Junk DNA: A Journey Through the Dark Matter of the Genome

Комментарии

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For information on the disorder and its genetics see www.omim.org record #160900

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Unless otherwise stated, the majority of the information in this chapter is from the edition of Nature published on 15th February 2001 which contained the data and analyses from the publicly funded consortium. The major reference is Initial sequencing and analysis of the human genome, authored by the International Human Genome Sequencing Consortium. Readers may also find the accompanying commentaries in the same issue of interest.

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Data from the American Cancer Society http://www.cancer.org/cancer/skincancer-melanoma/detailedguide/melanoma-skin-cancer-key-statistics

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Unless otherwise stated, the majority of the information in this chapter is from the edition of Nature published on 15th February 2001 which contained the data and analyses from the publicly funded consortium. The major reference is Initial sequencing and analysis of the human genome, authored by the International Human Genome Sequencing Consortium. The accompanying commentaries by David Baltimore and by Li et al in the same issue are also of interest, and rather more accessible in style and content.

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For more information on this condition and its causes, see http://www.ninds.nih.gov/disorders/charcot_marie_tooth/detail_charcot_marie_tooth.htm

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For more information on this condition and its causes, see http://www.nlm.nih.gov/medlineplus/ency/article/001116.htm

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There is a useful discussion of this problem in Armanios M., Blackburn E. H. The telomere syndromes. Nat Rev Genet. 2012 Oct; 13(10):693–704

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Armanios M., Blackburn E. H. The telomere syndromes. Nat Rev Genet. 2012 Oct; 13(10):693–704 provides a useful overview.

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Armanios M., Blackburn E. H. The telomere syndromes. Nat Rev Genet. 2012 Oct; 13(10):693–704

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For an excellent clinical description, and useful pictures, see Calado R. T., Young N. S. Telomere diseases. N Engl J Med. 2009 Dec 10; 361(24):2353–65

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Tsakiri K. D., Cronkhite J. T., Kuan P. J., Xing C., Raghu G., Weissler J. C., Rosenblatt R. L., Shay J. W., Garcia C. K. Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc Natl Acad Sci U S A. 2007 May 1; 104(18):7552–7

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For a useful description see http://www.patient.co.uk/doctor/aplastic-anaemia

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For a very good analysis of this model, see Sekulic N., Black B. E. Molecular underpinnings of centromere identity and maintenance. Trends Biochem Sci. 2012 Jun; 37(6):220–9

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If you are interested in learning more about the details of this process, and the epigenetic modifications involved, see González-Barrios R., Soto-Reyes E., Herrera L. A. Assembling pieces of the centromere epigenetics puzzle. Epigenetics. 2012 Jan 1; 7(1):3–13

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A particularly important protein in this respect is call HJURP, and more information can be found in Sekulic N., Black BE. Molecular underpinnings of centromere identity and maintenance. Trends Biochem Sci. 2012 Jun; 37(6):220–9

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For more information on this condition see http://www.nhs.uk/conditions/Rett-syndrome/Pages/Introduction.aspx

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Derrien T., Johnson R., Bussotti G., Tanzer A., Djebali S., Tilgner H., Guernec G., Martin D., Merkel A., Knowles D. G., Lagarde J., Veeravalli L., Ruan X., Ruan Y., Lassmann T., Carninci P., Brown J. B., Lipovich L., Gonzalez J. M., Thomas M., Davis C. A., Shiekhattar R., Gingeras T. R., Hubbard T. J., Notredame C., Harrow J., Guigó R. The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res. 2012 Sep; 22(9):1775–89

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Ulitsky I., Shkumatava A., Jan C. H., Sive H., Bartel D. P. Conserved function of lincRNAs in vertebrate embryonic development despite rapid sequence evolution. Cell. 2011 Dec 23; 147(7):1537–50

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Cabili M. N., Trapnell C., Goff L., Koziol M., Tazon-Vega B., Regev A., Rinn J. L. Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes Dev. 2011 Sep 15; 25(18):1915–27

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Church D. M., Goodstadt L., Hillier L. W., Zody M. C., Goldstein S., She X., Bult C. J., Agarwala R., Cherry J. L., DiCuccio M., Hlavina W., Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A. C., Graves T., Zhou S., Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., Forrest D., Amos-Landgraf J., Schwartz D. C., Cheng Z., Lindblad-Toh K., Eichler E. E., Ponting C. P; Mouse Genome Sequencing Consortium. Lineage-specific biology revealed by a finished genome assembly of the mouse. PLoS Biol. 2009 May 5; 7(5):e1000112

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Necsulea A., Soumillon M., Warnefors M., Liechti A., Daish T., Zeller U., Baker J. C., Grützner F., Kaessmann H. The evolution of long-noncoding RNA repertoires and expression patterns in tetrapods. Nature. 2014 Jan 30; 505(7485):635–40

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Wahlestedt C. Targeting long non-coding RNA to therapeutically upregulate gene expression. Nat Rev Drug Discov. 2013 Jun; 12(6):433–46

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Mercer T. R., Dinger M. E., Sunkin S. M., Mehler M. F., Mattick J. S. Specific expression of long noncoding RNAs in the mouse brain. Proc Natl Acad Sci U S A. 2008 Jan 15; 105(2):716–21

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For a very useful review of this class and how it fits into the wider long non-coding RNA landscape, see Ulitsky I., Bartel DP. lincRNAs: genomics, evolution, and mechanisms. Cell. 2013 Jul 3; 154(1):26–46

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Guttman M., Donaghey J., Carey B. W., Garber M., Grenier J. K., Munson G., Young G., Lucas A. B., Ach R., Bruhn L., Yang X., Amit I., Meissner A., Regev A., Rinn J. L., Root D. E., Lander E. S. lincRNAs act in the circuitry controlling pluripotency and differentiation. Nature. 2011 Aug 28; 477(7364):295–300

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Wang K. C., Yang Y. W., Liu B., Sanyal A., Corces-Zimmerman R., Chen Y., Lajoie B. R., Protacio A., Flynn R. A., Gupta R. A., Wysocka J., Lei M., Dekker J., Helms J. A., Chang H. Y. A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature. 2011 Apr 7; 472(7341):120–4

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Li L., Liu B., Wapinski O. L., Tsai M. C., Qu K., Zhang J., Carlson J. C., Lin M., Fang F., Gupta R. A., Helms J. A., Chang H. Y. Targeted disruption of Hotair leads to homeotic transformation and gene derepression. Cell Rep. 2013 Oct 17; 5(1):3–12

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Du Z., Fei T., Verhaak R. G., Su Z., Zhang Y., Brown M., Chen Y., Liu X. S. Integrative genomic analyses reveal clinically relevant long noncoding RNAs in human cancer. Nat Struct Mol Biol. 2013 Jul; 20(7):908–13

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For a useful review of this area, see Cheetham S. W., Gruhl F., Mattick J. S., Dinger M. E. Long noncoding RNAs and the genetics of cancer. Br J Cancer. 2013 Jun 25; 108(12):2419–25

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Yap K. L., Li S., Muñoz-Cabello A. M., Raguz S., Zeng L., Mujtaba S., Gil J., Walsh M. J., Zhou M. M. Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a. Mol Cell. 2010 Jun 11; 38(5):662–74

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Kotake Y., Nakagawa T., Kitagawa K., Suzuki S., Liu N., Kitagawa M., Xiong Y. Long non-coding RNA ANRIL is required for the PRC2 recruitment to and silencing of p15(INK4B) tumor suppressor gene. Oncogene. 2011 Apr 21; 30(16):1956–62

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Yang Z., Zhou L., Wu L. M., Lai M. C., Xie H. Y., Zhang F., Zheng S. S. Overexpression of long non-coding RNA HOTAIR predicts tumor recurrence in hepatocellular carcinoma patients following liver transplantation. Ann Surg Oncol. 2011 May; 18(5):1243–50

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Ishibashi M., Kogo R., Shibata K., Sawada G., Takahashi Y., Kurashige J., Akiyoshi S., Sasaki S., Iwaya T., Sudo T., Sugimachi K., Mimori K., Wakabayashi G., Mori M. Clinical significance of the expression of long non-coding RNA HOTAIR in primary hepatocellular carcinoma. Oncol Rep. 2013 Mar; 29(3):946–50

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Kim K., Jutooru I., Chadalapaka G., Johnson G., Frank J., Burghardt R., Kim S., Safe S. HOTAIR is a negative prognostic factor and exhibits pro-oncogenic activity in pancreatic cancer. Oncogene. 2013 Mar 8; 32(13):1616–25

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Gupta R. A., Shah N., Wang K. C., Kim J., Horlings H. M., Wong D. J., Tsai M. C., Hung T., Argani P., Rinn J. L., Wang Y., Brzoska P., Kong B., Li R., West R. B., van de Vijver M. J., Sukumar S., Chang H. Y. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010 Apr 15; 464(7291):1071–6

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Yang L., Lin C., Jin C., Yang J. C., Tanasa B., Li W., Merkurjev D., Ohgi K. A., Meng D., Zhang J., Evans C. P., Rosenfeld M. G. Long-noncoding RNA-dependent mechanisms of androgen-receptor-regulated gene activation programs. Nature. 2013 Aug 29; 500(7464):598–602

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Prensner J. R., Iyer M. K., Sahu A., Asangani I. A., Cao Q., Patel L., Vergara I. A., Davicioni E., Erho N., Ghadessi M., Jenkins R. B., Triche T. J., Malik R., Bedenis R., McGregor N., Ma T., Chen W., Han S., Jing X., Cao X., Wang X., Chandler B., Yan W., Siddiqui J., Kunju L. P., Dhanasekaran S. M., Pienta K. J., Feng F. Y., Chinnaiyan A. M. The long noncoding RNA SChLAP1 promotes aggressive prostate cancer and antagonizes the SWI/SNF complex. Nat Genet. 2013 Nov; 45(11):1392–8

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Necsulea A., Soumillon M., Warnefors M., Liechti A., Daish T., Zeller U., Baker J. C., Grützner F., Kaessmann H. The evolution of long-noncoding RNA repertoires and expression patterns in tetrapods. Nature. 2014 Jan 30; 505(7485):635–40

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For an interesting critique of this issue, see Fatica A., Bozzoni I. Long non-coding RNAs: new players in cell differentiation and development. Nat Rev Genet. 2014 Jan; 15(1):7–21

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Bernard D., Prasanth K. V., Tripathi V., Colasse S., Nakamura T., Xuan Z., Zhang M. Q., Sedel F., Jourdren L., Coulpier F., Triller A., Spector D. L., Bessis A. A long nuclear-retained non-coding RNA regulates synaptogenesis by modulating gene expression. EMBO J. 2010 Sep 15; 29(18):3082–93

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Pollard K. S., Salama S. R., Lambert N., Lambot M. A., Coppens S., Pedersen J. S., Katzman S., King B., Onodera C., Siepel A., Kern A. D., Dehay C., Igel H., Ares M Jr., Vanderhaeghen P., Haussler D. An RNA gene expressed during cortical development evolved rapidly in humans. Nature. 2006 Sep 14; 443(7108):167–72

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http://www.who.int/mental_health/publications/dementia_report_2012/en/

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Faghihi M. A., Modarresi F., Khalil A. M., Wood D. E., Sahagan B. G., Morgan T. E., Finch C. E., St Laurent G. 3rd., Kenny P. J., Wahlestedt C. Expression of a noncoding RNA is elevated in Alzheimer’s disease and drives rapid feed-forward regulation of beta-secretase. Nat Med. 2008 Jul; 14(7):723–30

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Modarresi F., Faghihi M. A., Patel N. S., Sahagan B. G., Wahlestedt C., Lopez-Toledano M. A. Knockdown of BACE1-AS Nonprotein-Coding Transcript Modulates Beta-Amyloid-Related Hippocampal Neurogenesis. Int J Alzheimers Dis. 2011; 2011:929042

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Zhao X., Tang Z., Zhang H., Atianjoh F. E., Zhao J. Y., Liang L., Wang W., Guan X., Kao S. C., Tiwari V., Gao Y. J., Hoffman P. N., Cui H., Li M., Dong X., Tao Y. X. A long noncoding RNA contributes to neuropathic pain by silencing Kcna2 in primary afferent neurons. Nat Neurosci. 2013 Aug; 16(8):1024–31

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For a useful review, see for example Wahlestedt C. Targeting long non-coding RNA to therapeutically upregulate gene expression. Nat Rev Drug Discov. 2013 Jun; 12(6):433–46

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Bird A. Genome biology: not drowning but waving. Cell. 2013 Aug 29; 154(5):951–2

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If you want to learn more about this topic, have a read of my first book, The Epigenetics Revolution.

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Guttman M., Donaghey J., Carey BW., Garber M., Grenier J. K., Munson G., Young G., Lucas A. B., Ach R., Bruhn L., Yang X., Amit I., Meissner A., Regev A., Rinn J. L., Root D. E., Lander E. S. lincRNAs act in the circuitry controlling pluripotency and differentiation. Nature. 2011 Aug 28; 477(7364):295–300

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Guil S., Soler M., Portela A., Carrère J., Fonalleras E., Gómez A., Villanueva A., Esteller M. Intronic RNAs mediate EZH2 regulation of epigenetic targets. Nat Struct Mol Biol. 2012 Jun 3; 19(7):664–70

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Varambally S., Dhanasekaran SM., Zhou M., Barrette T. R., Kumar-Sinha C., Sanda M. G., Ghosh D., Pienta K. J., Sewalt R. G., Otte A. P., Rubin M. A., Chinnaiyan A. M. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature. 2002 Oct 10; 419(6907):624–9

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Kleer C. G., Cao Q., Varambally S., Shen R., Ota I., Tomlins S. A., Ghosh D., Sewalt R. G., Otte A. P., Hayes D. F., Sabel M. S., Livant D., Weiss S. J., Rubin M. A., Chinnaiyan A. M. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci U S A. 2003 Sep 30; 100(20):11606–11.

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Sneeringer C. J., Scott M. P., Kuntz K. W., Knutson S. K., Pollock R. M., Richon V. M., Copeland R. A. Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas. Proc Natl Acad Sci U S A. 2010 Dec 7; 107(49):20980–5

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http://clinicaltrials.gov/ct2/show/NCT01897571?term=7438&rank=1

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Kotake Y., Nakagawa T., Kitagawa K., Suzuki S., Liu N., Kitagawa M., Xiong Y. Long non-coding RNA ANRIL is required for the PRC2 recruitment to and silencing of p15(INK4B) tumor suppressor gene. Oncogene. 2011 Apr 21; 30(16):1956–62

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Tsai M. C., Manor O., Wan Y., Mosammaparast N., Wang J. K., Lan F., Shi Y., Segal E., Chang H. Y. Long noncoding RNA as modular scaffold of histone modification complexes. Science. 2010 Aug 6; 329(5992):689–93

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For a recent major paper on this see Davidovich C., Zheng L., Goodrich K. J., Cech T. R. Promiscuous RNA binding by Polycomb repressive complex 2. Nat Struct Mol Biol. 2013 Nov; 20(11):1250–7

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For a slightly more accessible summary of the above paper, see Goff LA, Rinn JL. Poly-combing the genome for RNA. Nat Struct Mol Biol. 2013 Dec; 20(12):1344–6

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Di Ruscio A., Ebralidze A. K., Benoukraf T., Amabile G., Goff L. A., Terragni J., Figueroa M. E., De Figueiredo Pontes L. L., Alberich-Jorda M., Zhang P., Wu M., D’Alò F., Melnick A., Leone G., Ebralidze K. K., Pradhan S., Rinn J. L., Tenen D. G. DNMT1-interacting RNAs block gene-specific DNA methylation. Nature. 2013 Nov 21; 503(7476):371–6

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For an overview of all the complex stages in this process see Froberg J. E., Yang L., Lee J. T. Guided by RNAs: X-inactivation as a model for long non-coding RNA function. J Mol Biol. 2013 Oct 9; 425(19):3698–706

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Froberg J. E., Yang L., Lee J. T. Guided by RNAs: X-inactivation as a model for long non-coding RNA function. J Mol Biol. 2013 Oct 9; 425(19):3698–706

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Michaud E. J., van Vugt M. J., Bultman S. J., Sweet H. O., Davisson M. T., Woychik R. P. Differential expression of a new dominant agouti allele (Aiapy) is correlated with methylation state and is influenced by parental lineage. Genes Dev. 1994 Jun 15; 8(12):1463–72

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Reviewed in Skaar D. A., Li Y., Bernal A. J., Hoyo C., Murphy S. K., Jirtle R. L. The human imprintome: regulatory mechanisms, methods of ascertainment, and roles in disease susceptibility. ILAR J. 2012 Dec; 53(3–4):341–58

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A description of the actions of these proteins in the methylation of the maternal ICE can be found in Bourc’his D., Proudhon C. Sexual dimorphism in parental imprint ontogeny and contribution to embryonic development. Mol Cell Endocrinol. 2008 Jan 30; 282(1–2):87–94

185

The paper that demonstrated the importance of this protein for maintaining the maternal imprint is Hirasawa R., Chiba H., Kaneda M., Tajima S., Li E., Jaenisch R., Sasaki H. Maternal and zygotic Dnmt1 are necessary and sufficient for the maintenance of DNA methylation imprints during preimplantation development. Genes Dev. 2008 Jun 15; 22(12):1607–16

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Reinhart B., Paoloni-Giacobino A., Chaillet J. R. Specific differentially methylated domain sequences direct the maintenance of methylation at imprinted genes. Mol Cell Biol. 2006 Nov; 26(22):8347–56

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Skaar D. A., Li Y., Bernal A. J., Hoyo C., Murphy S. K., Jirtle R. L. The human imprintome: regulatory mechanisms., methods of ascertainment, and roles in disease susceptibility. ILAR J. 2012 Dec; 53(3–4):341–58

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Kawahara M., Wu Q., Takahashi N., Morita S., Yamada K., Ito M., Ferguson-Smith A. C., Kono T. High-frequency generation of viable mice from engineered bi-maternal embryos. Nat Biotechnol. 2007 Sep; 25(9):1045–50

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Reviewed in Fatica A., Bozzoni I. Long non-coding RNAs: new players in cell differentiation and development. Nat Rev Genet. 2014 Jan; 15(1):7–21

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For a review of this aspect, see Frost J. M., Moore G. E. The importance of imprinting in the human placenta. PLoS Genet. 2010 Jul 1; 6(7):e1001015

191

For a full description see http://omim.org/entry/176270

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For a full description see http://omim.org/entry/105830

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For a contemporaneous review of the work see Surani M. A., Barton S. C., Norris M. L. Experimental reconstruction of mouse eggs and embryos: an analysis of mammalian development. Biol Reprod. 1987 Feb; 36(1):1–16

194

An online depository of imprinted mouse sequences can be found at http://www.mousebook.org/catalog.php?catalog=imprinting

195

For a useful review see Guenzl P. M., Barlow D. P. Macro long non-coding RNAs: a new layer of cis-regulatory information in the mammalian genome. RNA Biol. 2012 Jun; 9(6):731–41

196

For a recent review of imprinting in marsupials see Graves J. A., Renfree M. B. Marsupials in the age of genomics. Annu Rev Genomics Hum Genet. 2013; 14:393–420

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Landers M., Bancescu D. L., Le Meur E., Rougeulle C., Glatt-Deeley H., Brannan C., Muscatelli F., Lalande M. Regulation of the large (approximately 1000 kb) imprinted murine Ube3a antisense transcript by alternative exons upstream of Snurf/Snrpn. Nucleic Acids Res. 2004 Jun 29; 32(11):3480–92

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Terranova R., Yokobayashi S., Stadler M. B., Otte A. P., van Lohuizen M., Orkin S. H., Peters A. H. Polycomb group proteins Ezh2 and Rnf2 direct genomic contraction and imprinted repression in early mouse embryos. Dev Cell. 2008 Nov; 15(5):668–79

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Wagschal A., Sutherland H. G., Woodfine K., Henckel A., Chebli K., Schulz R., Oakey R. J., Bickmore W. A., Feil R. G9a histone methyltransferase contributes to imprinting in the mouse placenta. Mol Cell Biol. 2008 Feb; 28(3):1104–13

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Nagano T., Mitchell J. A., Sanz L. A., Pauler F. M., Ferguson-Smith A. C., Feil R., Fraser P. The Air noncoding RNA epigenetically silences transcription by targeting G9a to chromatin. Science. 2008 Dec 12; 322(5908):1717–20

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Reviewed in Koerner M. V., Pauler F. M., Huang R., Barlow D. P. The function of non-coding RNAs in genomic imprinting. Development. 2009 Jun; 136(11):1771–83

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Barlow D. P. Methylation and imprinting: from host defense to gene regulation? Science. 1993 Apr 16; 260(5106):309–10

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de Smith A. J., Purmann C., Walters R. G., Ellis R. J., Holder S. E., Van Haelst M. M., Brady A. F., Fairbrother U. L., Dattani M., Keogh J. M., Henning E., Yeo G. S., O’Rahilly S., Froguel P., Farooqi I. S., Blakemore A. I. A deletion of the HBII-85 class of small nucleolar RNAs (snoRNAs) is associated with hyperphagia, obesity and hypogonadism. Hum Mol Genet. 2009 Sep 1; 18(17):3257–65

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Duker A. L., Ballif B. C., Bawle E. V., Person R. E., Mahadevan S., Alliman S., Thompson R., Traylor R., Bejjani B. A., Shaffer L. G., Rosenfeld J. A., Lamb A. N., Sahoo T. Paternally inherited microdeletion at 15q11.2 confirms a significant role for the SNORD116 C/D box snoRNA cluster in Prader-Willi syndrome. Eur J Hum Genet. 2010 Nov; 18(11):1196–201

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Sahoo T., del Gaudio D., German J. R., Shinawi M., Peters S. U., Person R. E., Garnica A., Cheung S. W., Beaudet A. L. Prader-Willi phenotype caused by paternal deficiency for the HBII-85 C/D box small nucleolar RNA cluster. Nat Genet. 2008 Jun; 40(6):719–21

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For a full description see http://omim.org/entry/180860

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For a full description see http://omim.org/entry/130650

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Data collated in Kotzot D. Maternal uniparental disomy 14 dissection of the phenotype with respect to rare autosomal recessively inherited traits, trisomy mosaicism, and genomic imprinting. Ann Genet. 2004 Jul-Sep; 47(3):251–60

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Kagami M., Sekita Y., Nishimura G., Irie M., Kato F., Okada M., Yamamori S., Kishimoto H., Nakayama M., Tanaka Y., Matsuoka K., Takahashi T., Noguchi M., Tanaka Y., Masumoto K., Utsunomiya T., Kouzan H., Komatsu Y., Ohashi H., Kurosawa K., Kosaki K., Ferguson-Smith AC., Ishino F., Ogata T. Deletions and epimutations affecting the human 14q32.2 imprinted region in individuals with paternal and maternal upd(14)-like phenotypes. Nat Genet. 2008 Feb; 40(2):237–42

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For a detailed review of the inheritance and clinical characteristics of various human imprinting disorders, see the review by Ishida M., Moore GE. The role of imprinted genes in humans. Mol Aspects Med. 2013 Jul-Aug; 34(4):826–40

211

Press release on 14 October 2013 from American Society for Reproductive Medicine http://www.asrm.org/Five_Million_Babies_Born_with_Help_of_Assisted_Reproductive_Technologies/

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This is discussed in some detail in Ishida M., Moore G. E. The role of imprinted genes in humans. Mol Aspects Med. 2013 Jul — Aug; 34(4):826–40

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Reviewed in Moss T., Langlois F., Gagnon-Kugler T., Stefanovsky V. A housekeeper with power of attorney: the rRNA genes in ribosome biogenesis. Cell Mol Life Sci. 2007 Jan; 64(1):29–49

214

For more information on ribosomes and rRNAs it is easiest to refer to a good molecular biology textbook such as Molecular Biology of the Cell., 5th Edition by Alberts., Johnson, Lewis, Raff, Roberts and Walter, 2012.

215

http://www.nobelprize.org/educational/medicine/dna/a/translation/trna.html

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http://www.bscb.org/?url=softcell/ribo

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Reviewed in Zentner G. E., Saiakhova A., Manaenkov P., Adams M. D., Scacheri P. C. Integrative genomic analysis of human ribosomal DNA. Nucleic Acids Res. 2011 Jul; 39(12):4949–60

218

This whole area of diseases caused by defects in ribosomal proteins is interestingly, if occasionally rather provocatively reviewed in Narla A., Ebert B. L. Ribosomopathies: human disorders of ribosome dysfunction. Blood. 2010 Apr 22; 115(16):3196–205

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International Human Genome Sequencing Consortium. Initial sequencing and analysis of the human genome. Nature. 2001 Feb 15; 409(6822):860–921

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See for example Hedges S. B., Blair J. E., Venturi M. L., Shoe J. L. A molecular timescale of eukaryote evolution and the rise of complex multicellular life. BMC Evol Biol. 2004 Jan 28; 4:2

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Reviewed in Wilson D. N. Ribosome-targeting antibiotics and mechanisms of bacterial resistance. Nat Rev Microbiol. 2014 Jan; 12(1):35–48

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http://www.genenames.org/rna/TRNA#MTTRNA

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Once again I would recommend a good molecular biology textbook if you would like to learn more, such as Molecular Biology of the Cell, 5th Edition by Alberts, Johnson, Lewis, Raff, Roberts and Walter, 2012

224

McFarland R., Schaefer A. M., Gardner J. L., Lynn S., Hayes C. M., Barron M. J., Walker M., Chinnery P. F., Taylor R. W., Turnbull D. M. Familial myopathy: new insights into the T14709C mitochondrial tRNA mutation. Ann Neurol. 2004 Apr; 55(4):478–84

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Zheng J., Ji Y., Guan M. X. Mitochondrial tRNA mutations associated with deafness. Mitochondrion. 2012 May; 12(3):406–13

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Qiu Q., Li R., Jiang P., Xue L., Lu Y., Song Y., Han J., Lu Z., Zhi S., Mo J. Q., Guan M. X. Mitochondrial tRNA mutations are associated with maternally inherited hypertension in two Han Chinese pedigrees. Hum Mutat. 2012 Aug; 33(8):1285–93

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Giordano C., Perli E., Orlandi M., Pisano A., Tuppen H. A., He L., Ierinò R., Petruzziello L., Terzi A., Autore C., Petrozza V., Gallo P., Taylor R. W., d’Amati G. Cardiomyopathies due to homoplasmic mitochondrial tRNA mutations: morphologic and molecular features. Hum Pathol. 2013 Jul; 44(7):1262–70

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Lincoln T. A., Joyce G. F. Self-sustained replication of an RNA enzyme. Science. 2009 Feb 27; 323(5918):1229–32

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Sczepanski J. T., Joyce G. F. A cross-chiral RNA polymerase ribozyme. Nature. Published online 29 October 2014

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An overview of MYC’s role, and the importance of chromosomal rearrangements can be found in Ott G., Rosenwald A., Campo E. Understanding MYC-driven aggressive B-cell lymphomas: pathogenesis and classification. Blood. 2013 Dec 5; 122(24):3884–91

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http://www.nlm.nih.gov/medlineplus/ency/article/001308.htm

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Whyte W. A., Orlando D. A., Hnisz D., Abraham B. J., Lin C. Y., Kagey M. H., Rahl P. B., Lee T. I., Young R. A. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell. 2013 Apr 11; 153(2):307–19

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Ostuni R., Piccolo V., Barozzi I., Polletti S., Termanini A., Bonifacio S., Curina A., Prosperini E., Ghisletti S., Natoli G. Latent enhancers activated by stimulation in differentiated cells. Cell. 2013 Jan 17; 152(1–2):157–71

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Akhtar-Zaidi B., Cowper-Sal-lari R., Corradin O., Saiakhova A., Bartels CF., Balasubramanian D., Myeroff L., Lutterbaugh J., Jarrar A., Kalady M. F., Willis J., Moore J. H., Tesar P. J., Laframboise T., Markowitz S., Lupien M., Scacheri P. C. Epigenomic enhancer profiling defines a signature of colon cancer. Science. 2012 May 11; 336(6082):736–9

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ENCODE Project Consortium., Bernstein B. E., Birney E., Dunham I., Green E. D., Gunter C., Snyder M. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012 Sep 6; 489(7414):57–74

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For a description of these types of long non-coding RNAs see Ørom U. A., Shiekhattar R. Long noncoding RNAs usher in a new era in the biology of enhancers. Cell. 2013 Sep 12; 154(6):1190–3

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Ørom U. A., Derrien T., Beringer M., Gumireddy K., Gardini A., Bussotti G., Lai F., Zytnicki M., Notredame C., Huang Q., Guigo R., Shiekhattar R. Long noncoding RNAs with enhancer-like function in human cells. Cell. 2010 Oct 1; 143(1):46–58

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De Santa F., Barozzi I., Mietton F., Ghisletti S., Polletti S., Tusi BK., Muller H., Ragoussis J., Wei C. L., Natoli G. A large fraction of extragenic RNA pol II transcription sites overlap enhancers. PLoS Biol. 2010 May 11; 8(5):e1000384

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Hah N., Murakami S., Nagari A., Danko C. G., Kraus W. L. Enhancer transcripts mark active estrogen receptor binding sites. Genome Res. 2013 Aug; 23(8):1210–23

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Lai F., Ørom U. A., Cesaroni M., Beringer M., Taatjes D. J., Blobel G. A., Shiekhattar R. Activating RNAs associate with Mediator to enhance chromatin architecture and transcription. Nature. 2013 Feb 28; 494(7438):497–501

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Risheg H., Graham J. M Jr., Clark R. D., Rogers R. C., Opitz J. M., Moeschler J. B., Peiffer A. P., May M., Joseph S. M., Jones J. R., Stevenson R. E., Schwartz C. E., Friez M. J. A recurrent mutation in MED12 leading to R961W causes Opitz-Kaveggia syndrome. Nat Genet. 2007 Apr; 39(4):451–3

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The role of super-enhancers in pluripotent cells was first identified in Whyte W. A., Orlando D. A., Hnisz D., Abraham B. J., Lin C. Y., Kagey M. H., Rahl P. B., Lee T. I., Young R. A. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell. 2013 Apr 11; 153(2):307–19

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Takahashi K., Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006 Aug 25; 126(4):663–76

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http://www.nobelprize.org/nobel_prizes/medicine/laureates/2012/

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For an overview of the various molecular causes see Skibbens R. V., Colquhoun J. M., Green M. J., Molnar C. A., Sin D. N., Sullivan B. J., Tanzosh E. E. Cohesinopathies of a feather flock together. PLoS Genet. 2013 Dec; 9(12):e1004036

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http://www.cdls.org.uk/information-centre/

248

Sanyal A., Lajoie B. R., Jain G., Dekker J. The long-range interaction landscape of gene promoters. Nature. 2012 Sep 6; 489(7414):109–13

249

Jackson D. A., Hassan A. B., Errington R. J., Cook P. R. Visualization of focal sites of transcription within human nuclei. EMBO J. 1993 Mar; 12(3):1059–65

250

For an excellent review of this topic see Rieder D., Trajanoski Z., McNally J. G. Transcription factories. Front Genet. 2012 Oct 23; 3:221. doi: 10.3389/fgene.2012.00221. eCollection 2012

251

Iborra F. J., Pombo A., Jackson D. A., Cook P. R. Active RNA polymerases are localized within discrete transcription ‘factories’ in human nuclei. J Cell Sci. 1996 Jun; 109 (Pt 6):1427–36

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Jackson D. A., Iborra F. J., Manders E. M., Cook P. R. Numbers and organization of RNA polymerases, nascent transcripts, and transcription units in HeLa nuclei. Mol Biol Cell. 1998 Jun; 9(6):1523–36

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Papantonis A., Larkin J. D., Wada Y., Ohta Y., Ihara S., Kodama T., Cook P. R. Active RNA polymerases: mobile or immobile molecular machines? PLoS Biol. 2010 Jul 13; 8(7):e1000419

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Osborne C. S., Chakalova L., Brown K. E., Carter D., Horton A., Debrand E., Goyenechea B., Mitchell J. A., Lopes S., Reik W., Fraser P. Active genes dynamically colocalize to shared sites of ongoing transcription. Nat Genet. 2004 Oct; 36(10):1065–71

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Osborne C. S., Chakalova L., Mitchell J. A., Horton A., Wood A. L., Bolland D. J., Corcoran A. E., Fraser P. Myc dynamically and preferentially relocates to a transcription factory occupied by Igh. PLoS Biol. 2007 Aug; 5(8):e192

256

It’s difficult to find a definitive first use of this description, as discussed in http://english.stackexchange.com/questions/103851/where-does-the-phrase-of-boredom-punctuated-by-moments-of-terror-come-from

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For a review of this, see Moltó E., Fernández A., Montoliu L. Boundaries in vertebrate genomes: different solutions to adequately insulate gene expression domains. Brief Funct Genomic Proteomic. 2009 Jul; 8(4):283–96

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Ishihara K., Oshimura M., Nakao M. CTCF-dependent chromatin insulator is linked to epigenetic remodeling. Mol Cell. 2006 Sep 1; 23(5):733–42

259

Lutz M., Burke L. J., Barreto G., Goeman F., Greb H., Arnold R., Schultheiss H., Brehm A., Kouzarides T., Lobanenkov V., Renkawitz R. Transcriptional repression by the insulator protein CTCF involves histone deacetylases. Nucleic Acids Res. 2000 Apr 15; 28(8):1707–13

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Lunyak V. V., Prefontaine G. G., Núñez E., Cramer T., Ju B. G., Ohgi K. A., Hutt K., Roy R., García-Díaz A., Zhu X., Yung Y., Montoliu L., Glass C. K., Rosenfeld M. G. Developmentally regulated activation of a SINE B2 repeat as a domain boundary in organogenesis. Science. 2007 Jul 13; 317(5835):248–51

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Reviewed in Kirkland J. G., Raab J. R., Kamakaka R. T. TFIIIC bound DNA elements in nuclear organization and insulation. Biochim Biophys Acta. 2013 Mar — Apr; 1829(3–4):418–24

262

This is known as Turner’s syndrome and more information can be found at http://www.nhs.uk/Conditions/Turners-syndrome/Pages/Introduction.aspx

263

For more information see http://ghr.nlm.nih.gov/condition/triple-x-syndrome

264

This condition is known as Klinefelter’s syndrome and more information can be found at http://ghr.nlm.nih.gov/condition/klinefelter-syndrome

265

Star Trek: First Contact (1996). By far the best of all the Star Trek movies, at least until the JJ Abrams franchise reboot.

266

See https://ghr.nlm.nih.gov/gene/SHOX

267

Hemani G., Yang J., Vinkhuyzen A., Powell J. E., Willemsen G., Hottenga J. J., Abdellaoui A., Mangino M., Valdes A. M., Medland S. E., Madden P. A., Heath A. C., Henders A. K., Nyholt D. R., de Geus E. J., Magnusson P. K., Ingelsson E., Montgomery G. W., Spector T. D., Boomsma D. I., Pedersen N. L., Martin N. G., Visscher P. M. Inference of the genetic architecture underlying BMI and height with the use of 20.,240 sibling pairs. Am J Hum Genet. 2013 Nov 7; 93(5):865–75

268

A wealth of information about ENCODE, including interviews with some of the leading scientists, can be accessed at http://www.nature.com/encode/

269

http://www.theguardian.com/science/2012/sep/05/genes-genome-junk-dna-encode

270

http://edition.cnn.com/2012/09/05/health/encode-human-genome/index.html?hpt=hp_bn12

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http://www.telegraph.co.uk/science/science-news/9524165/Worldwide-army-of-scientists-cracks-the-junk-DNA-code.html

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ENCODE Project Consortium, Bernstein B. E., Birney E., Dunham I., Green E. D., Gunter C., Snyder M. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012 Sep 6; 489(7414):57–74

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Mattick J. S. A new paradigm for developmental biology. J Exp Biol. 2007 May; 210(Pt 9):1526–47

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Sanyal A., Lajoie B. R., Jain G., Dekker J. The long-range interaction landscape of gene promoters. Nature. 2012 Sep 6; 489(7414):109–13

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Thurman R. E., Rynes E., Humbert R., Vierstra J., Maurano M. T., Haugen E., Sheffield N. C., Stergachis A. B., Wang H., Vernot B., Garg K., John S., Sandstrom R., Bates D., Boatman L., Canfield T. K., Diegel M., Dunn D., Ebersol A. K., Frum T., Giste E., Johnson A. K., Johnson E. M., Kutyavin T., Lajoie B., Lee B. K., Lee K., London D., Lotakis D., Neph S., Neri F., Nguyen E. D., Qu H., Reynolds A. P., Roach V., Safi A., Sanchez M. E., Sanyal A., Shafer A., Simon J. M., Song L., Vong S., Weaver M., Yan Y., Zhang Z., Zhang Z., Lenhard B., Tewari M., Dorschner M. O., Hansen R. S., Navas P. A., Stamatoyannopoulos G., Iyer V. R., Lieb J. D., Sunyaev S. R., Akey J. M., Sabo P. J., Kaul R., Furey T. S., Dekker J., Crawford G. E., Stamatoyannopoulos J. A. The accessible chromatin landscape of the human genome. Nature. 2012 Sep 6; 489(7414):75–82

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Djebali S., Davis C. A., Merkel A., Dobin A., Lassmann T., Mortazavi A., Tanzer A., Lagarde J., Lin W., Schlesinger F., Xue C., Marinov G. K., Khatun J., Williams B. A., Zaleski C., Rozowsky J., Röder M., Kokocinski F., Abdelhamid R. F., Alioto T., Antoshechkin I., Baer M. T., Bar N. S., Batut P., Bell K., Bell I., Chakrabortty S., Chen X., Chrast J., Curado J., Derrien T., Drenkow J., Dumais E., Dumais J., Duttagupta R., Falconnet E., Fastuca M., Fejes-Toth K., Ferreira P., Foissac S., Fullwood M. J., Gao H., Gonzalez D., Gordon A., Gunawardena H., Howald C., Jha S., Johnson R., Kapranov P., King B., Kingswood C., Luo O. J., Park E., Persaud K., Preall J. B., Ribeca P., Risk B., Robyr D., Sammeth M., Schaffer L., See L. H., Shahab A., Skancke J., Suzuki A. M., Takahashi H., Tilgner H., Trout D., Walters N., Wang H., Wrobel J., Yu Y., Ruan X., Hayashizaki Y., Harrow J., Gerstein M., Hubbard T., Reymond A., Antonarakis S. E., Hannon G., Giddings M. C., Ruan Y., Wold B., Carninci P., Guigó R., Gingeras T. R. Landscape of transcription in human cells. Nature. 2012 Sep 6; 489(7414):101–8

277

I originally used this description in a Huffington Post blog about the ENCODE project. I’ve decided I like it so much I will use it again here! For the original blog, see http://www.huffingtonpost.com/nessa-carey/the-value-of-encode_b_1909153.html

278

A good example can be found at http://blog.art21.org/2009/03/06/on-representations-of-the-artist-at-work-part-2/#.UyDZjZZFDIU

279

Ward L. D., Kellis M. Evidence of abundant purifying selection in humans for recently acquired regulatory functions. Science. 2012 Sep 28; 337(6102):1675–8.

280

Ecker J. R., Bickmore W. A., Barroso I., Pritchard J. K., Gilad Y., Segal E. Genomics: ENCODE explained. Nature. 2012 Sep 6; 489(7414)

281

For a fascinating example of epigenetic transgenerational inheritance see this paper, in which a fear response was passed on from parent to pups: Dias B. G., Ressler K. J. Parental olfactory experience influences behavior and neural structure in subsequent generations. Nat Neurosci. 2014 Jan; 17(1):89–96

282

Graur D., Zheng Y., Price N., Azevedo R. B., Zufall R. A., Elhaik E. On the immortality of television sets: ‘function’ in the human genome according to the evolution-free gospel of ENCODE. Genome Biol Evol. 2013; 5(3):578–90

283

http://womenshistory.about.com/od/mythsofwomenshistory/a/Did-Anne-Boleyn-Really-Have-Six-Fingers-On-One-Hand.htm

284

Lettice L. A., Heaney S. J., Purdie L. A., Li L., de Beer P., Oostra B. A., Goode D., Elgar G., Hill R. E., de Graaff E. A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly. Hum Mol Genet. 2003 Jul 15; 12(14):1725–35

285

www.hemingwayhome.com/cats/

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Lettice L. A., Hill A. E., Devenney P. S., Hill R. E. Point mutations in a distant sonic hedgehog cis-regulator generate a variable regulatory output responsible for preaxial polydactyly. Hum Mol Genet. 2008 Apr 1; 17(7):978–85

287

For a fuller description, see http://www.genome.gov/12512735

288

Jeong Y., Leskow F. C., El-Jaick K., Roessler E., Muenke M., Yocum A., Dubourg C., Li X., Geng X., Oliver G., Epstein D. J. Regulation of a remote Shh forebrain enhancer by the Six3 homeoprotein. Nat Genet. 2008 Nov; 40(11):1348–53

289

For more information see http://rarediseases.info.nih.gov/gard/10874/pancreatic-agenesis/resources/1

290

Lango Allen H., Flanagan S. E., Shaw-Smith C., De Franco E., Akerman I., Caswell R; International Pancreatic Agenesis Consortium., Ferrer J., Hattersley A. T., Ellard S. GATA6 haploinsufficiency causes pancreatic agenesis in humans. Nat Genet. 2011 Dec 11; 44(1):20–2

291

Sellick G. S., Barker K. T., Stolte-Dijkstra I., Fleischmann C., Coleman R. J., Garrett C., Gloyn A. L., Edghill E. L., Hattersley A. T., Wellauer P. K., Goodwin G., Houlston R. S. Mutations in PTF1A cause pancreatic and cerebellar agenesis. Nat Genet. 2004 Dec; 36(12):1301–5

292

Weedon M. N., Cebola I., Patch A. M., Flanagan S. E., De Franco E., Caswell R., Rodríguez-Seguí SA., Shaw-Smith C., Cho C. H., Lango Allen H., Houghton J. A., Roth C. L., Chen R., Hussain K., Marsh P., Vallier L., Murray A; International Pancreatic Agenesis Consortium, Ellard S., Ferrer J., Hattersley AT. Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis. Nat Genet. 2014 Jan; 46(1):61–4

293

For a review of this, see Sturm RA. Molecular genetics of human pigmentation diversity. Hum Mol Genet. 2009 Apr 15; 18(R1):R9–17

294

Durham-Pierre D., Gardner J. M., Nakatsu Y., King RA., Francke U., Ching A., Aquaron R., del Marmol V., Brilliant M. H. African origin of an intragenic deletion of the human P gene in tyrosinase positive oculocutaneous albinism. Nat Genet. 1994 Jun; 7(2):176–9

295

Visser M., Kayser M., Palstra R. J. HERC2 rs12913832 modulates human pigmentation by attenuating chromatin-loop formation between a long-range enhancer and the OCA2 promoter. Genome Res. 2012 Mar; 22(3):446–55

296

For an up-to-date catalogue, see www.genome.gov/gwastudies/

297

Hindorff L. A., Sethupathy P., Junkins H. A., Ramos E. M., Mehta J. P., Collins F. S., Manolio T. A. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci U S A. 2009 Jun 9; 106(23):9362–7

298

Gorkin D. U., Ren B. Genetics: Closing the distance on obesity culprits. Nature. 2014 Mar 20; 507(7492):309–10

299

Frayling T. M., Timpson N. J., Weedon M. N., Zeggini E., Freathy R. M., Lindgren C. M., Perry J. R., Elliott K. S., Lango H., Rayner N. W., Shields B., Harries L. W., Barrett J. C., Ellard S., Groves C. J., Knight B., Patch A. M., Ness A. R., Ebrahim S., Lawlor D. A., Ring S. M., Ben-Shlomo Y., Jarvelin M. R., Sovio U., Bennett A. J., Melzer D., Ferrucci L., Loos R. J., Barroso I., Wareham N. J., Karpe F., Owen K. R., Cardon L. R., Walker M., Hitman G. A., Palmer C. N., Doney A. S., Morris A. D., Smith G. D., Hattersley A. T., McCarthy M. I. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. 2007 May 11; 316(5826):889–94

300

Scuteri A., Sanna S., Chen WM., Uda M., Albai G., Strait J., Najjar S., Nagaraja R., Orrú M., Usala G., Dei M., Lai S., Maschio A., Busonero F., Mulas A., Ehret GB., Fink AA., Weder AB., Cooper RS., Galan P., Chakravarti A., Schlessinger D., Cao A., Lakatta E., Abecasis GR. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet. 2007 Jul; 3(7):e115

301

Church C., Moir L., McMurray F., Girard C., Banks G. T., Teboul L., Wells S., Brüning J. C., Nolan P. M., Ashcroft F. M., Cox R. D. Overexpression of Fto leads to increased food intake and results in obesity. Nat Genet. 2010 Dec; 42(12):1086–92

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Fischer J., Koch L., Emmerling C., Vierkotten J., Peters T., Brüning J. C., Rüther U. Inactivation of the Fto gene protects from obesity. Nature. 2009 Apr 16; 458(7240):894–8

303

Smemo S., Tena J. J., Kim K. H., Gamazon E. R., Sakabe N. J., Gómez-Marín C., Aneas I., Credidio F. L., Sobreira D. R., Wasserman N. F., Lee J. H., Puviindran V., Tam D., Shen M., Son J. E., Vakili N. A., Sung H. K., Naranjo S., Acemel R. D., Manzanares M., Nagy A., Cox N. J., Hui C. C., Gomez-Skarmeta J. L., Nóbrega M. A. Obesity-associated variants within FTO form long-range functional connections with IRX3. Nature. 2014 Mar 20; 507(7492):371–5

304

For a recent review of this field see Trent R. J., Cheong P. L., Chua E. W., Kennedy M. A. Progressing the utilisation of pharmacogenetics and pharmacogenomics into clinical care. Pathology. 2013 Jun; 45(4):357–70

305

http://www.nhs.uk/Conditions/Herceptin/Pages/Introduction.aspx

306

http://www.nature.com/scitable/topicpage/gleevec-the-breakthrough-in-cancer-treatment-565

307

http://www.cancer.gov/cancertopics/druginfo/fda-crizotinib

308

Examples of such cases can be found at http://medicalmisdiagnosisresearch.wordpress.com/category/osteogenesis-imperfecta-misdiagnosed-as-child-abuse/

309

For a good description of the symptoms and genetics, see http://ghr.nlm.nih.gov/condition/osteogenesis-imperfecta

310

Cho T. J., Lee K. E., Lee S. K., Song S. J., Kim K. J., Jeon D., Lee G., Kim H. N., Lee H. R., Eom H. H., Lee Z. H., Kim O. H., Park W. Y., Park S. S., Ikegawa S., Yoo W. J., Choi I. H., Kim J. W. A single recurrent mutation in the 5′-UTR of IFITM5 causes osteogenesis imperfecta type V. Am J Hum Genet. 2012 Aug 10; 91(2):343–8

311

Semler O., Garbes L., Keupp K., Swan D., Zimmermann K., Becker J., Iden S., Wirth B., Eysel P., Koerber F., Schoenau E., Bohlander S. K., Wollnik B., Netzer C. A mutation in the 5′-UTR of IFITM5 creates an in-frame start codon and causes autosomal-dominant osteogenesis imperfecta type V with hyperplastic callus. Am J Hum Genet. 2012 Aug 10; 91(2):349–57

312

Moffatt P., Gaumond M. H., Salois P., Sellin K., Bessette M. C., Godin E., de Oliveira P. T., Atkins G. J., Nanci A., Thomas G. Bril: a novel bone-specific modulator of mineralization. J Bone Miner Res. 2008 Sep; 23(9):1497–508

313

Liu L., Dilworth D., Gao L., Monzon J., Summers A., Lassam N., Hogg D. Mutation of the CDKN2A 5′ UTR creates an aberrant initiation codon and predisposes to melanoma. Nat Genet. 1999 Jan; 21(1):128–32

314

Tietze J. K., Pfob M., Eggert M., von Preußen A., Mehraein Y., Ruzicka T., Herzinger T. A non-coding mutation in the 5′ untranslated region of patched homologue 1 predisposes to basal cell carcinoma. Exp Dermatol. 2013 Dec; 22(12):834–5

315

For a full description see http://omim.org/entry/309550

316

Ashley C. T Jr., Wilkinson K. D., Reines D., Warren S. T. FMR1 protein: conserved RNP family domains and selective RNA binding. Science. 1993 Oct 22; 262(5133):563–6

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Qin M., Kang J., Burlin T. V., Jiang C., Smith C. B. Postadolescent changes in regional cerebral protein synthesis: an in vivo study in the FMR1 null mouse. J Neurosci. 2005 May 18; 25(20):5087–95

318

Azevedo F. A., Carvalho L. R., Grinberg L. T., Farfel J. M., Ferretti R. E., Leite R. E., Jacob Filho W., Lent R., Herculano-Houzel S. Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain. J Comp Neurol. 2009 Apr 10; 513(5):532–41

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Drachman D. A. Do we have brain to spare? Neurology. 2005 Jun 28; 64(12):2004–5

320

Darnell J. C., Van Driesche S. J., Zhang C., Hung K. Y., Mele A., Fraser C. E., Stone E. F., Chen C., Fak J. J., Chi S. W., Licatalosi D. D., Richter J. D., Darnell R. B. FMRP stalls ribosomal translocation on messenger RNAs linked to synaptic function and autism. Cell. 2011 Jul 22; 146(2):247–61

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Udagawa T., Farny N. G., Jakovcevski M., Kaphzan H., Alarcon J. M., Anilkumar S., Ivshina M., Hurt J. A., Nagaoka K., Nalavadi V. C., Lorenz L. J., Bassell G. J., Akbarian S., Chattarji S., Klann E., Richter J. D. Genetic and acute CPEB1 depletion ameliorate fragile X pathophysiology. Nat Med. 2013 Nov; 19(11):1473–7

322

Summarised in http://www.ncbi.nlm.nih.gov/books/NBK1165/

323

Jiang H., Mankodi A., Swanson M. S., Moxley R. T., Thornton C. A. Myotonic dystrophy type 1 is associated with nuclear foci of mutant RNA., sequestration of muscleblind proteins and deregulated alternative splicing in neurons. Hum Mol Genet. 2004 Dec 15; 13(24):3079–88

324

Savkur R. S., Philips A. V., Cooper T. A. Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy. Nat Genet. 2001 Sep; 29(1):40–7

325

Ho T. H., Charlet-B N., Poulos M. G., Singh G., Swanson M. S., Cooper T. A. Muscleblind proteins regulate alternative splicing. EMBO J. 2004 Aug 4; 23(15):3103–12

326

Kino Y., Washizu C., Oma Y., Onishi H., Nezu Y., Sasagawa N., Nukina N., Ishiura S. MBNL and CELF proteins regulate alternative splicing of the skeletal muscle chloride channel CLCN1. Nucleic Acids Res. 2009 Oct; 37(19):6477–90

327

Hanson E. L., Jakobs P. M., Keegan H., Coates K., Bousman S., Dienel N. H., Litt M., Hershberger R. E. Cardiac troponin T lysine 210 deletion in a family with dilated cardiomyopathy. J Card Fail. 2002 Feb; 8(1):28–32

328

Reviewed in Michalova E., Vojtesek B., Hrstka R. Impaired pre-messenger RNA processing and altered architecture of 3′ untranslated regions contribute to the development of human disorders. Int J Mol Sci. 2013 Jul 26; 14(8): 15681–94

329

For a full description of the syndrome see http://ghr.nlm.nih.gov/condition/immune-dysregulation-polyendocrinopathy-enteropathyx-linked-syndrome

330

Bennett C. L., Brunkow M. E., Ramsdell F., O’Briant K. C., Zhu Q., Fuleihan R. L., Shigeoka A. O., Ochs H. D., Chance P. F. A rare polyadenylation signal mutation of the FOXP3 gene (AAUAAA→AAUGAA) leads to the IPEX syndrome. Immunogenetics. 2001 Aug; 53(6):435–9

331

For further information see http://www.alsa.org/

332

A database of genes believed to be implicated in ALS can be found at http://alsod.iop.kcl.ac.uk/

333

Kwiatkowski T. J Jr., Bosco D. A., Leclerc A. L., Tamrazian E., Vanderburg C. R., Russ C., Davis A., Gilchrist J., Kasarskis E. J., Munsat T., Valdmanis P., Rouleau G. A., Hosler B. A., Cortelli P., de Jong P. J., Yoshinaga Y., Haines J. L., Pericak-Vance M. A., Yan J., Ticozzi N., Siddique T., McKenna-Yasek D., Sapp P. C., Horvitz H. R., Landers J. E., Brown R. H Jr. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science. 2009 Feb 27; 323(5918):1205–8

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Vance C., Rogelj B., Hortobágyi T., De Vos K. J., Nishimura A. L., Sreedharan J., Hu X., Smith B., Ruddy D., Wright P., Ganesalingam J., Williams K. L., Tripathi V., Al-Saraj S., Al-Chalabi A., Leigh P. N., Blair I. P., Nicholson G., de Belleroche J., Gallo J. M., Miller C. C., Shaw C. E. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science. 2009 Feb 27; 323(5918):1208–11

335

Lai S. L., Abramzon Y., Schymick J. C., Stephan D. A., Dunckley T., Dillman A., Cookson M., Calvo A., Battistini S., Giannini F., Caponnetto C., Mancardi G. L., Spataro R., Monsurro M. R., Tedeschi G., Marinou K., Sabatelli M., Conte A., Mandrioli J., Sola P., Salvi F., Bartolomei I., Lombardo F.; ITALSGEN Consortium, Mora G., Restagno G., Chiò A., Traynor B. J. FUS mutations in sporadic amyotrophic lateral sclerosis. Neurobiol Aging. 2011 Mar; 32(3):550.e1–4

336

Sabatelli M., Moncada A., Conte A., Lattante S., Marangi G., Luigetti M., Lucchini M., Mirabella M., Romano A., Del Grande A., Bisogni G., Doronzio P. N., Rossini P. M., Zollino M. Mutations in the 3′ untranslated region of FUS causing FUS overexpression are associated with amyotrophic lateral sclerosis. Hum Mol Genet. 2013 Dec 1; 22(23):4748–55

337

Johnson J. M., Castle J., Garrett-Engele P., Kan Z., Loerch P. M., Armour C. D., Santos R., Schadt E. E., Stoughton R., Shoemaker DD. Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays. Science. 2003 Dec 19; 302(5653):2141–4

338

Reviewed in Keren H., Lev-Maor G., Ast G. Alternative splicing and evolution: diversification, exon definition and function. Nat Rev Genet. 2010 May; 11(5):345–55

339

These steps are laid out very clearly in some reviews e.g. Wang G. S., Cooper T. A. Splicing in disease: disruption of the splicing code and the decoding machinery. Nat Rev Genet. 2007 Oct; 8(10):749–61

340

More information on the spliceosome can be found in e.g. Padgett RA. New connections between splicing and human disease. Trends Genet. 2012 Apr; 28(4):147–54

341

http://ghr.nlm.nih.gov/condition/retinitis-pigmentosa

342

Vithana E. N., Abu-Safieh L., Allen M. J., Carey A., Papaioannou M., Chakarova C., Al-Maghtheh M., Ebenezer N. D., Willis C., Moore A. T., Bird A. C., Hunt D. M., Bhattacharya S. S. A human homolog of yeast pre-mRNA splicing gene, PRP31, underlies autosomal dominant retinitis pigmentosa on chromosome 19q13.4 (RP11). Mol Cell. 2001 Aug; 8(2):375–81

343

McKie A. B., McHale J. C., Keen T. J., Tarttelin E. E., Goliath R., van Lith-Verhoeven J. J., Greenberg J., Ramesar R. S., Hoyng C. B., Cremers F. P., Mackey D. A., Bhattacharya S. S., Bird A. C., Markham A. F., Inglehearn C. F. Mutations in the pre-mRNA splicing factor gene PRPC8 in autosomal dominant retinitis pigmentosa (RP13). Hum Mol Genet. 2001 Jul 15; 10(15):1555–62

344

Chakarova C. F., Hims M. M., Bolz H., Abu-Safieh L., Patel R. J., Papaioannou M. G., Inglehearn C. F., Keen T. J., Willis C., Moore A. T., Rosenberg T., Webster A. R., Bird A. C., Gal A., Hunt D., Vithana E. N., Bhattacharya S. S. Mutations in HPRP3, a third member of pre-mRNA splicing factor genes, implicated in autosomal dominant retinitis pigmentosa. Hum Mol Genet. 2002 Jan 1; 11(1):87–92

345

Maita H., Kitaura H., Keen T. J., Inglehearn C. F., Ariga H., Iguchi-Ariga S. M. PAP-1, the mutated gene underlying the RP9 form of dominant retinitis pigmentosa, is a splicing factor. Exp Cell Res. 2004 Nov 1; 300(2):283–96

346

Microcephalic osteodysplastic primordial dwarfism type 1 also known as Taybi-Linder syndrome. http://rarediseases.info.nih.gov/gard/5120/microcephalic-osteodysplastic-primordial-dwarfism-type-1/resources/1

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Ameres S. L., Zamore P. D. Diversifying microRNA sequence and function. Nat Rev Mol Cell Biol. 2013 Aug; 14(8):475–88

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Kang S. G., Liu W. H., Lu P., Jin H. Y., Lim H. W., Shepherd J., Fremgen D., Verdin E., Oldstone M. B., Qi H., Teijaro J. R., Xiao C. MicroRNAs of the miR-17∼92 family are critical regulators of T(FH) differentiation. Nat Immunol. 2013 Aug; 14(8):849–57

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Kleinman C. L., Gerges N., Papillon-Cavanagh S., Sin-Chan P., Pramatarova A., Quang D. A., Adoue V., Busche S., Caron M., Djambazian H., Bemmo A., Fontebasso A. M., Spence T., Schwartzentruber J., Albrecht S., Hauser P., Garami M., Klekner A., Bognar L., Montes L., Staffa A., Montpetit A., Berube P., Zakrzewska M., Zakrzewski K., Liberski P. P., Dong Z., Siegel P. M., Duchaine T., Perotti C., Fleming A., Faury D., Remke M., Gallo M., Dirks P., Taylor M. D., Sladek R., Pastinen T., Chan J. A., Huang A., Majewski J., Jabado N. Fusion of TTYH1 with the C19MC microRNA cluster drives expression of a brain-specific DNMT3B isoform in the embryonal brain tumor ETMR. Nat Genet. 2014 Jan; 46(1):39–44

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392

See http://www.fiercepharma.com/special-reports/15-best-selling-drugs-2012 for a summary of the best-selling drugs in recent years

393

There are multiple blogs in this area, for example http://biopharmconsortium.com/rnai-therapeutics-stage-a-comeback

394

More information can be found at http://ghr.nlm.nih.gov/condition/transthyretin-amyloidosis

395

http://investors.alnylam.com/releasedetail.cfm?ReleaseID=805999

396

Updates on this programme can be found at http://mirnarx.com/pipeline/mirna-MRX34.html

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Koval E. D., Shaner C., Zhang P., du Maine X., Fischer K., Tay J., Chau B. N., Wu GF., Miller T. M. Method for widespread microRNA-155 inhibition prolongs survival in ALS-model mice. Hum Mol Genet. 2013 Oct 15; 22(20):4127–35

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Ozsolak F., Kapranov P., Foissac S., Kim S. W., Fishilevich E., Monaghan A. P., John B., Milos P. M. Comprehensive polyadenylation site maps in yeast and human reveal pervasive alternative polyadenylation. Cell. 2010 Dec 10; 143(6):1018–29

399

A very good review of how antisense expression can regulate genes is Pelechano V., Steinmetz L. M. Gene regulation by antisense transcription. Nat Rev Genet. 2013 Dec; 14(12):880–93

400

http://www.drugs.com/cons/fomivirsen-intraocular.html

401

https://www.bhf.org.uk/heart-matters-online/august-september-2012/medical/familial-hypercholesterolaemia.aspx

402

http://www.medscape.com/viewarticle/804574_5

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http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm337195.htm

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http://www.medscape.com/viewarticle/781317

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http://www.nature.com/nrd/journal/v12/n3/full/nrd3963.html

406

Lindow M., Kauppinen S. Discovering the first microRNA-targeted drug. J Cell Biol. 2012 Oct 29; 199(3):407–12

407

http://www.fiercebiotech.com/story/merck-writes-rnai-punts-sirnaalnylam-175m/2014-01-13

408

http://www.fiercebiotech.com/press-releases/rana-therapeutics-raises-207-million-harness-potential-long-non-coding-rna

409

http://www.bostonglobe.com/business/2014/01/30/dicerna-shares-soar-first-day-trading-after-biotech-raises-million-initial-public-offering/mbwMnXBSPsVCUVkGQLc64I/story.html

410

http://www.dicerna.com/pipeline.php as of 14 April 2014

411

http://www.fiercebiotech.com/story/breaking-novartis-slams-brakes-rnai-development-efforts/2014-04-14

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The final story draws together multiple findings from a number of different researchers. Rather than refer to each publication, I recommend the following excellent review article: van der Maarel S. M., Miller D. G., Tawil R., Filippova G. N., Tapscott S. J. Facioscapulohumeral muscular dystrophy: consequences of chromatin relaxation. Curr Opin Neurol. 2012 Oct; 25(5):614–20

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This is a distinction, and a terminology, first coined by Sidney Brenner.