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strong negative (purifying) selection for 300-400 million years.[2][5][7] More recently, this assumption has been replaced by two main hypotheses: that UCEs are created through a reduced negative selection rate, or through reduced mutation rates, also known as a “cold spot” of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]

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

  1. 1 2 3 4 5 6 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.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 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 10.1.1.380.9305. doi:10.1126/science.1098119. PMID 15131266. S2CID 2790337.
  3. 1 2 3 Pereira Zambalde E, Mathias C, Rodrigues AC, de Souza Fonseca Ribeiro EM, Fiori Gradia D, Calin GA, Carvalho de Oliveira J (March 2020). "Highlighting transcribed ultraconserved regions in human diseases". Wiley Interdisciplinary Reviews. RNA. 11 (2): e1567. doi:10.1002/wrna.1567. PMID 31489780. S2CID 201844414.
  4. ↑ Taccioli C, Fabbri E, Visone R, Volinia S, Calin GA, Fong LY, et al. (January 2009). "UCbase & miRfunc: a database of ultraconserved sequences and microRNA function". Nucleic Acids Research. 37 (Database issue): D41–D48. doi:10.1093/nar/gkn702. PMC 2686429. PMID 18945703.
  5. 1 2 Katzman S, Kern AD, Bejerano G, Fewell G, Fulton L, Wilson RK, et al. (August 2007). "Human genome ultraconserved elements are ultraselected". Science. 317 (5840): 915. Bibcode:2007Sci...317..915K. doi:10.1126/science.1142430. PMID 17702936. S2CID 35322654.
  6. 1 2 3 4 5 6 Calin GA, Liu CG, Ferracin M, Hyslop T, Spizzo R, Sevignani C, et al. (September 2007). "Ultraconserved regions encoding ncRNAs are altered in human leukemias and carcinomas". Cancer Cell. 12 (3): 215–229. doi:10.1016/j.ccr.2007.07.027. PMID 17785203.
  7. ↑ Sathirapongsasuti JF, Sathira N, Suzuki Y, Huttenhower C, Sugano S (March 2011). "Ultraconserved cDNA segments in the human transcriptome exhibit resistance to folding and implicate function in translation and alternative splicing". Nucleic Acids Research. 39 (6): 1967–1979. doi:10.1093/nar/gkq949. PMC 3064809. PMID 21062826.
  8. 1 2 3 Habic A, Mattick JS, Calin GA, Krese R, Konc J, Kunej T (November 2019). "Genetic Variations of Ultraconserved Elements in the Human Genome". Omics. 23 (11): 549–559. doi:10.1089/omi.2019.0156. PMC 6857462. PMID 31689173.
  9. 1 2 Ahituv N, Zhu Y, Visel A, Holt A, Afzal V, Pennacchio LA, Rubin EM (September 2007). "Deletion of ultraconserved elements yields viable mice". PLOS Biology. 5 (9): e234. doi:10.1371/journal.pbio.0050234. PMC 1964772. PMID 17803355.
  10. ↑ Snetkova V, Ypsilanti AR, Akiyama JA, Mannion BJ, Plajzer-Frick I, Novak CS, et al. (April 2021). "Ultraconserved enhancer function does not require perfect sequence conservation". Nature Genetics. 53 (4): 521–528. doi:10.1038/s41588-021-00812-3. PMC 8038972. PMID 33782603.
  11. 1 2 3 4 Fedorova L, Mulyar OA, Lim J, Fedorov A (November 2022). "Nucleotide Composition of Ultra-Conserved Elements Shows Excess of GpC and Depletion of GG and CC Dinucleotides". Genes. 13 (11): 2053. doi:10.3390/genes13112053. PMC 9690913. PMID 36360290.
  12. 1 2 Saygin D, Tabib T, Bittar HE, Valenzi E, Sembrat J, Chan SY, et al. (January 2005). "Transcriptional profiling of lung cell populations in idiopathic pulmonary arterial hypertension". Pulmonary Circulation. 10 (1): e19. doi:10.1371/journal.pbio.0030019. PMC 544543. PMID 32166015. Open access icon
  13. ↑ Woolfe A, Goodson M, Goode DK, Snell P, McEwen GK, Vavouri T, et al. (January 2005). "Highly conserved non-coding sequences are associated with vertebrate development". PLOS Biology. 3 (1): e7. doi:10.1371/journal.pbio.0030007. PMC 526512. PMID 15630479. Open access icon
  14. ↑ Elizabeth Pennisi (2017) Mysterious unchanging DNA finds a purpose in life, Science 02 Jun 2017]
  15. ↑ Braconi C, Valeri N, Kogure T, Gasparini P, Huang N, Nuovo GJ, et al. (January 2011). "Expression and functional role of a transcribed noncoding RNA with an ultraconserved element in hepatocellular carcinoma". Proceedings of the National Academy of Sciences of the United States of America. 108 (2): 786–791. Bibcode:2011PNAS..108..786B. doi:10.1073/pnas.1011098108. PMC 3021052. PMID 21187392.
  16. ↑ McCole RB, Fonseka CY, Koren A, Wu CT (October 2014). "Abnormal dosage of ultraconserved elements is highly disfavored in healthy cells but not cancer cells". PLOS Genetics. 10 (10): e1004646. doi:10.1371/journal.pgen.1004646. PMC 4207606. PMID 25340765.
  17. ↑ Derti A, Roth FP, Church GM, Wu CT (October 2006). "Mammalian ultraconserved elements are strongly depleted among segmental duplications and copy number variants". Nature Genetics. 38 (10): 1216–1220. doi:10.1038/ng1888. PMID 16998490. S2CID 10671674.
  18. ↑ Chiang CW, Derti A, Schwartz D, Chou MF, Hirschhorn JN, Wu CT (December 2008). "Ultraconserved elements: analyses of dosage sensitivity, motifs and boundaries". Genetics. 180 (4): 2277–2293. doi:10.1534/genetics.108.096537. PMC 2600958. PMID 18957701.
  19. ↑ De Grassi A, Segala C, Iannelli F, Volorio S, Bertario L, Radice P, et al. (January 2010). Hastie N (ed.). "Ultradeep sequencing of a human ultraconserved region reveals somatic and constitutional genomic instability". PLOS Biology. 8 (1): e1000275. doi:10.1371/journal.pbio.1000275. PMC 2794366. PMID 20052272.
  20. 1 2 3 Sekino Y, Sakamoto N, Goto K, Honma R, Shigematsu Y, Sentani K, et al. (November 2017). "Transcribed ultraconserved region Uc.63+ promotes resistance to docetaxel through regulation of androgen receptor signaling in prostate cancer". Oncotarget. 8 (55): 94259–94270. doi:10.18632/oncotarget.21688. PMC 5706872. PMID 29212226.
  21. 1 2 Goto K, Ishikawa S, Honma R, Tanimoto K, Sakamoto N, Sentani K, et al. (July 2016). "The transcribed-ultraconserved regions in prostate and gastric cancer: DNA hypermethylation and microRNA-associated regulation" (PDF). Oncogene. 35 (27): 3598–3606. doi:10.1038/onc.2015.445. PMID 26640143. S2CID 8494774.
  22. ↑ Pang W, Su J, Wang Y, Feng H, Dai X, Yuan Y, et al. (October 2015). "Pancreatic cancer-secreted miR-155 implicates in the conversion from normal fibroblasts to cancer-associated fibroblasts". Cancer Science. 106 (10): 1362–1369. doi:10.1111/cas.12747. PMC 4638007. PMID 26195069.
  23. ↑ Liz J, Portela A, Soler M, Gómez A, Ling H, Michlewski G, et al. (July 2014). "Regulation of pri-miRNA processing by a long noncoding RNA transcribed from an ultraconserved region". Molecular Cell. 55 (1): 138–147. doi:10.1016/j.molcel.2014.05.005. PMID 24910097.
  24. ↑ Guo J, Fang W, Sun L, Lu Y, Dou L, Huang X, et al. (February 2018). "Ultraconserved element uc.372 drives hepatic lipid accumulation by suppressing miR-195/miR4668 maturation". Nature Communications. 9 (1): 612. Bibcode:2018NatCo...9..612G. doi:10.1038/s41467-018-03072-8. PMC 5807361. PMID 29426937.
  25. ↑ Xiao L, Wu J, Wang JY, Chung HK, Kalakonda S, Rao JN, et al. (February 2018). "Long Noncoding RNA uc.173 Promotes Renewal of the Intestinal Mucosa by Inducing Degradation of MicroRNA 195". Gastroenterology. 154 (3): 599–611. doi:10.1053/j.gastro.2017.10.009. PMC 5811324. PMID 29042220.
  26. ↑ Wojcik SE, Rossi S, Shimizu M, Nicoloso MS, Cimmino A, Alder H, et al. (February 2010). "Non-codingRNA sequence variations in human chronic lymphocytic leukemia and colorectal cancer". Carcinogenesis. 31 (2): 208–215. doi:10.1093/carcin/bgp209. PMC 2812567. PMID 19926640.
  27. ↑ Nan A, Zhou X, Chen L, Liu M, Zhang N, Zhang L, et al. (January 2016). "A transcribed ultraconserved noncoding RNA, Uc.173, is a key molecule for the inhibition of lead-induced neuronal apoptosis". Oncotarget. 7 (1): 112–124. doi:10.18632/oncotarget.6590. PMC 4807986. PMID 26683706.
  28. ↑ Wang JY, Cui YH, Xiao L, Chung HK, Zhang Y, Rao JN, et al. (July 2018). "Regulation of Intestinal Epithelial Barrier Function by Long Noncoding RNA uc.173 through Interaction with MicroRNA 29b". Molecular and Cellular Biology. 38 (13): e00010–18. doi:10.1128/MCB.00010-18. PMC 6002690. PMID 29632078.
  29. ↑ Vannini I, Wise PM, Challagundla KB, Plousiou M, Raffini M, Bandini E, et al. (November 2017). "Transcribed ultraconserved region 339 promotes carcinogenesis by modulating tumor suppressor microRNAs". Nature Communications. 8 (1): 1801. Bibcode:2017NatCo...8.1801V. doi:10.1038/s41467-017-01562-9. PMC 5703849. PMID 29180617.
  30. ↑ Olivieri M, Ferro M, Terreri S, Durso M, Romanelli A, Avitabile C, et al. (April 2016). "Long non-coding RNA containing ultraconserved genomic region 8 promotes bladder cancer tumorigenesis". Oncotarget. 7 (15): 20636–20654. doi:10.18632/oncotarget.7833. PMC 4991481. PMID 26943042.
  31. ↑ Kottorou AE, Antonacopoulou AG, Dimitrakopoulos FD, Diamantopoulou G, Sirinian C, Kalofonou M, et al. (April 2018). "Deregulation of methylation of transcribed-ultra conserved regions in colorectal cancer and their value for detection of adenomas and adenocarcinomas". Oncotarget. 9 (30): 21411–21428. doi:10.18632/oncotarget.25115. PMC 5940382. PMID 29765549.
  32. ↑ Kajita K, Kuwano Y, Satake Y, Kano S, Kurokawa K, Akaike Y, et al. (April 2016). "Ultraconserved region-containing Transformer 2β4 controls senescence of colon cancer cells". Oncogenesis. 5 (4): e213. doi:10.1038/oncsis.2016.18. PMC 4848834. PMID 27043659.
  33. ↑ Terreri S, Durso M, Colonna V, Romanelli A, Terracciano D, Ferro M, et al. (December 2016). "New Cross-Talk Layer between Ultraconserved Non-Coding RNAs, MicroRNAs and Polycomb Protein YY1 in Bladder Cancer". Genes. 7 (12): 127. doi:10.3390/genes7120127. PMC 5192503. PMID 27983635.
  34. ↑ Cronin S, Berger S, Ding J, Schymick JC, Washecka N, Hernandez DG, et al. (March 2008). "A genome-wide association study of sporadic ALS in a homogenous Irish population". Human Molecular Genetics. 17 (5): 768–774. doi:10.1093/hmg/ddm361. PMID 18057069.
  35. ↑ Hansen MF, Neckmann U, Lavik LA, Vold T, Gilde B, Toft RK, Sjursen W (March 2014). "A massive parallel sequencing workflow for diagnostic genetic testing of mismatch repair genes". Molecular Genetics & Genomic Medicine. 2 (2): 186–200. doi:10.1002/mgg3.62. PMC 3960061. PMID 24689082.
  36. ↑ Chiang CW, Liu CT, Lettre G, Lange LA, Jorgensen NW, Keating BJ, et al. (September 2012). "Ultraconserved elements in the human genome: association and transmission analyses of highly constrained single-nucleotide polymorphisms". Genetics. 192 (1): 253–266. doi:10.1534/genetics.112.141945. PMC 3430540. PMID 22714408.
  37. ↑ Khor CC, Miyake M, Chen LJ, Shi Y, Barathi VA, Qiao F, et al. (December 2013). "Genome-wide association study identifies ZFHX1B as a susceptibility locus for severe myopia". Human Molecular Genetics. 22 (25): 5288–5294. doi:10.1093/hmg/ddt385. PMID 23933737.
  38. 1 2 Dobbs MB, Gurnett CA, Pierce B, Exner GU, Robarge J, Morcuende JA, et al. (March 2006). "HOXD10 M319K mutation in a family with isolated congenital vertical talus". Journal of Orthopaedic Research. 24 (3): 448–453. doi:10.1002/jor.20052. PMID 16450407. S2CID 28670628.
  39. ↑ Lu Y, Vitart V, Burdon KP, Khor CC, Bykhovskaya Y, Mirshahi A, et al. (February 2013). "Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus". Nature Genetics. 45 (2): 155–163. doi:10.1038/ng.2506. PMC 3720123. PMID 23291589.
  40. 1 2 3 Bosch DG, Boonstra FN, Gonzaga-Jauregui C, Xu M, de Ligt J, Jhangiani S, et al. (February 2014). "NR2F1 mutations cause optic atrophy with intellectual disability". American Journal of Human Genetics. 94 (2): 303–309. doi:10.1016/j.ajhg.2014.01.002. PMC 3928641. PMID 24462372.
  41. ↑ Soravia C, Sugg SL, Berk T, Mitri A, Cheng H, Gallinger S, et al. (January 1999). "Familial adenomatous polyposis-associated thyroid cancer: a clinical, pathological, and molecular genetics study". The American Journal of Pathology. 154 (1): 127–135. doi:10.1016/S0002-9440(10)65259-5. PMC 1853451. PMID 9916927.
  42. ↑ Chang YS, Lin CY, Yang SF, Ho CM, Chang JG (2016-03-28). "Analysing the mutational status of adenomatous polyposis coli (APC) gene in breast cancer". Cancer Cell International. 16: 23. doi:10.1186/s12935-016-0297-2. PMC 4810512. PMID 27028212.
  43. ↑ Fodde R, van der Luijt R, Wijnen J, Tops C, van der Klift H, van Leeuwen-Cornelisse I, et al. (August 1992). "Eight novel inactivating germ line mutations at the APC gene identified by denaturing gradient gel electrophoresis". Genomics. 13 (4): 1162–1168. doi:10.1016/0888-7543(92)90032-n. PMID 1324223.
  44. ↑ Curia MC, Esposito DL, Aceto G, Palmirotta R, Crognale S, Valanzano R, et al. (1998). "Transcript dosage effect in familial adenomatous polyposis: model offered by two kindreds with exon 9 APC gene mutations". Human Mutation. 11 (3): 197–201. doi:10.1002/(SICI)1098-1004(1998)11:3<197::AID-HUMU3>3.0.CO;2-F. PMID 9521420. S2CID 7241178.
  45. ↑ Johnson JO, Pioro EP, Boehringer A, Chia R, Feit H, Renton AE, et al. (May 2014). "Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis". Nature Neuroscience. 17 (5): 664–666. doi:10.1038/nn.3688. PMC 4000579. PMID 24686783.
  46. ↑ Au PY, You J, Caluseriu O, Schwartzentruber J, Majewski J, Bernier FP, et al. (October 2015). "GeneMatcher aids in the identification of a new malformation syndrome with intellectual disability, unique facial dysmorphisms, and skeletal and connective tissue abnormalities caused by de novo variants in HNRNPK". Human Mutation. 36 (10): 1009–1014. doi:10.1002/humu.22837. PMC 4589226. PMID 26173930.
  47. ↑ Mallery DL, Tanganelli B, Colella S, Steingrimsdottir H, van Gool AJ, Troelstra C, et al. (January 1998). "Molecular analysis of mutations in the CSB (ERCC6) gene in patients with Cockayne syndrome". American Journal of Human Genetics. 62 (1): 77–85. doi:10.1086/301686. PMC 1376810. PMID 9443879.
  48. ↑ Schimmenti LA, Shim HH, Wirtschafter JD, Panzarino VA, Kashtan CE, Kirkpatrick SJ, et al. (1999). "Homonucleotide expansion and contraction mutations of PAX2 and inclusion of Chiari 1 malformation as part of renal-coloboma syndrome". Human Mutation. 14 (5): 369–376. doi:10.1002/(SICI)1098-1004(199911)14:5<369::AID-HUMU2>3.0.CO;2-E. PMID 10533062. S2CID 25564812.
  49. ↑ Amiel J, Audollent S, Joly D, Dureau P, Salomon R, Tellier AL, et al. (November 2000). "PAX2 mutations in renal-coloboma syndrome: mutational hotspot and germline mosaicism". European Journal of Human Genetics. 8 (11): 820–826. doi:10.1038/sj.ejhg.5200539. PMID 11093271. S2CID 30359554.
  50. ↑ Schimmenti LA, Cunliffe HE, McNoe LA, Ward TA, French MC, Shim HH, et al. (April 1997). "Further delineation of renal-coloboma syndrome in patients with extreme variability of phenotype and identical PAX2 mutations". American Journal of Human Genetics. 60 (4): 869–878. PMC 1712484. PMID 9106533.
  51. ↑ Barua M, Stellacci E, Stella L, Weins A, Genovese G, Muto V, et al. (September 2014). "Mutations in PAX2 associate with adult-onset FSGS". Journal of the American Society of Nephrology. 25 (9): 1942–1953. doi:10.1681/ASN.2013070686. PMC 4147972. PMID 24676634.
  52. ↑ Chettier R, Nelson L, Ogilvie JW, Albertsen HM, Ward K (2015-02-12). Fang S (ed.). "Haplotypes at LBX1 have distinct inheritance patterns with opposite effects in adolescent idiopathic scoliosis". PLOS ONE. 10 (2): e0117708. Bibcode:2015PLoSO..1017708C. doi:10.1371/journal.pone.0117708. PMC 4326419. PMID 25675428.
  53. ↑ Gao W, Peng Y, Liang G, Liang A, Ye W, Zhang L, et al. (2013-01-04). "Association between common variants near LBX1 and adolescent idiopathic scoliosis replicated in the Chinese Han population". PLOS ONE. 8 (1): e53234. Bibcode:2013PLoSO...853234G. doi:10.1371/journal.pone.0053234. PMC 3537668. PMID 23308168.
  54. ↑ Grauers A, Wang J, Einarsdottir E, Simony A, Danielsson A, Åkesson K, et al. (October 2015). "Candidate gene analysis and exome sequencing confirm LBX1 as a susceptibility gene for idiopathic scoliosis". The Spine Journal. 15 (10): 2239–2246. doi:10.1016/j.spinee.2015.05.013. hdl:10616/44765. PMID 25987191.
  55. ↑ Jiang H, Qiu X, Dai J, Yan H, Zhu Z, Qian B, Qiu Y (February 2013). "Association of rs11190870 near LBX1 with adolescent idiopathic scoliosis susceptibility in a Han Chinese population". European Spine Journal. 22 (2): 282–286. doi:10.1007/s00586-012-2532-4. PMC 3555620. PMID 23096252.
  56. ↑ Londono D, Kou I, Johnson TA, Sharma S, Ogura Y, Tsunoda T, et al. (June 2014). "A meta-analysis identifies adolescent idiopathic scoliosis association with LBX1 locus in multiple ethnic groups". Journal of Medical Genetics. 51 (6): 401–406. doi:10.1136/jmedgenet-2013-102067. PMID 24721834. S2CID 23646905.
  57. ↑ Miyake A, Kou I, Takahashi Y, Johnson TA, Ogura Y, Dai J, et al. (2013-09-04). "Identification of a susceptibility locus for severe adolescent idiopathic scoliosis on chromosome 17q24.3". PLOS ONE. 8 (9): e72802. Bibcode:2013PLoSO...872802M. doi:10.1371/journal.pone.0072802. PMC 3762929. PMID 24023777.
  58. ↑ Jiang Y, Ben Q, Shen H, Lu W, Zhang Y, Zhu J (November 2011). "Diabetes mellitus and incidence and mortality of colorectal cancer: a systematic review and meta-analysis of cohort studies". European Journal of Epidemiology. 26 (11): 863–876. doi:10.1007/s10654-011-9617-y. PMID 21938478. S2CID 99605.
  59. ↑ Takahashi Y, Kou I, Takahashi A, Johnson TA, Kono K, Kawakami N, et al. (October 2011). "A genome-wide association study identifies common variants near LBX1 associated with adolescent idiopathic scoliosis". Nature Genetics. 43 (12): 1237–1240. doi:10.1038/ng.974. PMID 22019779. S2CID 7533298.
  60. ↑ Buchert R, Tawamie H, Smith C, Uebe S, Innes AM, Al Hallak B, et al. (November 2014). "A peroxisomal disorder of severe intellectual disability, epilepsy, and cataracts due to fatty acyl-CoA reductase 1 deficiency". American Journal of Human Genetics. 95 (5): 602–610. doi:10.1016/j.ajhg.2014.10.003. PMC 4225589. PMID 25439727.
  61. ↑ O'Donnell PH, Stark AL, Gamazon ER, Wheeler HE, McIlwee BE, Gorsic L, et al. (August 2012). "Identification of novel germline polymorphisms governing capecitabine sensitivity". Cancer. 118 (16): 4063–4073. doi:10.1002/cncr.26737. PMC 3413892. PMID 22864933.
  62. ↑ De R, Verma SS, Drenos F, Holzinger ER, Holmes MV, Hall MA, et al. (June 2015). "Identifying gene-gene interactions that are highly associated with Body Mass Index using Quantitative Multifactor Dimensionality Reduction (QMDR)". BioData Mining. 8 (1): 41. doi:10.1186/s13040-015-0074-0. PMC 4678717. PMID 26674805.
  63. ↑ Guo Y, Lanktree MB, Taylor KC, Hakonarson H, Lange LA, Keating BJ (January 2013). "Gene-centric meta-analyses of 108 912 individuals confirm known body mass index loci and reveal three novel signals". Human Molecular Genetics. 22 (1): 184–201. doi:10.1093/hmg/dds396. PMC 3522401. PMID 23001569.
  64. ↑ Hromatka BS, Tung JY, Kiefer AK, Do CB, Hinds DA, Eriksson N (May 2015). "Genetic variants associated with motion sickness point to roles for inner ear development, neurological processes and glucose homeostasis". Human Molecular Genetics. 24 (9): 2700–2708. doi:10.1093/hmg/ddv028. PMC 4383869. PMID 25628336.
  65. ↑ Al Turki S, Manickaraj AK, Mercer CL, Gerety SS, Hitz MP, Lindsay S, et al. (April 2014). "Rare variants in NR2F2 cause congenital heart defects in humans". American Journal of Human Genetics. 94 (4): 574–585. doi:10.1016/j.ajhg.2014.03.007. PMC 3980509. PMID 24702954.
  66. ↑ Hofstra RM, Mulder IM, Vossen R, de Koning-Gans PA, Kraak M, Ginjaar IB, et al. (January 2004). "DGGE-based whole-gene mutation scanning of the dystrophin gene in Duchenne and Becker muscular dystrophy patients". Human Mutation. 23 (1): 57–66. doi:10.1002/humu.10283. PMID 14695533. S2CID 36020079.
  67. ↑ Roberts RG, Bobrow M, Bentley DR (March 1992). "Point mutations in the dystrophin gene". Proceedings of the National Academy of Sciences of the United States of America. 89 (6): 2331–2335. Bibcode:1992PNAS...89.2331R. doi:10.1073/pnas.89.6.2331. PMC 48651. PMID 1549596.
  68. ↑ Tuffery-Giraud S, Saquet C, Thorel D, Disset A, Rivier F, Malcolm S, Claustres M (December 2005). "Mutation spectrum leading to an attenuated phenotype in dystrophinopathies". European Journal of Human Genetics. 13 (12): 1254–1260. doi:10.1038/sj.ejhg.5201478. PMID 16077730. S2CID 22585201.
  69. ↑ Gorman MP, Golomb MR, Walsh LE, Hobson GM, Garbern JY, Kinkel RP, et al. (April 2007). "Steroid-responsive neurologic relapses in a child with a proteolipid protein-1 mutation". Neurology. 68 (16): 1305–1307. doi:10.1212/01.wnl.0000259522.49388.53. PMID 17438221. S2CID 45639125.
  70. ↑ Saugier-Veber P, Munnich A, Bonneau D, Rozet JM, Le Merrer M, Gil R, Boespflug-Tanguy O (March 1994). "X-linked spastic paraplegia and Pelizaeus-Merzbacher disease are allelic disorders at the proteolipid protein locus". Nature Genetics. 6 (3): 257–262. doi:10.1038/ng0394-257. PMID 8012387. S2CID 13607673.
  71. ↑ Hodes ME, Blank CA, Pratt VM, Morales J, Napier J, Dlouhy SR (March 1997). "Nonsense mutation in exon 3 of the proteolipid protein gene (PLP) in a family with an unusual form of Pelizaeus-Merzbacher disease". American Journal of Medical Genetics. 69 (2): 121–125. doi:10.1002/(SICI)1096-8628(19970317)69:2<121::AID-AJMG2>3.0.CO;2-S. PMID 9056547.
  72. ↑ Wu Y, Arai AC, Rumbaugh G, Srivastava AK, Turner G, Hayashi T, et al. (November 2007). "Mutations in ionotropic AMPA receptor 3 alter channel properties and are associated with moderate cognitive impairment in humans". Proceedings of the National Academy of Sciences of the United States of America. 104 (46): 18163–18168. Bibcode:2007PNAS..10418163W. doi:10.1073/pnas.0708699104. PMC 2084314. PMID 17989220.
  73. ↑ Gueneau L, Bertrand AT, Jais JP, Salih MA, Stojkovic T, Wehnert M, et al. (September 2009). "Mutations of the FHL1 gene cause Emery-Dreifuss muscular dystrophy". American Journal of Human Genetics. 85 (3): 338–353. doi:10.1016/j.ajhg.2009.07.015. PMC 2771595. PMID 19716112.
  74. ↑ Knoblauch H, Geier C, Adams S, Budde B, Rudolph A, Zacharias U, et al. (January 2010). "Contractures and hypertrophic cardiomyopathy in a novel FHL1 mutation". Annals of Neurology. 67 (1): 136–140. doi:10.1002/ana.21839. PMID 20186852. S2CID 30441775.
  75. 1 2 Schoser B, Goebel HH, Janisch I, Quasthoff S, Rother J, Bergmann M, et al. (August 2009). "Consequences of mutations within the C terminus of the FHL1 gene". Neurology. 73 (7): 543–551. doi:10.1212/WNL.0b013e3181b2a4b3. PMID 19687455. S2CID 13107330.
  76. 1 2 Windpassinger C, Schoser B, Straub V, Hochmeister S, Noor A, Lohberger B, et al. (January 2008). "An X-linked myopathy with postural muscle atrophy and generalized hypertrophy, termed XMPMA, is caused by mutations in FHL1". American Journal of Human Genetics. 82 (1): 88–99. doi:10.1016/j.ajhg.2007.09.004. PMC 2253986. PMID 18179888.
  77. ↑ Zahorakova D, Rosipal R, Hadac J, Zumrova A, Bzduch V, Misovicova N, et al. (2007). "Mutation analysis of the MECP2 gene in patients of Slavic origin with Rett syndrome: novel mutations and polymorphisms". Journal of Human Genetics. 52 (4): 342–348. doi:10.1007/s10038-007-0121-x. PMID 17387578. S2CID 7962500.
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.