndrome Amiel et al. (2000)[54]
rs76675173 Papillorenal syndrome Schimmenti et al. (1997)[55]
rs587777708 Focal segmental glomerulosclerosis 7 Barua et al. (2014)[56]
rs11190870 Adolescent idiopathic scoliosis, no association with breast cancer Chettier et al. (2015)[57]; Gao et al. (2013)[58]; Grauers et al. (2015)[59]; Jiang et al. (2013)[60]; Londono et al. (2014)[61]; Miyake et al. (2013)[62]; Shen et al. (2011)[63]; Takahashi et al. (2011)[64]
rs724159963 Peroxisomal fatty acyl-CoA reductase 1 disorder Buchert et al. (2014)[65]
rs16932455 Capecitabine sensitivity O’Donnell et al. (2012)[66]
rs997295 Motion sickness; BMI De et al. (2015)[67]; Guo et al. (2013)[68]; Hromatka et al. (2015)
rs587777373 Congenital heart defects multiple types 4 Al Turki et al. (2014)[69]
rs398123839 Duchenne muscular dystrophy Hofstra et al. (2004)[70]; Roberts et al. (1992)[71]
rs863224976 Becker muscular dystrophy Tuffery-Giraud et al. (2005)[72]
rs132630295 Spastic paraplegia 2 X-linked Gorman et al. (2007)[73]
rs132630287 Spastic paraplegia 2 X-linked Saugier-Veber et al. (1994)[74]
rs132630292 Pelizaeus/Merzbacher disease atypical Hodes et al. (1997)[75]
rs137852350 Mental retardation X-linked 94 Wu et al. (2007)[76]
rs122459149 Emery-Dreifuss muscular dystrophy 6 X-linked Gueneau et al. (2009)[77]; Knoblauch et al. (2010)[78]
rs122458141 Myopathy X-linked with postural muscle atrophy Schoser et al. (2009)[79]; Windpassinger et al. (2008)[80]
rs786200914 Myopathy X-linked with postural muscle atrophy Schoser et al. (2009)[79]
rs267606811 Myopathy X-linked with postural muscle atrophy Windpassinger et al. (2008)[80]
rs62621672 Rett syndrome (nonpathogenic variant) Zahorakova et al. (2007)[81]

See also

Bibliography

This is where you will compile the bibliography for your Wikipedia assignment. Add the name and/or notes about what each source covers, then use the "Cite" button to generate the citation for that source.

  • Pereira Zambalde (2019). Highlighting transcribed ultraconserved regions in human diseases.[21]
    • This is a peer-reviewed scientific journal, so it should be a reliable source. It covers the topic in some depth, so it's helpful in establishing notability.
  • De Grass (2010). Ultradeep sequencing of a human ultraconserved region reveals somatic and constitutional genomic instability. PLoS Biolog[22]
    • This is a peer-reviewed scientific journal, so it should be a reliable source. It covers the topic in some depth, so it's helpful in establishing notability.
  • Ferdin J (2013). HINCUTs in cancer: Hypoxia-induced noncoding ultraconserved transcripts. Cell Death Differ.[20]
    • This is a peer-reviewed scientific journal, so it should be a reliable source for a specific fact. Since it only dedicates a few sentences to the topic, it can't be used to establish notability.
  • Habic, A., Mattick, (2019). Genetic variations of ultraconserved elements in the human genome. OMICS: A Journal of Integrative Biology[6]
    • This is a peer-reviewed scientific journal, so it should be a reliable source. It covers the topic in some depth, so it's helpful in establishing notability.
  • Calin, G. A. (2007). Ultraconserved regions encoding ncRNAs are altered in human leukemias and carcinomas. Cancer Cell.[4]
    • This is a peer-reviewed scientific journal, so it should be a reliable source for a specific fact. Since it only dedicates a few sentences to the topic, it can't be used to establish notability.
  • Sekino, Y (2017). Transcribed ultraconserved region Uc.63+ promotes resistance to docetaxel through regulation of androgen receptor signaling in prostate cancer. Oncotarget[23]
    • This is a peer-reviewed scientific journal, so it should be a reliable source for a specific fact. Since it only dedicates a few sentences to the topic, it can't be used to establish notability.
  • Goto, K. (2016). The transcribed-ultraconserved regions in prostate and gastric cancer: DNA hypermethylation and microRNA-associated regulation. Oncogene. [24]
    • This is a peer-reviewed scientific journal, so it should be a reliable source for a specific fact. Since it only dedicates a few sentences to the topic, it can't be used to establish notability.
  • Pang, L. (2018). Transcribed ultraconserved noncoding RNA uc.160 acts as a negative regulator in gastric cancer. American Journal of Translational Research.[25]
    • This is a peer-reviewed scientific journal, so it should be a reliable source for a specific fact. Since it only dedicates a few sentences to the topic, it can't be used to establish notability.
  • Liz, J. (2014). Regulation of pri-miRNA processing by a long noncoding RNA transcribed from an ultraconserved region. Molecular Cell.[26]
    • This is a peer-reviewed scientific journal, so it should be a reliable source for a specific fact. Since it only dedicates a few sentences to the topic, it can't be used to establish notability.
  • Guo, J. (2018). Ultraconserved element uc.372 drives hepatic lipid accumulation by suppressing miR-195/miR4668 maturation. Nature Communications.[27]
    • This is a peer-reviewed scientific journal, so it should be a reliable source for a specific fact. Since it only dedicates a few sentences to the topic, it can't be used to establish notability.
  • Xiao, L. (2018). Long noncoding RNA uc.173 promotes renewal of the intestinal mucosa by inducing degradation of microRNA 195. Gastroenterology.[28]
    • This is a peer-reviewed scientific journal, so it should be a reliable source for a specific fact. Since it only dedicates a few sentences to the topic, it can't be used to establish notability.
  • Wojcik, S. E. (2010). Non-codingRNA sequence variations in human chronic lymphocytic leukemia and colorectal cancer. Carcinogenesis.[29]
    • This is a peer-reviewed scientific journal, so it should be a reliable source for a specific fact. Since it only dedicates a few sentences to the topic, it can't be used to establish notability.
  • Nan, A. (2016). A transcribed ultraconserved noncoding RNA, Uc.173, is a key molecule for the inhibition of lead-induced neuronal apoptosis. Oncotarget.[82]
    • This is a peer-reviewed scientific journal, so it should be a reliable source for a specific fact. Since it only dedicates a few sentences to the topic, it can't be used to establish notability.
  • Wang, J. Y. (2018). Regulation of intestinal epithelial barrier function by long noncoding RNA. Molecular and Cellular Biology.[31]
    • This is a peer-reviewed scientific journal, so it should be a reliable source for a specific fact. Since it only dedicates a few sentences to the topic, it can't be used to establish notability.
  • Vannini, I. (2017). Transcribed ultraconserved region 339 promotes carcinogenesis by modulating tumor suppressor microRNAs. Nature Communications.[32]
    • This is a peer-reviewed scientific journal, so it should be a reliable source for a specific fact. Since it only dedicates a few sentences to the topic, it can't be used to establish notability.
  • Olivieri, M. (2016). Long non-coding RNA containing ultraconserved genomic region 8 promotes bladder cancer tumorigenesis. Oncotarget.[33]
    • This is a peer-reviewed scientific journal, so it should be a reliable source for a specific fact. Since it only dedicates a few sentences to the topic, it can't be used to establish notability.
  • Kottorou, A. E. (2018). Deregulation of methylation of transcribed-ultra conserved regions in colorectal cancer and their value for detection of adenomas and adenocarcinomas. Oncotarget.[34]
    • This is a peer-reviewed scientific journal, so it should be a reliable source for a specific fact. Since it only dedicates a few sentences to the topic, it can't be used to establish notability.
  • Lujambio, A. (2010). CpG Island hypermethylation-associated silencing of non-coding RNAs transcribed from ultraconserved regions in human cancer. Oncogene.[83]
    • This is a peer-reviewed scientific journal, so it should be a reliable source for a specific fact. Since it only dedicates a few sentences to the topic, it can't be used to establish notability.
  • Kajita, K. (2016). Ultraconserved region-containing transformer 2β4 controls senescence of colon cancer cells. Oncogene.[35]
    • This is a peer-reviewed scientific journal, so it should be a reliable source for a specific fact. Since it only dedicates a few sentences to the topic, it can't be used to establish notability.
  • Terreri, S. (2016). New cross-talk layer between ultraconserved non-coding RNAs, microRNAs and polycomb protein YY1 in bladder cancer. Genes (Basel).[36]
    • This is a peer-reviewed scientific journal, so it should be a reliable source for a specific fact. Since it only dedicates a few sentences to the topic, it can't be used to establish notability.
  • Snetkova, V. (2021) Ultraconserved enhancer function does not require perfect sequence conservation. Nature Genetics[8]
    • This is a peer reviewed scientific journal. It is entirely focused on the topic of UCEs, so it can establish notability.
  • Cronin S (2008). A genome-wide association study of sporadic ALS in a homogenous Irish population. Hum Mol Genet 17, 768–774[37]
  • Hansen MF, Neckmann U, Lavik LAS, et al. (2014). A massive parallel sequencing workflow for diagnostic genetic testing of mismatch repair genes. Mol Genet Genomic Med 2, 186–200.

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Ryu et al. BMC Evolutionary Biology 2012 http://www.biomedcentral.com/1471-2148/12/236 Open access icon

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