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.[1][2] 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.[3][4] 481 of these segments have been identified in the human genome.[3][4] If ribosomal DNA (rDNA regions) are excluded, these range in size from 200 bp to 781 bp.[4] UCEs are found on all human chromosomes except for 21 and Y.[5]

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.[3][4] By some definitions, segments need not be syntenic between species.[3] Human UCEs also show high conservation with more evolutionarily distant species, such as chicken and fugu.[4] 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.[4] 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.[4] Despite often being noncoding DNA,[6] some ultraconserved elements have been found to be transcriptionally active, producing non-coding RNA molecules.[7]

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strong negative (purifying) selection for 300-400 million years.[4][6][8] More recently, this assumption has been replaced by two main hypotheses: that UCEs are created through a reduced negative selection rate, or through reduced mutation rates, also known as a "cold spot" of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.[3][4] 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.[4] 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.[4] This fold change difference in mutation rates was consistent between humans, chimpanzees, and chickens.[4] 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.[9] However, affected phenotypes were only caused by 112 of these polymorphisms, most of which were located in coding regions of the UCEs.[9] 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.[10] Affected mice were fertile and targeted screens of the nearby coding genes showed no altered phenotype.[10] 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.[11] Computational analysis of human ultraconserved noncoding elements (UCNEs) found that the regions are enriched for A-T sequences and are generally GC poor.[12] However, the UNCEs were found to be enriched for CpG, or highly methylated.[12] 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.[12]

Function

Often, ultraconserved elements are located near transcriptional regulators or developmental genes performing functions such as gene enhancing and splicing regulation.[3][4][13] A study comparing ultraconserved 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 ultraconserved noncoding elements.[12] However, many UCRs in humans are extensively transcribed.[7] A small number of those which are transcribed, known as transcribed UCEs (T-UCEs), have been connected with human carcinomas and leukemias.[7] 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.[5] The tables below highlight transcripts and polymorphisms within UCRs that have been shown to contribute to human diseases.[5][9] 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-UCRsDiseaseReferences
miR-24-1/uc.160LeukemiaCalin et al., 2007 [7]
miR-130b/uc.63Prostate CASekino et al., 2017 [20]
miR-153/uc.416Colorectal and renal CAGoto et al., 2016;[21] Sekino et al., 2017[20]
miR-155/uc.160Gastric CACalin et al., 2007;[7] Pang et al., 2018[22]
miR-155/uc346ALeukemiaCalin et al., 2007 [7]
mir-195/uc.283Bladder CALiz et al., 2014 [23]
miR-195, miR-4668/uc.372Lipid metabolismGuo et al., 2018 [24]
mir-195/uc.173Gastrointestinal tractXiao et al., 2018[25]
miR-214/uc.276Colorectal CAWojcik et al., 2010[26]
miR-291a-3p/uc.173Nervous systemNan et al., 2016 [27]
miR-29b/uc.173Gastrointestinal tractJ. Y. Wang et al., 2018 [28]
miR-339-3p, miR-663b-3p, miR-95-5p/uc.339Lung CAVannini et al., 2017[29]
miR-596/uc.8Bladder CAOlivieri et al., 2016 [30]
DNA methylation/uc.160, uc.283, and uc.346Colorectal CAKottorou et al., 2018 [31]
DNA methylation/uc.158 + A, uc.160+, uc.241 + A, uc.283 + A, uc.346 + AGastric CAGoto et al., 2016;[21] Lujambio et al., 2010 [20]
Transcription factor SP1/uc.138 (TRA2β4)Colorectal CAKajita et al., 2016 [32]
Transcription factor YY1/uc.8Bladder CATerreri et al., 2016 [33]

Phenotype-associated polymorphisms within ultraconserved elements

Polymorphism nameAssociated phenotype descriptionSource
rs17105335Amyotrophic lateral sclerosisCronin et al. (2008)[34]
rs2020906Lynch syndromeHansen et al. (2014)[35]
rs10496382HeightChiang et al. (2012)[36]
rs13382811Severe myopiaKhor et al. (2013)[37]
rs104893634Vertical talus congenitalDobbs et al. (2006);[38] Shrimpton et al. (2004)[38]
rs2307121Central corneal thicknessLu et al. (2013)[39]
rs587777277Bosch-Boonstra-Schaaf optic atrophy syndromeBosch et al. (2014)[40]
rs587777275Bosch-Boonstra-Schaaf optic atrophy syndromeBosch et al. (2014)[40]
rs587777274Bosch-Boonstra-Schaaf optic atrophy syndromeBosch et al. (2014)[40]
rs387906239Familial adenomatous polyposis 1 attenuatedSoravia et al. (1999)[41]
rs3797704No association with breast cancerChang et al. (2016)[42]
rs387906232Familial adenomatous polyposis 1Fodde et al. (1992)[43]
rs387906237Familial adenomatous polyposis 1 attenuatedCuria et al. (1998)[44]
rs121434591Distal myopathySenderek et al. (2009)[13]
rs587777300Amyotrophic lateral sclerosis 21Johnson et al. (2014)[45]
rs863223403Au-Kline syndromeAu et al. (2015)[46]
rs121917900Cockayne syndrome BMallery et al. (1998)[47]
rs75462234Papillorenal syndromeSchimmenti et al. (1999)[48]
rs77453353Renal coloboma syndromeAmiel et al. (2000)[49]
rs76675173Papillorenal syndromeSchimmenti et al. (1997)[50]
rs587777708Focal segmental glomerulosclerosis 7Barua et al. (2014)[51]
rs11190870Adolescent idiopathic scoliosis, no association with breast cancerChettier 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]
rs724159963Peroxisomal fatty acyl-CoA reductase 1 disorderBuchert et al. (2014)[60]
rs16932455Capecitabine sensitivityO'Donnell et al. (2012)[61]
rs997295Motion sickness; BMIDe et al. (2015);[62] Guo et al. (2013);[63] Hromatka et al.[64]
rs587777373Congenital heart defects multiple types 4Al Turki et al. (2014)[65]
rs398123839Duchenne muscular dystrophyHofstra et al. (2004);[66] Roberts et al. (1992)[67]
rs863224976Becker muscular dystrophyTuffery-Giraud et al. (2005)[68]
rs132630295Spastic paraplegia 2 X-linkedGorman et al. (2007)[69]
rs132630287Spastic paraplegia 2 X-linkedSaugier-Veber et al. (1994)[70]
rs132630292Pelizaeus/Merzbacher disease atypicalHodes et al. (1997)[71]
rs137852350Mental retardation X-linked 94Wu et al. (2007)[72]
rs122459149Emery-Dreifuss muscular dystrophy 6 X-linkedGueneau et al. (2009);[73] Knoblauch et al. (2010)[74]
rs122458141Myopathy X-linked with postural muscle atrophySchoser et al. (2009);[75] Windpassinger et al. (2008)[76]
rs786200914Myopathy X-linked with postural muscle atrophySchoser et al. (2009)[75]
rs267606811Myopathy X-linked with postural muscle atrophyWindpassinger et al. (2008)[76]
rs62621672Rett syndrome (nonpathogenic variant)Zahorakova et al. (2007)[77]

See also

References

  1. ^ Faircloth BC, McCormack JE, Crawford NG, Harvey MG, Brumfield RT, Glenn TC (October 2012). "Ultraconserved elements anchor thousands of genetic markers spanning multiple evolutionary timescales". Systematic Biology. 61 (5): 717–726. doi:10.1093/sysbio/sys004. PMID 22232343
  2. ^ Zhang YM, Williams JL, Lucky A (3 September 2019). "Understanding UCEs: A Comprehensive Primer on Using Ultraconserved Elements for Arthropod Phylogenomics". Insect Systematics and Diversity. 3 (5). doi:10.1093/isd/ixz016
  3. ^ 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
  4. ^ 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
  5. ^ 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). doi:10.1002/wrna.1567. PMID 31489780. S2CID 201844414
  6. ^ Katzman S, Kern AD, Bejerano G, Fewell G, Fulton L, Wilson RK, Salama SR, Haussler D (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
  7. ^ 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 (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
  8. ^ 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
  9. ^ 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
  10. ^ 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). doi:10.1371/journal.pbio.0050234. PMC 1964772. PMID 17803355
  11. ^ 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 (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
  12. ^ 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
  13. ^ 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 (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
  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, Terracciano L, Croce CM, Patel T (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). 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, Bernard L, Ciccarelli FD (January 2010). "Ultradeep sequencing of a human ultraconserved region reveals somatic and constitutional genomic instability". PLOS Biology. 8 (1). doi:10.1371/journal.pbio.1000275. PMC 2794366. PMID 20052272
  20. ^ Sekino Y, Sakamoto N, Goto K, Honma R, Shigematsu Y, Sentani K, Oue N, Teishima J, Matsubara A, Yasui W (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. ^ Goto K, Ishikawa S, Honma R, Tanimoto K, Sakamoto N, Sentani K, Oue N, Teishima J, Matsubara A, Yasui W (July 2016). "The transcribed-ultraconserved regions in prostate and gastric cancer: DNA hypermethylation and microRNA-associated regulation". 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, Chen X, Yao W (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, Calin GA, Guil S, Esteller M (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, Tang W, Yu L, Li J (February 2018). "Ultraconserved element uc.372 drives hepatic lipid accumulation by suppressing miR-195/miR4668 maturation". Nature Communications. 9 (1). 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, Gorospe M, Wang JY (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, Herlea V, Rassenti LZ, Rai KR, Kipps TJ, Keating MJ, Croce CM, Calin GA (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, Luo Y, Liu Z, Dai L, Jiang Y (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, Gorospe M, Wang JY (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, Fanini F, Paliaga G, Crawford M, Ferracin M, Ivan C, Fabris L, Davuluri RV, Guo Z, Cortez MA, Zhang X, Chen L, Zhang S, Fernandez-Cymering C, Han L, Carloni S, Salvi S, Ling H, Murtadha M, Neviani P, Gitlitz BJ, Laird-Offringa IA, Nana-Sinkam P, Negrini M, Liang H, Amadori D, Cimmino A, Calin GA, Fabbri M (November 2017). "Transcribed ultraconserved region 339 promotes carcinogenesis by modulating tumor suppressor microRNAs". Nature Communications. 8 (1). 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, De Cobelli O, Messere A, Bruzzese D, Vannini I, Marinelli L, Novellino E, Zhang W, Incoronato M, Ilardi G, Staibano S, Marra L, Franco R, Perdonà S, Terracciano D, Czerniak B, Liguori GL, Colonna V, Fabbri M, Febbraio F, Calin GA, Cimmino A (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, Theodorakopoulos T, Oikonomou C, Katsakoulis EC, Koutras A, Makatsoris T, Demopoulos N, Stephanou G, Stavropoulos M, Thomopoulos KC, Kalofonos HP (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, Masuda K, Nishida K, Rokutan K (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, Perdonà S, Castaldo L, Febbraio F, de Nigris F, Cimmino A (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, Greenway MJ, Bradley DG, Traynor BJ, Hardiman O (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, Vedantam S, Nock NL, Franceschini N, Reiner AP, Demerath EW, Boerwinkle E, Rotter JI, Wilson JG, North KE, Papanicolaou GJ, Cupples LA, Murabito JM, Hirschhorn JN (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, Nakata I, Yamashiro K, Zhou X, Tam PO, Cheng CY, Tai ES, Vithana EN, Aung T, Teo YY, Wong TY, Moriyama M, Ohno-Matsui K, Mochizuki M, Matsuda F, Yong RY, Yap EP, Yang Z, Pang CP, Saw SM, Yoshimura N (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. ^ Dobbs MB, Gurnett CA, Pierce B, Exner GU, Robarge J, Morcuende JA, Cole WG, Templeton PA, Foster B, Bowcock AM (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, Hewitt AW, Koehn D, Hysi PG, Ramdas WD, Zeller T, Vithana EN, Cornes BK, Tay WT, Tai ES, Cheng CY, Liu J, Foo JN, Saw SM, Thorleifsson G, Stefansson K, Dimasi DP, Mills RA, Mountain J, Ang W, Hoehn R, Verhoeven VJ, Grus F, Wolfs R, Castagne R, Lackner KJ, Springelkamp H, Yang J, Jonasson F, Leung DY, Chen LJ, Tham CC, Rudan I, Vatavuk Z, Hayward C, Gibson J, Cree AJ, MacLeod A, Ennis S, Polasek O, Campbell H, Wilson JF, Viswanathan AC, Fleck B, Li X, Siscovick D, Taylor KD, Rotter JI, Yazar S, Ulmer M, Li J, Yaspan BL, Ozel AB, Richards JE, Moroi SE, Haines JL, Kang JH, Pasquale LR, Allingham RR, Ashley-Koch A, Mitchell P, Wang JJ, Wright AF, Pennell C, Spector TD, Young TL, Klaver CC, Martin NG, Montgomery GW, Anderson MG, Aung T, Willoughby CE, Wiggs JL, Pang CP, Thorsteinsdottir U, Lotery AJ, Hammond CJ, van Duijn CM, Hauser MA, Rabinowitz YS, Pfeiffer N, Mackey DA, Craig JE, Macgregor S, Wong TY (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. ^ Bosch DG, Boonstra FN, Gonzaga-Jauregui C, Xu M, de Ligt J, Jhangiani S, Wiszniewski W, Muzny DM, Yntema HG, Pfundt R, Vissers LE, Spruijt L, Blokland EA, Chen CA, Lewis RA, Tsai SY, Gibbs RA, Tsai MJ, Lupski JR, Zoghbi HY, Cremers FP, de Vries BB, Schaaf CP (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, Cohen Z, Asa SL, Bapat BV (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. 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, Griffioen G, Vasen H, Khan PM (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, Ficari F, Tonelli F, Battista P, Mariani-Costantini R, Cama A (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, Pliner HA, Abramzon Y, Marangi G, Winborn BJ, Gibbs JR, Nalls MA, Morgan S, Shoai M, Hardy J, Pittman A, Orrell RW, Malaspina A, Sidle KC, Fratta P, Harms MB, Baloh RH, Pestronk A, Weihl CC, Rogaeva E, Zinman L, Drory VE, Borghero G, Mora G, Calvo A, Rothstein JD, Drepper C, Sendtner M, Singleton AB, Taylor JP, Cookson MR, Restagno G, Sabatelli M, Bowser R, Chiò A, Traynor BJ (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, Ferguson M, Valle D, Parboosingh JS, Sobreira N, Innes AM, Kline AD (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, Stefanini M, Lehmann AR (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, Wargowski DS, France TD, Michel E, Dobyns WB (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, Augé J, Bouissou F, Antignac C, Gubler MC, Eccles MR, Munnich A, Vekemans M, Lyonnet S, Attié-Bitach T (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, Zhang YH, Proesmans W, Leys A, Byerly KA, Braddock SR, Masuno M, Imaizumi K, Devriendt K, Eccles MR (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, Caputo V, Toka HR, Charoonratana VT, Tartaglia M, Pollak MR (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). "Haplotypes at LBX1 have distinct inheritance patterns with opposite effects in adolescent idiopathic scoliosis". PLOS ONE. 10 (2). 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, Sharma S, Su P, Huang D (2013-01-04). "Association between common variants near LBX1 and adolescent idiopathic scoliosis replicated in the Chinese Han population". PLOS ONE. 8 (1). 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, Ohlin A, Halldin K, Grabowski P, Tenne M, Laivuori H, Dahlman I, Andersen M, Christensen SB, Karlsson MK, Jiao H, Kere J, Gerdhem P (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, Takahashi A, Matsumoto M, Herring JA, Lam TP, Wang X, Tam EM, Song YQ, Fan YH, Chan D, Cheah KS, Qiu X, Jiang H, Huang D, Su P, Sham P, Cheung KM, Luk KD, Gordon D, Qiu Y, Cheng J, Tang N, Ikegawa S, Wise CA (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, Qiu X, Takahashi A, Jiang H, Yan H, Kono K, Kawakami N, Uno K, Ito M, Minami S, Yanagida H, Taneichi H, Hosono N, Tsuji T, Suzuki T, Sudo H, Kotani T, Yonezawa I, Kubo M, Tsunoda T, Watanabe K, Chiba K, Toyama Y, Qiu Y, Matsumoto M, Ikegawa S (2013-09-04). "Identification of a susceptibility locus for severe adolescent idiopathic scoliosis on chromosome 17q24.3". PLOS ONE. 8 (9). 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, Uno K, Ito M, Minami S, Yanagida H, Taneichi H, Tsuji T, Suzuki T, Sudo H, Kotani T, Watanabe K, Chiba K, Hosono N, Kamatani N, Tsunoda T, Toyama Y, Kubo M, Matsumoto M, Ikegawa S (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, Ekici AB, Sticht H, Schwarze B, Lamont RE, Parboosingh JS, Bernier FP, Abou Jamra R (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, Im HK, Huang RS, Cox NJ, Dolan ME (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, Crosslin DR, Carrell DS, Hakonarson H, Jarvik G, Larson E, Pacheco JA, Rasmussen-Torvik LJ, Moore CB, Asselbergs FW, Moore JH, Ritchie MD, Keating BJ, Gilbert-Diamond D (June 2015). "Identifying gene-gene interactions that are highly associated with Body Mass Index using Quantitative Multifactor Dimensionality Reduction (QMDR)". BioData Mining. 8 (1). 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, D'Alessandro LC, Swaminathan GJ, Bentham J, Arndt AK, Louw J, Low J, Breckpot J, Gewillig M, Thienpont B, Abdul-Khaliq H, Harnack C, Hoff K, Kramer HH, Schubert S, Siebert R, Toka O, Cosgrove C, Watkins H, Lucassen AM, O'Kelly IM, Salmon AP, Bu'lock FA, Granados-Riveron J, Setchfield K, Thornborough C, Brook JD, Mulder B, Klaassen S, Bhattacharya S, Devriendt K, Fitzpatrick DF, Wilson DI, Mital S, Hurles ME (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, van der Hout AH, Bakker E, Buys CH, van Ommen GJ, van Essen AJ, den Dunnen JT (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, Darras BT, Urion DK, Eksioglu YZ (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, Suzuki E, Jiang Y, Zhang L, Rodriguez J, Boyle J, Tarpey P, Raymond FL, Nevelsteen J, Froyen G, Stratton M, Futreal A, Gecz J, Stevenson R, Schwartz CE, Valle D, Huganir RL, Wang T (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, Hoeltzenbein M, Spuler S, Saitoh S, Verschueren A, Tranchant C, Beuvin M, Lacene E, Romero NB, Heath S, Zelenika D, Voit T, Eymard B, Ben Yaou R, Bonne G (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, Schulz-Menger J, Spuler A, Yaou RB, Nürnberg P, Voit T, Bonne G, Spuler S (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. ^ Schoser B, Goebel HH, Janisch I, Quasthoff S, Rother J, Bergmann M, Müller-Felber W, Windpassinger C (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. ^ Windpassinger C, Schoser B, Straub V, Hochmeister S, Noor A, Lohberger B, Farra N, Petek E, Schwarzbraun T, Ofner L, Löscher WN, Wagner K, Lochmüller H, Vincent JB, Quasthoff S (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, Baxova A, Zeman J, Martasek P (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