Biology:Ultra-conserved element

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strong negative (purifying) selection for 300-400 million years.[2][5][7] More recently, this assumption has been replaced by two main hypotheses: that UCEs are created through a reduced negative selection rate, or through reduced mutation rates, also known as a “cold spot” of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

Regulation Mechanisms of Disease Related Ultra-conserved Element Transcripts

miR/methylation/transcript factor associated with T-UCRs Disease References
miR-24-1/uc.160 Leukemia Calin et al., 2007 [6]
miR-130b/uc.63 Prostate CA Sekino et al., 2017 [20]
miR-153/uc.416 Colorectal and renal CA Goto et al., 2016;[21] Sekino et al., 2017[20]
miR-155/uc.160 Gastric CA Calin et al., 2007;[6] Pang et al., 2018[22]
miR-155/uc346A Leukemia Calin et al., 2007 [6]
mir-195/uc.283 Bladder CA Liz et al., 2014 [23]
miR-195, miR-4668/uc.372 Lipid metabolism Guo et al., 2018 [24]
mir-195/uc.173 Gastrointestinal tract Xiao et al., 2018[25]
miR-214/uc.276 Colorectal CA Wojcik et al., 2010[26]
miR-291a-3p/uc.173 Nervous system Nan et al., 2016 [27]
miR-29b/uc.173 Gastrointestinal tract J. Y. Wang et al., 2018 [28]
miR-339-3p, miR-663b-3p, miR-95-5p/uc.339 Lung CA Vannini et al., 2017[29]
miR-596/uc.8 Bladder CA Olivieri et al., 2016 [30]
DNA methylation/uc.160, uc.283, and uc.346 Colorectal CA Kottorou et al., 2018 [31]
DNA methylation/uc.158 + A, uc.160+, uc.241 + A, uc.283 + A, uc.346 + A Gastric CA Goto et al., 2016;[21] Lujambio et al., 2010 [20]
Transcription factor SP1/uc.138 (TRA2β4) Colorectal CA Kajita et al., 2016 [32]
Transcription factor YY1/uc.8 Bladder CA Terreri et al., 2016 [33]

Phenotype-Associated Polymorphisms within Ultra-conserved Elements

Polymorphism name Associated phenotype description Source
rs17105335 Amyotrophic lateral sclerosis Cronin et al. (2008)[34]
rs2020906 Lynch syndrome Hansen et al. (2014)[35]
rs10496382 Height Chiang et al. (2012)[36]
rs13382811 Severe myopia Khor et al. (2013)[37]
rs104893634 Vertical talus congenital Dobbs et al. (2006);[38] Shrimpton et al. (2004)[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
rs132630292 Pelizaeus/Merzbacher disease atypical Hodes et al. (1997)[70]
rs137852350 Mental retardation X-linked 94 Wu et al. (2007)[71]
rs122459149 Emery-Dreifuss muscular dystrophy 6 X-linked Gueneau et al. (2009);[72] Knoblauch et al. (2010)[73]
rs122458141 Myopathy X-linked with postural muscle atrophy
rs786200914 Myopathy X-linked with postural muscle atrophy Schoser et al. (2009)[74]
rs267606811 Myopathy X-linked with postural muscle atrophy Windpassinger et al. (2008)[75]
rs62621672 Rett syndrome (nonpathogenic variant) Zahorakova et al. (2007)[76]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 "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. May 2012. doi:10.1073/pnas.1121356109. PMID 22496592. 
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 "Ultraconserved elements in the human genome". Science 304 (5675): 1321–1325. May 2004. doi:10.1126/science.1098119. PMID 15131266. Bibcode: 2004Sci...304.1321B. 
  3. ↑ 3.0 3.1 3.2 "Highlighting transcribed ultraconserved regions in human diseases". Wiley Interdisciplinary Reviews. RNA 11 (2): e1567. March 2020. doi:10.1002/wrna.1567. PMID 31489780. 
  4. ↑ "UCbase & miRfunc: a database of ultraconserved sequences and microRNA function". Nucleic Acids Research 37 (Database issue): D41–D48. January 2009. doi:10.1093/nar/gkn702. PMID 18945703. 
  5. ↑ 5.0 5.1 "Human genome ultraconserved elements are ultraselected". Science 317 (5840): 915. August 2007. doi:10.1126/science.1142430. PMID 17702936. Bibcode: 2007Sci...317..915K. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 "Ultraconserved regions encoding ncRNAs are altered in human leukemias and carcinomas". Cancer Cell 12 (3): 215–229. September 2007. doi:10.1016/j.ccr.2007.07.027. PMID 17785203. 
  7. ↑ "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. March 2011. doi:10.1093/nar/gkq949. PMID 21062826. 
  8. ↑ 8.0 8.1 8.2 "Genetic Variations of Ultraconserved Elements in the Human Genome". Omics 23 (11): 549–559. November 2019. doi:10.1089/omi.2019.0156. PMID 31689173. 
  9. ↑ 9.0 9.1 "Deletion of ultraconserved elements yields viable mice". PLOS Biology 5 (9): e234. September 2007. doi:10.1371/journal.pbio.0050234. PMID 17803355. 
  10. ↑ "Ultraconserved enhancer function does not require perfect sequence conservation". Nature Genetics 53 (4): 521–528. April 2021. doi:10.1038/s41588-021-00812-3. PMID 33782603. 
  11. ↑ 11.0 11.1 11.2 11.3 "Nucleotide Composition of Ultra-Conserved Elements Shows Excess of GpC and Depletion of GG and CC Dinucleotides". Genes 13 (11): 2053. November 2022. doi:10.3390/genes13112053. PMID 36360290. 
  12. ↑ 12.0 12.1 "Transcriptional profiling of lung cell populations in idiopathic pulmonary arterial hypertension". Pulmonary Circulation 10 (1): e19. January 2005. doi:10.1371/journal.pbio.0030019. PMID 32166015.  open access
  13. ↑ "Highly conserved non-coding sequences are associated with vertebrate development". PLOS Biology 3 (1): e7. January 2005. doi:10.1371/journal.pbio.0030007. PMID 15630479.  open access
  14. ↑ Elizabeth Pennisi (2017) Mysterious unchanging DNA finds a purpose in life, Science 02 Jun 2017]
  15. ↑ "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. January 2011. doi:10.1073/pnas.1011098108. PMID 21187392. Bibcode: 2011PNAS..108..786B. 
  16. ↑ "Abnormal dosage of ultraconserved elements is highly disfavored in healthy cells but not cancer cells". PLOS Genetics 10 (10): e1004646. October 2014. doi:10.1371/journal.pgen.1004646. PMID 25340765. 
  17. ↑ "Mammalian ultraconserved elements are strongly depleted among segmental duplications and copy number variants". Nature Genetics 38 (10): 1216–1220. October 2006. doi:10.1038/ng1888. PMID 16998490. 
  18. ↑ "Ultraconserved elements: analyses of dosage sensitivity, motifs and boundaries". Genetics 180 (4): 2277–2293. December 2008. doi:10.1534/genetics.108.096537. PMID 18957701. 
  19. ↑ "Ultradeep sequencing of a human ultraconserved region reveals somatic and constitutional genomic instability". PLOS Biology 8 (1): e1000275. January 2010. doi:10.1371/journal.pbio.1000275. PMID 20052272. 
  20. ↑ 20.0 20.1 20.2 "Transcribed ultraconserved region Uc.63+ promotes resistance to docetaxel through regulation of androgen receptor signaling in prostate cancer". Oncotarget 8 (55): 94259–94270. November 2017. doi:10.18632/oncotarget.21688. PMID 29212226. 
  21. ↑ 21.0 21.1 "The transcribed-ultraconserved regions in prostate and gastric cancer: DNA hypermethylation and microRNA-associated regulation". Oncogene 35 (27): 3598–3606. July 2016. doi:10.1038/onc.2015.445. PMID 26640143. http://ir.lib.hiroshima-u.ac.jp/files/public/4/44074/20181220104357706239/k6837_1.pdf. 
  22. ↑ "Pancreatic cancer-secreted miR-155 implicates in the conversion from normal fibroblasts to cancer-associated fibroblasts". Cancer Science 106 (10): 1362–1369. October 2015. doi:10.1111/cas.12747. PMID 26195069. 
  23. ↑ "Regulation of pri-miRNA processing by a long noncoding RNA transcribed from an ultraconserved region". Molecular Cell 55 (1): 138–147. July 2014. doi:10.1016/j.molcel.2014.05.005. PMID 24910097. 
  24. ↑ "Ultraconserved element uc.372 drives hepatic lipid accumulation by suppressing miR-195/miR4668 maturation". Nature Communications 9 (1): 612. February 2018. doi:10.1038/s41467-018-03072-8. PMID 29426937. Bibcode: 2018NatCo...9..612G. 
  25. ↑ "Long Noncoding RNA uc.173 Promotes Renewal of the Intestinal Mucosa by Inducing Degradation of MicroRNA 195". Gastroenterology 154 (3): 599–611. February 2018. doi:10.1053/j.gastro.2017.10.009. PMID 29042220. 
  26. ↑ "Non-codingRNA sequence variations in human chronic lymphocytic leukemia and colorectal cancer". Carcinogenesis 31 (2): 208–215. February 2010. doi:10.1093/carcin/bgp209. PMID 19926640. 
  27. ↑ "A transcribed ultraconserved noncoding RNA, Uc.173, is a key molecule for the inhibition of lead-induced neuronal apoptosis". Oncotarget 7 (1): 112–124. January 2016. doi:10.18632/oncotarget.6590. PMID 26683706. 
  28. ↑ "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. July 2018. doi:10.1128/MCB.00010-18. PMID 29632078. 
  29. ↑ "Transcribed ultraconserved region 339 promotes carcinogenesis by modulating tumor suppressor microRNAs". Nature Communications 8 (1): 1801. November 2017. doi:10.1038/s41467-017-01562-9. PMID 29180617. Bibcode: 2017NatCo...8.1801V. 
  30. ↑ "Long non-coding RNA containing ultraconserved genomic region 8 promotes bladder cancer tumorigenesis". Oncotarget 7 (15): 20636–20654. April 2016. doi:10.18632/oncotarget.7833. PMID 26943042. 
  31. ↑ "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. April 2018. doi:10.18632/oncotarget.25115. PMID 29765549. 
  32. ↑ "Ultraconserved region-containing Transformer 2β4 controls senescence of colon cancer cells". Oncogenesis 5 (4): e213. April 2016. doi:10.1038/oncsis.2016.18. PMID 27043659. 
  33. ↑ "New Cross-Talk Layer between Ultraconserved Non-Coding RNAs, MicroRNAs and Polycomb Protein YY1 in Bladder Cancer". Genes 7 (12): 127. December 2016. doi:10.3390/genes7120127. PMID 27983635. 
  34. ↑ "A genome-wide association study of sporadic ALS in a homogenous Irish population". Human Molecular Genetics 17 (5): 768–774. March 2008. doi:10.1093/hmg/ddm361. PMID 18057069. 
  35. ↑ "A massive parallel sequencing workflow for diagnostic genetic testing of mismatch repair genes". Molecular Genetics & Genomic Medicine 2 (2): 186–200. March 2014. doi:10.1002/mgg3.62. PMID 24689082. 
  36. ↑ "Ultraconserved elements in the human genome: association and transmission analyses of highly constrained single-nucleotide polymorphisms". Genetics 192 (1): 253–266. September 2012. doi:10.1534/genetics.112.141945. PMID 22714408. 
  37. ↑ "Genome-wide association study identifies ZFHX1B as a susceptibility locus for severe myopia". Human Molecular Genetics 22 (25): 5288–5294. December 2013. doi:10.1093/hmg/ddt385. PMID 23933737. 
  38. ↑ 38.0 38.1 "HOXD10 M319K mutation in a family with isolated congenital vertical talus". Journal of Orthopaedic Research 24 (3): 448–453. March 2006. doi:10.1002/jor.20052. PMID 16450407. 
  39. ↑ "Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus". Nature Genetics 45 (2): 155–163. February 2013. doi:10.1038/ng.2506. PMID 23291589. 
  40. ↑ 40.0 40.1 40.2 "NR2F1 mutations cause optic atrophy with intellectual disability". American Journal of Human Genetics 94 (2): 303–309. February 2014. doi:10.1016/j.ajhg.2014.01.002. PMID 24462372. 
  41. ↑ "Familial adenomatous polyposis-associated thyroid cancer: a clinical, pathological, and molecular genetics study". The American Journal of Pathology 154 (1): 127–135. January 1999. doi:10.1016/S0002-9440(10)65259-5. PMID 9916927. 
  42. ↑ "Analysing the mutational status of adenomatous polyposis coli (APC) gene in breast cancer". Cancer Cell International 16: 23. 2016-03-28. doi:10.1186/s12935-016-0297-2. PMID 27028212. 
  43. ↑ "Eight novel inactivating germ line mutations at the APC gene identified by denaturing gradient gel electrophoresis". Genomics 13 (4): 1162–1168. August 1992. doi:10.1016/0888-7543(92)90032-n. PMID 1324223. 
  44. ↑ "Transcript dosage effect in familial adenomatous polyposis: model offered by two kindreds with exon 9 APC gene mutations". Human Mutation 11 (3): 197–201. 1998. doi:10.1002/(SICI)1098-1004(1998)11:3<197::AID-HUMU3>3.0.CO;2-F. PMID 9521420. 
  45. ↑ "Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis". Nature Neuroscience 17 (5): 664–666. May 2014. doi:10.1038/nn.3688. PMID 24686783. 
  46. ↑ "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. October 2015. doi:10.1002/humu.22837. PMID 26173930. 
  47. ↑ "Molecular analysis of mutations in the CSB (ERCC6) gene in patients with Cockayne syndrome". American Journal of Human Genetics 62 (1): 77–85. January 1998. doi:10.1086/301686. PMID 9443879. 
  48. ↑ "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. 1999. doi:10.1002/(SICI)1098-1004(199911)14:5<369::AID-HUMU2>3.0.CO;2-E. PMID 10533062. 
  49. ↑ "PAX2 mutations in renal-coloboma syndrome: mutational hotspot and germline mosaicism". European Journal of Human Genetics 8 (11): 820–826. November 2000. doi:10.1038/sj.ejhg.5200539. PMID 11093271. 
  50. ↑ "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. April 1997. PMID 9106533. 
  51. ↑ "Mutations in PAX2 associate with adult-onset FSGS". Journal of the American Society of Nephrology 25 (9): 1942–1953. September 2014. doi:10.1681/ASN.2013070686. PMID 24676634. 
  52. ↑ "Haplotypes at LBX1 have distinct inheritance patterns with opposite effects in adolescent idiopathic scoliosis". PLOS ONE 10 (2): e0117708. 2015-02-12. doi:10.1371/journal.pone.0117708. PMID 25675428. Bibcode: 2015PLoSO..1017708C. 
  53. ↑ "Association between common variants near LBX1 and adolescent idiopathic scoliosis replicated in the Chinese Han population". PLOS ONE 8 (1): e53234. 2013-01-04. doi:10.1371/journal.pone.0053234. PMID 23308168. Bibcode: 2013PLoSO...853234G. 
  54. ↑ "Candidate gene analysis and exome sequencing confirm LBX1 as a susceptibility gene for idiopathic scoliosis". The Spine Journal 15 (10): 2239–2246. October 2015. doi:10.1016/j.spinee.2015.05.013. PMID 25987191. 
  55. ↑ "Association of rs11190870 near LBX1 with adolescent idiopathic scoliosis susceptibility in a Han Chinese population". European Spine Journal 22 (2): 282–286. February 2013. doi:10.1007/s00586-012-2532-4. PMID 23096252. 
  56. ↑ "A meta-analysis identifies adolescent idiopathic scoliosis association with LBX1 locus in multiple ethnic groups". Journal of Medical Genetics 51 (6): 401–406. June 2014. doi:10.1136/jmedgenet-2013-102067. PMID 24721834. 
  57. ↑ "Identification of a susceptibility locus for severe adolescent idiopathic scoliosis on chromosome 17q24.3". PLOS ONE 8 (9): e72802. 2013-09-04. doi:10.1371/journal.pone.0072802. PMID 24023777. Bibcode: 2013PLoSO...872802M. 
  58. ↑ "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. November 2011. doi:10.1007/s10654-011-9617-y. PMID 21938478. 
  59. ↑ "A genome-wide association study identifies common variants near LBX1 associated with adolescent idiopathic scoliosis". Nature Genetics 43 (12): 1237–1240. October 2011. doi:10.1038/ng.974. PMID 22019779. 
  60. ↑ "A peroxisomal disorder of severe intellectual disability, epilepsy, and cataracts due to fatty acyl-CoA reductase 1 deficiency" (in English). American Journal of Human Genetics 95 (5): 602–610. November 2014. doi:10.1016/j.ajhg.2014.10.003. PMID 25439727. 
  61. ↑ "Identification of novel germline polymorphisms governing capecitabine sensitivity". Cancer 118 (16): 4063–4073. August 2012. doi:10.1002/cncr.26737. PMID 22864933. 
  62. ↑ "Identifying gene-gene interactions that are highly associated with Body Mass Index using Quantitative Multifactor Dimensionality Reduction (QMDR)". BioData Mining 8 (1): 41. June 2015. doi:10.1186/s13040-015-0074-0. PMID 26674805. 
  63. ↑ "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. January 2013. doi:10.1093/hmg/dds396. PMID 23001569. 
  64. ↑ "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. May 2015. doi:10.1093/hmg/ddv028. PMID 25628336. 
  65. ↑ "Rare variants in NR2F2 cause congenital heart defects in humans". American Journal of Human Genetics 94 (4): 574–585. April 2014. doi:10.1016/j.ajhg.2014.03.007. PMID 24702954. 
  66. ↑ "DGGE-based whole-gene mutation scanning of the dystrophin gene in Duchenne and Becker muscular dystrophy patients". Human Mutation 23 (1): 57–66. January 2004. doi:10.1002/humu.10283. PMID 14695533. 
  67. ↑ "Point mutations in the dystrophin gene". Proceedings of the National Academy of Sciences of the United States of America 89 (6): 2331–2335. March 1992. doi:10.1073/pnas.89.6.2331. PMID 1549596. Bibcode: 1992PNAS...89.2331R. 
  68. ↑ "Mutation spectrum leading to an attenuated phenotype in dystrophinopathies". European Journal of Human Genetics 13 (12): 1254–1260. December 2005. doi:10.1038/sj.ejhg.5201478. PMID 16077730. 
  69. ↑ "Steroid-responsive neurologic relapses in a child with a proteolipid protein-1 mutation". Neurology 68 (16): 1305–1307. April 2007. doi:10.1212/01.wnl.0000259522.49388.53. PMID 17438221. 
  70. ↑ "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. March 1997. doi:10.1002/(SICI)1096-8628(19970317)69:2<121::AID-AJMG2>3.0.CO;2-S. PMID 9056547. https://pubmed.ncbi.nlm.nih.gov/9056547. 
  71. ↑ "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. November 2007. doi:10.1073/pnas.0708699104. PMID 17989220. Bibcode: 2007PNAS..10418163W. 
  72. ↑ "Mutations of the FHL1 gene cause Emery-Dreifuss muscular dystrophy". American Journal of Human Genetics 85 (3): 338–353. September 2009. doi:10.1016/j.ajhg.2009.07.015. PMID 19716112. 
  73. ↑ "Contractures and hypertrophic cardiomyopathy in a novel FHL1 mutation". Annals of Neurology 67 (1): 136–140. January 2010. doi:10.1002/ana.21839. PMID 20186852. 
  74. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Schoser-2009
  75. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Windpassinger-2008
  76. ↑ "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. 2007. doi:10.1007/s10038-007-0121-x. PMID 17387578. 



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