2. Campuzano V, Montermini L, Moltò MD, Pianese L, Cossée M, Cavalcanti F, Monros E, Rodius F, Duclos F, Monticelli A, Zara F, Cañizares J, Koutnikova H, Bidichandani SI, Gellera C, Brice A, Trouillas P, De Michele G, Filla A, De Frutos R, Palau F, Patel PI, Di Donato S, Mandel JL, Cocozza S, Koenig M, Pandolfo M. Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science. 1996 Mar 8;271(5254):1423–7
3. Bidichandani SI, Ashizawa T, Patel PI. The GAA triplet-repeat expansion in Friedreich ataxia interferes with transcription and may be associated with an unusual DNA structure. Am J Hum Genet. 1998 Jan;62(1):111–21
4. Babcock M, de Silva D, Oaks R, Davis-Kaplan S, Jiralerspong S, Montermini L, Pandolfo M, Kaplan J. Regulation of mitochondrial iron accumulation by Yfh1p, a putative homolog of frataxin. Science. 1997 Jun 13;276(5319):1709–12
5. Kremer EJ, Pritchard M, Lynch M, Yu S, Holman K, Baker E, Warren ST, Schlessinger D, Sutherland GR, Richards RI. Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n. Science. 1991 Jun 21;252(5013):1711–4
6. Verkerk AJ, Pieretti M, Sutcliffe JS, Fu YH, Kuhl DP, Pizzuti A, Reiner O, Richards S, Victoria MF, Zhang FP, et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell. 1991 May 31;65(5):905–14
7. Pieretti M, Zhang FP, Fu YH, Warren ST, Oostra BA, Caskey CT, Nelson DL. Absence of expression of the FMR-1 gene in fragile X syndrome. Cell. 1991 Aug 23;66(4):817–22
8. Qin M, Kang J, Burlin TV, Jiang C, Smith CB. 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
9. Reviewed in Echeverria GV, Cooper TA. RNA-binding proteins in microsatellite expansion disorders: mediators of RNA toxicity. Brain Res. 2012 Jun 26;1462:100–11
2. 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.
1. 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.
2. Vlangos CN, Siuniak AN, Robinson D, Chinnaiyan AM, Lyons RH Jr, Cavalcoli JD, Keegan CE. Next-generation sequencing identifies the Danforth’s short tail mouse mutation as a retrotransposon insertion affecting Ptf1a expression. PLoS Genet. 2013;9(2):e1003205
3. Bogdanik LP, Chapman HD, Miers KE, Serreze DV, Burgess RW. A MusD retrotransposon insertion in the mouse Slc6a5 gene causes alterations in neuromuscular junction maturation and behavioral phenotypes. PLoS One. 2012;7(1):e30217
4. Schneuwly S, Klemenz R, Gehring WJ. Redesigning the body plan of Drosophila by ectopic expression of the homoeotic gene Antennapedia. Nature. 1987 Feb 26–Mar 4;325(6107):816–8
5. Mortlock DP, Post LC, Innis JW. The molecular basis of hypodactyly (Hd): a deletion in Hoxa 13 leads to arrest of digital arch formation. Nat Genet. 1996 Jul;13(3):284–9
7. Young GR, Eksmond U, Salcedo R, Alexopoulou L, Stoye JP, Kassiotis G. Resurrection of endogenous retroviruses in antibody-deficient mice. Nature. 2012 Nov 29;491(7426):774–8
9. For an interesting recent review of the field of xenotransplanation, see Cooper DK. A brief history of cross-species organ transplantation. Proc (Bayl Univ Med Cent). 2012 Jan;25(1):49–57
10. Patience C, Takeuchi Y, Weiss RA. Infection of human cells by an endogenous retrovirus of pigs. Nat Med. 1997 Mar;3(3):282–6
11. Di Nicuolo G, D’Alessandro A, Andria B, Scuderi V, Scognamiglio M, Tammaro A, Mancini A, Cozzolino S, Di Florio E, Bracco A, Calise F, Chamuleau RA. Long-term absence of porcine endogenous retrovirus infection in chronically immunosuppressed patients after treatment with the porcine cell-based Academic Medical Center bioartificial liver. Xenotransplantation. 2010 Nov–Dec;17(6):431–9
12. For a useful recent review of the effects of segmental duplication, including abnormal crossing-over, see Rudd MK, Keene J, Bunke B, Kaminsky EB, Adam MP, Mulle JG, Ledbetter DH, Martin CL. Segmental duplications mediate novel, clinically relevant chromosome rearrangements. Hum Mol Genet. 2009 Aug 15;18(16):2957–62
2. Reviewed in Boxer LM, Dang CV. Translocations involving c-myc and c-myc function. Oncogene. 2001 Sep 20(40):5595–610
3. Moyzis RK, Buckingham JM, Cram LS, Dani M, Deaven LL, Jones MD, Meyne J, Ratliff RL, Wu JR. A highly conserved repetitive DNA sequence, (TTAGGG)n, present at the telomeres of human chromosomes. Proc Natl Acad Sci U S A. 1988 Sep;85(18):6622–6
4. Vaziri H, Schächter F, Uchida I, Wei L, Zhu X, Effros R, Cohen D, Harley CB. Loss of telomeric DNA during aging of normal and trisomy 21 human lymphocytes. Am J Hum Genet. 1993 Apr;52(4):661–7
5. Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961 Dec;25:585–621
6. Harley CB, Futcher AB, Greider CW. Telomeres shorten during ageing of human fibroblasts. Nature. 1990 May 31;345(6274):458–60
7. Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, Harley CB, Shay JW, Lichtsteiner S, Wright WE. Extension of life-span by introduction of telomerase into normal human cells. Science. 1998 Jan 16;279(5349):349–52
8. There is a useful discussion of this problem in Armanios M, Blackburn EH. The telomere syndromes. Nat Rev Genet. 2012 Oct;13(10):693–704
9. Armanios M, Blackburn EH. The telomere syndromes. Nat Rev Genet. 2012 Oct;13(10):693–704 provides a useful overview.
10. Wright WE, Piatyszek MA, Rainey WE, Byrd W, Shay JW. Telomerase activity in human germline and embryonic tissues and cells. Dev Genet. 1996;18(2):173–9
11. Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, Coviello GM, Wright WE, Weinrich SL, Shay JW. Specific association of human telomerase activity with immortal cells and cancer. Science. 1994 Dec 23;266(5193):2011–5
13. Chiu CP, Dragowska W, Kim NW, Vaziri H, Yui J, Thomas TE, Harley CB, Lansdorp PM. Differential expression of telomerase activity in hematopoietic progenitors from adult human bone marrow. Stem Cells. 1996 Mar;14(2):239–48
14. Vaziri H, Dragowska W, Allsopp RC, Thomas TE, Harley CB, Lansdorp PM. Evidence for a mitotic clock in human hematopoietic stem cells: loss of telomeric DNA with age. Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9857–60
15. Armanios M, Blackburn EH. The telomere syndromes. Nat Rev Genet. 2012 Oct;13(10):693–704
16. Armanios M, Blackburn EH. The telomere syndromes. Nat Rev Genet. 2012 Oct;13(10):693–704
17. For an excellent clinical description, and useful pictures, see Calado RT, Young NS. Telomere diseases. N Engl J Med. 2009 Dec 10;361(24):2353–65
18. Alder JK, Chen JJ, Lancaster L, Danoff S, Su SC, Cogan JD, Vulto I, Xie M, Qi X, Tuder RM, Phillips JA 3rd, Lansdorp PM, Loyd JE, Armanios MY. Short telomeres are a risk factor for idiopathic pulmonary fibrosis. Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):13051–6
19. Armanios MY, Chen JJ, Cogan JD, Alder JK, Ingersoll RG, Markin C, Lawson WE, Xie M, Vulto I, Phillips JA 3rd, Lansdorp PM, Greider CW, Loyd JE. Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med. 2007 Mar 29;356(13):1317–26
20. Tsakiri KD, Cronkhite JT, Kuan PJ, Xing C, Raghu G, Weissler JC, Rosenblatt RL, Shay JW, Garcia CK. Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc Natl Acad Sci U S A. 2007 May 1;104(18):7552–7
21. Cronkhite JT, Xing C, Raghu G, Chin KM, Torres F, Rosenblatt RL, Garcia CK. Telomere shortening in familial and sporadic pulmonary fibrosis. Am J Respir Crit Care Med. 2008 Oct 1;178(7):729–37
23. de la Fuente J, Dokal I. Dyskeratosis congenita: advances in the understanding of the telomerase defect and the role of stem cell transplantation. Pediatr Transplant. 2007 Sep;11(6):584–94
24. Armanios M, Chen JL, Chang YP, Brodsky RA, Hawkins A, Griffin CA, Eshleman JR, Cohen AR, Chakravarti A, Hamosh A, Greider CW. Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):15960–4
26. Alder JK, Guo N, Kembou F, Parry EM, Anderson CJ, Gorgy AI, Walsh MF, Sussan T, Biswal S, Mitzner W, Tuder RM, Armanios M. Telomere length is a determinant of emphysema susceptibility. Am J Respir Crit Care Med. 2011 Oct 15;184(8):904–12
27. Cited in Sahin E, Depinho RA. Linking functional decline of telomeres, mitochondria and stem cells during ageing. Nature. 2010 Mar 25;464(7288):520–8
28. Statistical factsheet from the American Heart Association on Older Americans & Cardiovascular Diseases, 2013 update
30. Valdes AM, Andrew T, Gardner JP, Kimura M, Oelsner E, Cherkas LF, Aviv A, Spector TD. Obesity, cigarette smoking, and telomere length in women. Lancet. 2005 Aug 20–26;366(9486):662–4
31. Cawthon RM, Smith KR, O’Brien E, Sivatchenko A, Kerber RA. Association between telomere length in blood and mortality in people aged 60 years or older. Lancet. 2003 Feb 1;361(9355):393–5
32. Fitzpatrick AL, Kronmal RA, Kimura M, Gardner JP, Psaty BM, Jenny NS, Tracy RP, Hardikar S, Aviv A. Leukocyte telomere length and mortality in the Cardiovascular Health Study. J Gerontol A Biol Sci Med Sci. 2011 Apr;66(4):421–9
33. Atzmon G, Cho M, Cawthon RM, Budagov T, Katz M, Yang X, Siegel G, Bergman A, Huffman DM, Schechter CB, Wright WE, Shay JW, Barzilai N, Govindaraju DR, Suh Y. Evolution in health and medicine Sackler colloquium: Genetic variation in human telomerase is associated with telomere length in Ashkenazi centenarians. Proc Natl Acad Sci U S A. 2010 Jan 26;107 Suppl 1:1710–7
34. Segerstrom SC, Miller GE. Psychological stress and the human immune system: a meta-analytic study of 30 years of inquiry. Psychol Bull. 2004 Jul;130(4):601–30
35. Epel ES, Blackburn EH, Lin J, Dhabhar FS, Adler NE, Morrow JD, Cawthon RM. Accelerated telomere shortening in response to life stress. Proc Natl Acad Sci U S A. 2004 Dec 7;101(49):17312–5
37. For a useful introduction to this field, see Tennen RI, Chua KF. Chromatin regulation and genome maintenance by mammalian SIRT6. Trends Biochem Sci. 2011 Jan;36(1):39–46
38. Valdes AM, Andrew T, Gardner JP, Kimura M, Oelsner E, Cherkas LF, Aviv A, Spector TD. Obesity, cigarette smoking, and telomere length in women. Lancet. 2005 Aug 20–26;366(9486):662–4
39. UNFPA report on Ageing in The Twenty-First Century, 2012
40. Jennings BJ, Ozanne SE, Dorling MW, Hales CN. Early growth determines longevity in male rats and may be related to telomere shortening in the kidney. FEBS Lett. 1999 Apr 1;448(1):4–8
Chapter 6
1. From The King and I, 1956, screenplay by Ernest Lehman, 20th Century Fox
2. A good overview of the types of centromeres in the different arms of the evolutionary tree can be found in Ogiyama Y, Ishii K. The smooth and stable operation of centromeres. Genes Genet Syst. 2012;87(2):63–73
3. For a useful review, see Verdaasdonk JS, Bloom K. Centromeres: unique chromatin structures that drive chromosome segregation. Nat Rev Mol Cell Biol. 2011 May;12(5):320–32
4. Palmer DK, O’Day K, Wener MH, Andrews BS, Margolis RL. A 17-kD centromere protein (CENP-A) copurifies with nucleosome core particles and with histones. J Cell Biol. 1987 Apr;104(4):805–15
5. Takahashi K, Chen ES, Yanagida M. Requirement of Mis6 centromere connector for localizing a CENP-A-like protein in fission yeast. Science. 2000 Jun 23;288(5474):2215–9
6. Blower MD, Karpen GH. The role of Drosophila CID in kinetochore formation, cell-cycle progression and heterochromatin interactions. Nat Cell Biol. 2001 Aug;3(8):730–9
7. Hori T, Amano M, Suzuki A, Backer CB, Welburn JP, Dong Y, McEwen BF, Shang WH, Suzuki E, Okawa K, Cheeseman IM, Fukagawa T. CCAN makes multiple contacts with centromeric DNA to provide distinct pathways to the outer kinetochore. Cell. 2008 Dec 12;135(6):1039–52
8. Heun P, Erhardt S, Blower MD, Weiss S, Skora AD, Karpen GH. Mislocalization of the Drosophila centromere-specific histone CID promotes formation of functional ectopic kinetochores. Dev Cell. 2006 Mar;10(3):303–15.
9. Van Hooser AA, Ouspenski II, Gregson HC, Starr DA, Yen TJ, Goldberg ML, Yokomori K, Earnshaw WC, Sullivan KF, Brinkley BR. Specification of kinetochore-forming chromatin by the histone H3 variant CENP-A. J Cell Sci. 2001 Oct;114(Pt 19):3529–42
10. Zuccolo M, Alves A, Galy V, Bolhy S, Formstecher E, Racine V, Sibarita JB, Fukagawa T, Shiekhattar R, Yen T, Doye V. The human Nup107-160 nuclear pore subcomplex contributes to proper kinetochore functions. EMBO J. 2007 Apr 4;26(7):1853–64
11. Palmer DK, O’Day K, Wener MH, Andrews BS, Margolis RL. A 17-kD centromere protein (CENP-A) copurifies with nucleosome core particles and with histones. J Cell Biol. 1987 Apr;104(4):805–15
12. Sekulic N, Bassett EA, Rogers DJ, Black BE. The structure of (CENP-A-H4)(2) reveals physical features that mark centromeres. Nature. 2010 Sep 16;467(7313):347–51
13. Warburton PE, Cooke CA, Bourassa S, Vafa O, Sullivan BA, Stetten G, Gimelli G, Warburton D, Tyler-Smith C, Sullivan KF, Poirier GG, Earnshaw WC. Immunolocalization of CENP-A suggests a distinct nucleosome structure at the inner kinetochore plate of active centromeres. Curr Biol. 1997 Nov 1;7(11):901–4
14. For a very good analysis of this model, see Sekulic N, Black BE. Molecular underpinnings of centromere identity and maintenance. Trends Biochem Sci. 2012 Jun;37(6):220–9
15. 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 LA. Assembling pieces of the centromere epigenetics puzzle. Epigenetics. 2012 Jan 1;7(1):3–13
16. From the song ‘Something Good’ in the movie version of The Sound of Music, 1965, 20th Century Fox
17. 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
18. Palmer DK, O’Day K, Margolis RL. The centromere specific histone CENP-A is selectively retained in discrete foci in mammalian sperm nuclei. Chromosoma. 1990 Dec;100(1):32–6
19. Schiff PB, Fant J, Horwitz SB. Promotion of microtubule assembly in vitro by taxol. Nature. 1979 Feb 22;277(5698):665–7
21. Figure quoted in Rajagopalan H, Lengauer C. Aneuploidy and cancer. Nature. 2004 Nov 18;432(7015):338–41
22. For a review of this issue, see Pfau SJ, Amon A. Chromosomal instability and aneuploidy in cancer: from yeast to man. EMBO Rep. 2012 Jun 1;13(6):515–27
23. Rehen SK, Yung YC, McCreight MP, Kaushal D, Yang AH, Almeida BS, Kingsbury MA, Cabral KM, McConnell MJ, Anliker B, Fontanoz M, Chun J. Constitutional aneuploidy in the normal human brain. J Neurosci. 2005 Mar 2;25(9):2176–80
24. Rehen SK, McConnell MJ, Kaushal D, Kingsbury MA, Yang AH, Chun J. Chromosomal variation in neurons of the developing and adult mammalian nervous system. Proc Natl Acad Sci U S A. 2001 Nov 6;98(23):13361–6
25. Kingsbury MA, Friedman B, McConnell MJ, Rehen SK, Yang AH, Kaushal D, Chun J. Aneuploid neurons are functionally active and integrated into brain circuitry. Proc Natl Acad Sci U S A. 2005 Apr 26;102(17):6143–7
26. Melchiorri C, Chieco P, Zedda AI, Coni P, Ledda-Columbano GM, Columbano A. Ploidy and nuclearity of rat hepatocytes after compensatory regeneration or mitogen-induced liver growth. Carcinogenesis. 1993 Sep;14(9):1825–30
28. For more information on the medical and social aspects of Down’s Syndrome there are a large number of patient advocacy groups such as http://www.downs-syndrome.org.uk/
31. Toner JP, Grainger DA, Frazier LM. Clinical outcomes among recipients of donated eggs: an analysis of the U.S. national experience, 1996–1998. Fertil Steril. 2002 Nov;78(5):1038–45
1. Statistical Bulletin from the Office for National Statistics, 8 August 2013 Annual Mid-year Population Estimates, 2011 and 2012
2. The publication that demonstrated the importance of this gene is Berta P, Hawkins JR, Sinclair AH, Taylor A, Griffiths BL, Goodfellow PN, Fellous M. Genetic evidence equating SRY and the testis-determining factor. Nature. 1990 Nov 29;348(6300):448–50
3. Yamauchi Y, Riel JM, Stoytcheva Z, Ward MA. Two Y genes can replace the entire Y chromosome for assisted reproduction in the mouse. Science. 2014 Jan 3;343(6166):69–72
4. Ross MT et al., The DNA sequence of the human X chromosome. Nature. 2005 Mar 17;434(7031):325–37
5. Brown CJ, Lafreniere RG, Powers VE, Sebastio G, Ballabio A, Pettigrew AL, Ledbetter DH, Levy E, Craig IW, Willard HF. Localization of the X inactivation centre on the human X chromosome in Xq13. Nature. 1991 Jan 3;349(6304):82–4
6. Brown CJ, Ballabio A, Rupert JL, Lafreniere RG, Grompe M, Tonlorenzi R, Willard HF. A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome. Nature. 1991 Jan 3;349(6304):38–44
7. Brown CJ, Hendrich BD, Rupert JL, Lafrenière RG, Xing Y, Lawrence J, Willard HF. The human XIST gene: analysis of a 17 kb inactive X-specific RNA that contains conserved repeats and is highly localized within the nucleus. Cell. 1992 Oct 30;71(3):527–42
8. Brockdorff N, Ashworth A, Kay GF, McCabe VM, Norris DP, Cooper PJ, Swift S, Rastan S. The product of the mouse Xist gene is a 15 kb inactive X-specific transcript containing no conserved ORF and located in the nucleus. Cell. 1992 Oct 30;71(3):515–26
9. Lee JT, Strauss WM, Dausman JA, Jaenisch R. A 450 kb transgene displays properties of the mammalian X-inactivation center. Cell. 1996 Jul 12;86(1):83–94
10. For a comprehensive review of this process, see Lee JT. The X as model for RNA’s niche in epigenomic regulation. Cold Spring Harb Perspect Biol. 2010 Sep;2(9):a003749
11. Xu N, Tsai CL, Lee JT. Transient homologous chromosome pairing marks the onset of X inactivation. Science. 2006 Feb 24;311(5764):1149–52
14. Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999 Oct;23(2):185–8
16. Hoffman EP, Brown RH Jr, Kunkel LM. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell. 1987 Dec 24;51(6):919–28
17. Pena SD, Karpati G, Carpenter S, Fraser FC. The clinical consequences of X-chromosome inactivation: Duchenne muscular dystrophy in one of monozygotic twins. J Neurol Sci. 1987 Jul;79(3):337–44
18. Shin T, Kraemer D, Pryor J, Liu L, Rugila J, Howe L, Buck S, Murphy K, Lyons L, Westhusin M. A cat cloned by nuclear transplantation. Nature. 2002 Feb 21;415(6874):859
Chapter 8
1. Schmitt AM, Chang HY. Gene regulation: Long RNAs wire up cancer growth. Nature. 2013 Aug 29;500(7464):536–7
2. Volders PJ, Helsens K, Wang X, Menten B, Martens L, Gevaert K, Vandesompele J, Mestdagh P. LNCipedia: a database for annotated human long-noncoding RNA transcript sequences and structures. Nucleic Acids Res. 2013 Jan;41(Database issue):D246–51
3. ENCODE Project Consortium, Bernstein BE, Birney E, Dunham I, Green ED, Gunter C, Snyder M. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012 Sep 6;489(7414):57–74
4. Tay Y, Rinn J, Pandolfi PP. The multilayered complexity of ceRNA crosstalk and competition. Nature. 2014 Jan 16;505(7483):344–52
5. Derrien T, Johnson R, Bussotti G, Tanzer A, Djebali S, Tilgner H, Guernec G, Martin D, Merkel A, Knowles DG, Lagarde J, Veeravalli L, Ruan X, Ruan Y, Lassmann T, Carninci P, Brown JB, Lipovich L, Gonzalez JM, Thomas M, Davis CA, Shiekhattar R, Gingeras TR, Hubbard TJ, 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
6. Ulitsky I, Shkumatava A, Jan CH, Sive H, Bartel DP. Conserved function of lincRNAs in vertebrate embryonic development despite rapid sequence evolution. Cell. 2011 Dec 23; 147(7): 1537–50
7. Cabili MN, Trapnell C, Goff L, Koziol M, Tazon-Vega B, Regev A, Rinn JL. Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes Dev. 2011 Sep 15;25(18):1915–27
8. Church DM, Goodstadt L, Hillier LW, Zody MC, Goldstein S, She X, Bult CJ, Agarwala R, Cherry JL, DiCuccio M, Hlavina W, Kapustin Y, Meric P, Maglott D, Birtle Z, Marques AC, Graves T, Zhou S, Teague B, Potamousis K, Churas C, Place M, Herschleb J, Runnheim R, Forrest D, Amos-Landgraf J, Schwartz DC, Cheng Z, Lindblad-Toh K, Eichler EE, Ponting CP; Mouse Genome Sequencing Consortium. Lineage-specific biology revealed by a finished genome assembly of the mouse. PLoS Biol. 2009 May 5;7(5):e1000112
9. Necsulea A, Soumillon M, Warnefors M, Liechti A, Daish T, Zeller U, Baker JC, Grützner F, Kaessmann H. The evolution of long-noncoding RNA repertoires and expression patterns in tetrapods. Nature. 2014 Jan 30;505(7485):635–40
10. Wahlestedt C. Targeting long non-coding RNA to therapeutically upregulate gene expression. Nat Rev Drug Discov. 2013 Jun;12(6):433–46
11. Mercer TR, Dinger ME, Sunkin SM, Mehler MF, Mattick JS. Specific expression of long noncoding RNAs in the mouse brain. Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):716–21
12. 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
13. Guttman M, Donaghey J, Carey BW, Garber M, Grenier JK, Munson G, Young G, Lucas AB, Ach R, Bruhn L, Yang X, Amit I, Meissner A, Regev A, Rinn JL, Root DE, Lander ES. lincRNAs act in the circuitry controlling pluripotency and differentiation. Nature. 2011 Aug 28;477(7364):295–300
14. Wang KC, Yang YW, Liu B, Sanyal A, Corces-Zimmerman R, Chen Y, Lajoie BR, Protacio A, Flynn RA, Gupta RA, Wysocka J, Lei M, Dekker J, Helms JA, Chang HY. A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature. 2011 Apr 7;472(7341):120–4
15. Li L, Liu B, Wapinski OL, Tsai MC, Qu K, Zhang J, Carlson JC, Lin M, Fang F, Gupta RA, Helms JA, Chang HY. Targeted disruption of Hotair leads to homeotic transformation and gene derepression. Cell Rep. 2013 Oct 17;5(1):3–12
16. Du Z, Fei T, Verhaak RG, Su Z, Zhang Y, Brown M, Chen Y, Liu XS. Integrative genomic analyses reveal clinically relevant long noncoding RNAs in human cancer. Nat Struct Mol Biol. 2013 Jul;20(7):908–13
17. For a useful review of this area, see Cheetham SW, Gruhl F, Mattick JS, Dinger ME. Long noncoding RNAs and the genetics of cancer. Br J Cancer. 2013 Jun 25;108(12):2419–25
18. Yap KL, Li S, Muñoz-Cabello AM, Raguz S, Zeng L, Mujtaba S, Gil J, Walsh MJ, Zhou MM. 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
19. 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
20. Yang Z, Zhou L, Wu LM, Lai MC, Xie HY, Zhang F, Zheng SS. 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
21. 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
22. 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
23. Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, Tsai MC, Hung T, Argani P, Rinn JL, Wang Y, Brzoska P, Kong B, Li R, West RB, van de Vijver MJ, Sukumar S, Chang HY. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010 Apr 15;464(7291):1071–6
24. Yang L, Lin C, Jin C, Yang JC, Tanasa B, Li W, Merkurjev D, Ohgi KA, Meng D, Zhang J, Evans CP, Rosenfeld MG. Long-noncoding RNA-dependent mechanisms of androgen-receptor-regulated gene activation programs. Nature. 2013 Aug 29;500(7464):598–602
25. Prensner JR, Iyer MK, Sahu A, Asangani IA, Cao Q, Patel L, Vergara IA, Davicioni E, Erho N, Ghadessi M, Jenkins RB, Triche TJ, 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 LP, Dhanasekaran SM, Pienta KJ, Feng FY, Chinnaiyan AM. The long noncoding RNA SChLAP1 promotes aggressive prostate cancer and antagonizes the SWI/SNF complex. Nat Genet. 2013 Nov;45(11):1392–8
26. Necsulea A, Soumillon M, Warnefors M, Liechti A, Daish T, Zeller U, Baker JC, Grützner F, Kaessmann H. The evolution of long-noncoding RNA repertoires and expression patterns in tetrapods. Nature. 2014 Jan 30;505(7485):635–40
27. 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
28. Bernard D, Prasanth KV, Tripathi V, Colasse S, Nakamura T, Xuan Z, Zhang MQ, Sedel F, Jourdren L, Coulpier F, Triller A, Spector DL, Bessis A. A long nuclear-retained non-coding RNA regulates synaptogenesis by modulating gene expression. EMBO J. 2010 Sep 15;29(18):3082–93
29. Pollard KS, Salama SR, Lambert N, Lambot MA, Coppens S, Pedersen JS, Katzman S, King B, Onodera C, Siepel A, Kern AD, 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
31. Faghihi MA, Modarresi F, Khalil AM, Wood DE, Sahagan BG, Morgan TE, Finch CE, St Laurent G 3rd, Kenny PJ, 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
33. Zhao X, Tang Z, Zhang H, Atianjoh FE, Zhao JY, Liang L, Wang W, Guan X, Kao SC, Tiwari V, Gao YJ, Hoffman PN, Cui H, Li M, Dong X, Tao YX. A long noncoding RNA contributes to neuropathic pain by silencing Kcna2 in primary afferent neurons. Nat Neurosci. 2013 Aug; 16(8):1024–31
34. 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
35. Bird A. Genome biology: not drowning but waving. Cell. 2013 Aug 29;154(5):951–2
Chapter 9
1. If you want to learn more about this topic, have a read of my first book, The Epigenetics Revolution.
2. Guttman M, Donaghey J, Carey BW, Garber M, Grenier JK, Munson G, Young G, Lucas AB, Ach R, Bruhn L, Yang X, Amit I, Meissner A, Regev A, Rinn JL, Root DE, Lander ES. lincRNAs act in the circuitry controlling pluripotency and differentiation. Nature. 2011 Aug 28;477(7364):295–300
3. 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
4. Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C, Sanda MG, Ghosh D, Pienta KJ, Sewalt RG, Otte AP, Rubin MA, Chinnaiyan AM. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature. 2002 Oct 10;419(6907):624–9
5. Kleer CG, Cao Q, Varambally S, Shen R, Ota I, Tomlins SA, Ghosh D, Sewalt RG, Otte AP, Hayes DF, Sabel MS, Livant D, Weiss SJ, Rubin MA, Chinnaiyan AM. 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.
6. Sneeringer CJ, Scott MP, Kuntz KW, Knutson SK, Pollock RM, Richon VM, Copeland RA. 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
8. 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
9. Tsai MC, Manor O, Wan Y, Mosammaparast N, Wang JK, Lan F, Shi Y, Segal E, Chang HY. Long noncoding RNA as modular scaffold of histone modification complexes. Science. 2010 Aug 6;329(5992):689–93
10. For a recent major paper on this see Davidovich C, Zheng L, Goodrich KJ, Cech TR. Promiscuous RNA binding by Polycomb repressive complex 2. Nat Struct Mol Biol. 2013 Nov;20(11):1250–7
11. 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
12. Di Ruscio A, Ebralidze AK, Benoukraf T, Amabile G, Goff LA, Terragni J, Figueroa ME, De Figueiredo Pontes LL, Alberich-Jorda M, Zhang P, Wu M, D’Alò F, Melnick A, Leone G, Ebralidze KK, Pradhan S, Rinn JL, Tenen DG. DNMT1-interacting RNAs block gene-specific DNA methylation. Nature. 2013 Nov 21;503(7476):371–6
13. For an overview of all the complex stages in this process see Froberg JE, Yang L, Lee JT. Guided by RNAs: X-inactivation as a model for long non-coding RNA function. J Mol Biol. 2013 Oct 9;425(19):3698–706
14. Froberg JE, Yang L, Lee JT. Guided by RNAs: X-inactivation as a model for long non-coding RNA function. J Mol Biol. 2013 Oct 9;425(19):3698–706
15. Michaud EJ, van Vugt MJ, Bultman SJ, Sweet HO, Davisson MT, Woychik RP. 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
Chapter 10
1. For a contemporaneous review of the work see Surani MA, Barton SC, Norris ML. Experimental reconstruction of mouse eggs and embryos: an analysis of mammalian development. Biol Reprod. 1987 Feb;36(1):1–16
3. For a useful review see Guenzl PM, Barlow DP. Macro long non-coding RNAs: a new layer of cis-regulatory information in the mammalian genome. RNA Biol. 2012 Jun;9(6):731–41
4. For a recent review of imprinting in marsupials see Graves JA, Renfree MB. Marsupials in the age of genomics. Annu Rev Genomics Hum Genet. 2013;14:393–420
5. Landers M, Bancescu DL, 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
6. Terranova R, Yokobayashi S, Stadler MB, Otte AP, van Lohuizen M, Orkin SH, Peters AH. Polycomb group proteins Ezh2 and Rnf2 direct genomic contraction and imprinted repression in early mouse embryos. Dev Cell. 2008 Nov;15(5):668–79
7. Wagschal A, Sutherland HG, Woodfine K, Henckel A, Chebli K, Schulz R, Oakey RJ, Bickmore WA, Feil R. G9a histone methyltransferase contributes to imprinting in the mouse placenta. Mol Cell Biol. 2008 Feb;28(3):1104–13
8. Nagano T, Mitchell JA, Sanz LA, Pauler FM, Ferguson-Smith AC, Feil R, Fraser P. The Air noncoding RNA epigenetically silences transcription by targeting G9a to chromatin. Science. 2008 Dec 12;322(5908):1717–20
9. Reviewed in Koerner MV, Pauler FM, Huang R, Barlow DP. The function of non-coding RNAs in genomic imprinting. Development. 2009 Jun;136(11):1771–83
10. Barlow DP. Methylation and imprinting: from host defense to gene regulation? Science. 1993 Apr 16;260(5106):309–10
11. Reviewed in Skaar DA, Li Y, Bernal AJ, Hoyo C, Murphy SK, Jirtle RL. The human imprintome: regulatory mechanisms, methods of ascertainment, and roles in disease susceptibility. ILAR J. 2012 Dec;53(3–4):341–58
12. 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
13. 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
14. Reinhart B, Paoloni-Giacobino A, Chaillet JR. Specific differentially methylated domain sequences direct the maintenance of methylation at imprinted genes. Mol Cell Biol. 2006 Nov;26(22):8347–56
15. Skaar DA, Li Y, Bernal AJ, Hoyo C, Murphy SK, Jirtle RL. The human imprintome: regulatory mechanisms, methods of ascertainment, and roles in disease susceptibility. ILAR J. 2012 Dec;53(3–4):341–58
16. Kawahara M, Wu Q, Takahashi N, Morita S, Yamada K, Ito M, Ferguson-Smith AC, Kono T. High-frequency generation of viable mice from engineered bi-maternal embryos. Nat Biotechnol. 2007 Sep;25(9):1045–50
17. 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
18. For a review of this aspect, see Frost JM, Moore GE. The importance of imprinting in the human placenta. PLoS Genet. 2010 Jul 1;6(7):e1001015
21. de Smith AJ, Purmann C, Walters RG, Ellis RJ, Holder SE, Van Haelst MM, Brady AF, Fairbrother UL, Dattani M, Keogh JM, Henning E, Yeo GS, O’Rahilly S, Froguel P, Farooqi IS, Blakemore AI. 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
22. Duker AL, Ballif BC, Bawle EV, Person RE, Mahadevan S, Alliman S, Thompson R, Traylor R, Bejjani BA, Shaffer LG, Rosenfeld JA, Lamb AN, 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
23. Sahoo T, del Gaudio D, German JR, Shinawi M, Peters SU, Person RE, Garnica A, Cheung SW, Beaudet AL. 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
26. 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
27. 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
28. 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
30. This is discussed in some detail in Ishida M, Moore GE. The role of imprinted genes in humans. Mol Aspects Med. 2013 Jul–Aug;34(4):826–40
Chapter 11
1. 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
2. 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.
5. Reviewed in Zentner GE, Saiakhova A, Manaenkov P, Adams MD, Scacheri PC. Integrative genomic analysis of human ribosomal DNA. Nucleic Acids Res. 2011 Jul;39(12):4949–60
6. This whole area of diseases caused by defects in ribosomal proteins is interestingly, if occasionally rather provocatively reviewed in Narla A, Ebert BL. Ribosomopathies: human disorders of ribosome dysfunction. Blood. 2010 Apr 22;115(16):3196–205
7. International Human Genome Sequencing Consortium. Initial sequencing and analysis of the human genome. Nature. 2001 Feb 15;409(6822):860–921
8. See for example Hedges SB, Blair JE, Venturi ML, Shoe JL. A molecular timescale of eukaryote evolution and the rise of complex multicellular life. BMC Evol Biol. 2004 Jan 28;4:2
9. Reviewed in Wilson DN. Ribosome-targeting antibiotics and mechanisms of bacterial resistance. Nat Rev Microbiol. 2014 Jan;12(1):35–48
11. 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
12. McFarland R, Schaefer AM, Gardner JL, Lynn S, Hayes CM, Barron MJ, Walker M, Chinnery PF, Taylor RW, Turnbull DM. Familial myopathy: new insights into the T14709C mitochondrial tRNA mutation. Ann Neurol. 2004 Apr;55(4):478–84
13. Zheng J, Ji Y, Guan MX. Mitochondrial tRNA mutations associated with deafness. Mitochondrion. 2012 May;12(3):406–13
14. Qiu Q, Li R, Jiang P, Xue L, Lu Y, Song Y, Han J, Lu Z, Zhi S, Mo JQ, Guan MX. Mitochondrial tRNA mutations are associated with maternally inherited hypertension in two Han Chinese pedigrees. Hum Mutat. 2012 Aug;33(8):1285–93
15. Giordano C, Perli E, Orlandi M, Pisano A, Tuppen HA, He L, Ierinò R, Petruzziello L, Terzi A, Autore C, Petrozza V, Gallo P, Taylor RW, d’Amati G. Cardiomyopathies due to homoplasmic mitochondrial tRNA mutations: morphologic and molecular features. Hum Pathol. 2013 Jul;44(7): 1262–70
16. Lincoln TA, Joyce GF. Self-sustained replication of an RNA enzyme. Science. 2009 Feb 27;323(5918): 1229–32
17. Sczepanski JT, Joyce GF. A cross-chiral RNA polymerase ribozyme. Nature. Published online 29 October 2014
Chapter 12
1. 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
3. Whyte WA, Orlando DA, Hnisz D, Abraham BJ, Lin CY, Kagey MH, Rahl PB, Lee TI, Young RA. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell. 2013 Apr 11;153(2):307–19
4. 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
5. Akhtar-Zaidi B, Cowper-Sal-lari R, Corradin O, Saiakhova A, Bartels CF, Balasubramanian D, Myeroff L, Lutterbaugh J, Jarrar A, Kalady MF, Willis J, Moore JH, Tesar PJ, Laframboise T, Markowitz S, Lupien M, Scacheri PC. Epigenomic enhancer profiling defines a signature of colon cancer. Science. 2012 May 11;336(6082):736–9
6. ENCODE Project Consortium, Bernstein BE, Birney E, Dunham I, Green ED, Gunter C, Snyder M. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012 Sep 6;489(7414):57–74
7. For a description of these types of long non-coding RNAs see Ørom UA, Shiekhattar R. Long noncoding RNAs usher in a new era in the biology of enhancers. Cell. 2013 Sep 12;154(6):1190–3
8. Ørom UA, 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
9. De Santa F, Barozzi I, Mietton F, Ghisletti S, Polletti S, Tusi BK, Muller H, Ragoussis J, Wei CL, Natoli G. A large fraction of extragenic RNA pol II transcription sites overlap enhancers. PLoS Biol. 2010 May 11;8(5):e1000384
10. Hah N, Murakami S, Nagari A, Danko CG, Kraus WL. Enhancer transcripts mark active estrogen receptor binding sites. Genome Res. 2013 Aug;23(8):1210–23
11. Lai F, Ørom UA, Cesaroni M, Beringer M, Taatjes DJ, Blobel GA, Shiekhattar R. Activating RNAs associate with Mediator to enhance chromatin architecture and transcription. Nature. 2013 Feb 28;494(7438):497–501
12. Risheg H, Graham JM Jr, Clark RD, Rogers RC, Opitz JM, Moeschler JB, Peiffer AP, May M, Joseph SM, Jones JR, Stevenson RE, Schwartz CE, Friez MJ. A recurrent mutation in MED12 leading to R961W causes Opitz-Kaveggia syndrome. Nat Genet. 2007 Apr;39(4):451–3
13. The role of super-enhancers in pluripotent cells was first identified in Whyte WA, Orlando DA, Hnisz D, Abraham BJ, Lin CY, Kagey MH, Rahl PB, Lee TI, Young RA. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell. 2013 Apr 11;153(2):307–19
14. 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
16. Lovén J, Hoke HA, Lin CY, Lau A, Orlando DA, Vakoc CR, Bradner JE, Lee TI, Young RA. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell. 2013 Apr 11;153(2):320–34
17. For an overview of the various molecular causes see Skibbens RV, Colquhoun JM, Green MJ, Molnar CA, Sin DN, Sullivan BJ, Tanzosh EE. Cohesinopathies of a feather flock together. PLoS Genet. 2013 Dec;9(12):e1004036
19. Sanyal A, Lajoie BR, Jain G, Dekker J. The long-range interaction landscape of gene promoters. Nature. 2012 Sep 6;489(7414):109–13
20. Jackson DA, Hassan AB, Errington RJ, Cook PR. Visualization of focal sites of transcription within human nuclei. EMBO J. 1993 Mar;12(3):1059–65
21. For an excellent review of this topic see Rieder D, Trajanoski Z, McNally JG. Transcription factories. Front Genet. 2012 Oct 23;3:221. doi: 10.3389/fgene.2012.00221. eCollection 2012
22. Iborra FJ, Pombo A, Jackson DA, Cook PR. Active RNA polymerases are localized within discrete transcription ‘factories’ in human nuclei. J Cell Sci. 1996 Jun;109 (Pt 6):1427–36
23. Jackson DA, Iborra FJ, Manders EM, Cook PR. Numbers and organization of RNA polymerases, nascent transcripts, and transcription units in HeLa nuclei. Mol Biol Cell. 1998 Jun;9(6): 1523–36
24. Papantonis A, Larkin JD, Wada Y, Ohta Y, Ihara S, Kodama T, Cook PR. Active RNA polymerases: mobile or immobile molecular machines? PLoS Biol. 2010 Jul 13;8(7):e1000419
25. Osborne CS, Chakalova L, Brown KE, Carter D, Horton A, Debrand E, Goyenechea B, Mitchell JA, Lopes S, Reik W, Fraser P. Active genes dynamically colocalize to shared sites of ongoing transcription. Nat Genet. 2004 Oct;36(10):1065–71
26. Osborne CS, Chakalova L, Mitchell JA, Horton A, Wood AL, Bolland DJ, Corcoran AE, Fraser P. Myc dynamically and preferentially relocates to a transcription factory occupied by Igh. PLoS Biol. 2007 Aug;5(8):e192
2. 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
3. Ishihara K, Oshimura M, Nakao M. CTCF-dependent chromatin insulator is linked to epigenetic remodeling. Mol Cell. 2006 Sep 1;23(5):733–42
4. Lutz M, Burke LJ, 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
5. Lunyak VV, Prefontaine GG, Núñez E, Cramer T, Ju BG, Ohgi KA, Hutt K, Roy R, García-Díaz A, Zhu X, Yung Y, Montoliu L, Glass CK, Rosenfeld MG. Developmentally regulated activation of a SINE B2 repeat as a domain boundary in organogenesis. Science. 2007 Jul 13;317(5835):248–51
6. Reviewed in Kirkland JG, Raab JR, Kamakaka RT. TFIIIC bound DNA elements in nuclear organization and insulation. Biochim Biophys Acta. 2013 Mar–Apr;1829(3–4):418–24
12. Hemani G, Yang J, Vinkhuyzen A, Powell JE, Willemsen G, Hottenga JJ, Abdellaoui A, Mangino M, Valdes AM, Medland SE, Madden PA, Heath AC, Henders AK, Nyholt DR, de Geus EJ, Magnusson PK, Ingelsson E, Montgomery GW, Spector TD, Boomsma DI, Pedersen NL, Martin NG, Visscher PM. 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
Chapter 14
1. A wealth of information about ENCODE, including interviews with some of the leading scientists, can be accessed at http://www.nature.com/encode/
5. ENCODE Project Consortium, Bernstein BE, Birney E, Dunham I, Green ED, Gunter C, Snyder M. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012 Sep 6;489(7414):57–74
6. Mattick JS. A new paradigm for developmental biology. J Exp Biol. 2007 May;210(Pt 9):1526–47
7. Sanyal A, Lajoie BR, Jain G, Dekker J. The long-range interaction landscape of gene promoters. Nature. 2012 Sep 6;489(7414):109–13
8. Thurman RE, Rynes E, Humbert R, Vierstra J, Maurano MT, Haugen E, Sheffield NC, Stergachis AB, Wang H, Vernot B, Garg K, John S, Sandstrom R, Bates D, Boatman L, Canfield TK, Diegel M, Dunn D, Ebersol AK, Frum T, Giste E, Johnson AK, Johnson EM, Kutyavin T, Lajoie B, Lee BK, Lee K, London D, Lotakis D, Neph S, Neri F, Nguyen ED, Qu H, Reynolds AP, Roach V, Safi A, Sanchez ME, Sanyal A, Shafer A, Simon JM, Song L, Vong S, Weaver M, Yan Y, Zhang Z, Zhang Z, Lenhard B, Tewari M, Dorschner MO, Hansen RS, Navas PA, Stamatoyannopoulos G, Iyer VR, Lieb JD, Sunyaev SR, Akey JM, Sabo PJ, Kaul R, Furey TS, Dekker J, Crawford GE, Stamatoyannopoulos JA. The accessible chromatin landscape of the human genome. Nature. 2012 Sep 6;489(7414):75–82
9. Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A, Tanzer A, Lagarde J, Lin W, Schlesinger F, Xue C, Marinov GK, Khatun J, Williams BA, Zaleski C, Rozowsky J, Röder M, Kokocinski F, Abdelhamid RF, Alioto T, Antoshechkin I, Baer MT, Bar NS, 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 MJ, Gao H, Gonzalez D, Gordon A, Gunawardena H, Howald C, Jha S, Johnson R, Kapranov P, King B, Kingswood C, Luo OJ, Park E, Persaud K, Preall JB, Ribeca P, Risk B, Robyr D, Sammeth M, Schaffer L, See LH, Shahab A, Skancke J, Suzuki AM, 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 SE, Hannon G, Giddings MC, Ruan Y, Wold B, Carninci P, Guigó R, Gingeras TR. Landscape of transcription in human cells. Nature. 2012 Sep 6;489(7414):101–8
12. Ward LD, Kellis M. Evidence of abundant purifying selection in humans for recently acquired regulatory functions. Science. 2012 Sep 28;337(6102):1675–8.
13. Ecker JR, Bickmore WA, Barroso I, Pritchard JK, Gilad Y, Segal E. Genomics: ENCODE explained. Nature. 2012 Sep 6;489(7414)
14. For a fascinating example of epigenetic transgenerational inheritance see this paper, in which a fear response was passed on from parent to pups: Dias BG, Ressler KJ. Parental olfactory experience influences behavior and neural structure in subsequent generations. Nat Neurosci. 2014 Jan;17(1):89–96
15. Graur D, Zheng Y, Price N, Azevedo RB, Zufall RA, 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
2. Lettice LA, Heaney SJ, Purdie LA, Li L, de Beer P, Oostra BA, Goode D, Elgar G, Hill RE, 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
4. Lettice LA, Hill AE, Devenney PS, Hill RE. 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
6. Jeong Y, Leskow FC, El-Jaick K, Roessler E, Muenke M, Yocum A, Dubourg C, Li X, Geng X, Oliver G, Epstein DJ. Regulation of a remote Shh forebrain enhancer by the Six3 homeoprotein. Nat Genet. 2008 Nov;40(11):1348–53
8. Lango Allen H, Flanagan SE, Shaw-Smith C, De Franco E, Akerman I, Caswell R; International Pancreatic Agenesis Consortium, Ferrer J, Hattersley AT, Ellard S. GATA6 haploinsufficiency causes pancreatic agenesis in humans. Nat Genet. 2011 Dec 11;44(1):20–2
9. Sellick GS, Barker KT, Stolte-Dijkstra I, Fleischmann C, Coleman RJ, Garrett C, Gloyn AL, Edghill EL, Hattersley AT, Wellauer PK, Goodwin G, Houlston RS. Mutations in PTF1A cause pancreatic and cerebellar agenesis. Nat Genet. 2004 Dec;36(12):1301–5
10. Weedon MN, Cebola I, Patch AM, Flanagan SE, De Franco E, Caswell R, Rodríguez-Seguí SA, Shaw-Smith C, Cho CH, Lango Allen H, Houghton JA, Roth CL, 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
11. For a review of this, see Sturm RA. Molecular genetics of human pigmentation diversity. Hum Mol Genet. 2009 Apr 15;18(R1):R9–17
12. Durham-Pierre D, Gardner JM, Nakatsu Y, King RA, Francke U, Ching A, Aquaron R, del Marmol V, Brilliant MH. African origin of an intragenic deletion of the human P gene in tyrosinase positive oculocutaneous albinism. Nat Genet. 1994 Jun;7(2): 176–9
13. Visser M, Kayser M, Palstra RJ. 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
15. Hindorff LA, Sethupathy P, Junkins HA, Ramos EM, Mehta JP, Collins FS, Manolio TA. 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
16. Gorkin DU, Ren B. Genetics: Closing the distance on obesity culprits. Nature. 2014 Mar 20;507(7492):309–10
17. Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, Perry JR, Elliott KS, Lango H, Rayner NW, Shields B, Harries LW, Barrett JC, Ellard S, Groves CJ, Knight B, Patch AM, Ness AR, Ebrahim S, Lawlor DA, Ring SM, Ben-Shlomo Y, Jarvelin MR, Sovio U, Bennett AJ, Melzer D, Ferrucci L, Loos RJ, Barroso I, Wareham NJ, Karpe F, Owen KR, Cardon LR, Walker M, Hitman GA, Palmer CN, Doney AS, Morris AD, Smith GD, Hattersley AT, McCarthy MI. 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
18. 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
19. Church C, Moir L, McMurray F, Girard C, Banks GT, Teboul L, Wells S, Brüning JC, Nolan PM, Ashcroft FM, Cox RD. Overexpression of Fto leads to increased food intake and results in obesity. Nat Genet. 2010 Dec;42(12):1086–92
20. Fischer J, Koch L, Emmerling C, Vierkotten J, Peters T, Brüning JC, Rüther U. Inactivation of the Fto gene protects from obesity. Nature. 2009 Apr 16;458(7240):894–8
21. Smemo S, Tena JJ, Kim KH, Gamazon ER, Sakabe NJ, Gómez-Marín C, Aneas I, Credidio FL, Sobreira DR, Wasserman NF, Lee JH, Puviindran V, Tam D, Shen M, Son JE, Vakili NA, Sung HK, Naranjo S, Acemel RD, Manzanares M, Nagy A, Cox NJ, Hui CC, Gomez-Skarmeta JL, Nóbrega MA. Obesity-associated variants within FTO form long-range functional connections with IRX3. Nature. 2014 Mar 20;507(7492):371–5
22. For a recent review of this field see Trent RJ, Cheong PL, Chua EW, Kennedy MA. Progressing the utilisation of pharmacogenetics and pharmacogenomics into clinical care. Pathology. 2013 Jun;45(4):357–70
3. Cho TJ, Lee KE, Lee SK, Song SJ, Kim KJ, Jeon D, Lee G, Kim HN, Lee HR, Eom HH, Lee ZH, Kim OH, Park WY, Park SS, Ikegawa S, Yoo WJ, Choi IH, Kim JW. 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
4. Semler O, Garbes L, Keupp K, Swan D, Zimmermann K, Becker J, Iden S, Wirth B, Eysel P, Koerber F, Schoenau E, Bohlander SK, 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
5. Moffatt P, Gaumond MH, Salois P, Sellin K, Bessette MC, Godin E, de Oliveira PT, Atkins GJ, Nanci A, Thomas G. Bril: a novel bone-specific modulator of mineralization. J Bone Miner Res. 2008 Sep;23(9): 1497–508
6. 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
7. Tietze JK, 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
9. Ashley CT Jr, Wilkinson KD, Reines D, Warren ST. FMR1 protein: conserved RNP family domains and selective RNA binding. Science. 1993 Oct 22;262(5133):563–6
10. Qin M, Kang J, Burlin TV, Jiang C, Smith CB. 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
11. Azevedo FA, Carvalho LR, Grinberg LT, Farfel JM, Ferretti RE, Leite RE, 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
12. Drachman DA. Do we have brain to spare? Neurology. 2005 Jun 28;64(12):2004–5
13. Darnell JC, Van Driesche SJ, Zhang C, Hung KY, Mele A, Fraser CE, Stone EF, Chen C, Fak JJ, Chi SW, Licatalosi DD, Richter JD, Darnell RB. FMRP stalls ribosomal translocation on messenger RNAs linked to synaptic function and autism. Cell. 2011 Jul 22;146(2):247–61
14. Udagawa T, Farny NG, Jakovcevski M, Kaphzan H, Alarcon JM, Anilkumar S, Ivshina M, Hurt JA, Nagaoka K, Nalavadi VC, Lorenz LJ, Bassell GJ, Akbarian S, Chattarji S, Klann E, Richter JD. Genetic and acute CPEB1 depletion ameliorate fragile X pathophysiology. Nat Med. 2013 Nov; 19(11): 1473–7
16. Jiang H, Mankodi A, Swanson MS, Moxley RT, Thornton CA. 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
17. Savkur RS, Philips AV, Cooper TA. Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy. Nat Genet. 2001 Sep;29(1):40–7
18. Ho TH, Charlet-B N, Poulos MG, Singh G, Swanson MS, Cooper TA. Muscleblind proteins regulate alternative splicing. EMBO J. 2004 Aug 4;23(15):3103–12
19. 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
20. Hanson EL, Jakobs PM, Keegan H, Coates K, Bousman S, Dienel NH, Litt M, Hershberger RE. Cardiac troponin T lysine 210 deletion in a family with dilated cardiomyopathy. J Card Fail. 2002 Feb;8(1):28–32
21. 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
26. Kwiatkowski TJ Jr, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C, Davis A, Gilchrist J, Kasarskis EJ, Munsat T, Valdmanis P, Rouleau GA, Hosler BA, Cortelli P, de Jong PJ, Yoshinaga Y, Haines JL, Pericak-Vance MA, Yan J, Ticozzi N, Siddique T, McKenna-Yasek D, Sapp PC, Horvitz HR, Landers JE, Brown RH Jr. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science. 2009 Feb 27;323(5918):1205–8
27. Vance C, Rogelj B, Hortobágyi T, De Vos KJ, Nishimura AL, Sreedharan J, Hu X, Smith B, Ruddy D, Wright P, Ganesalingam J, Williams KL, Tripathi V, Al-Saraj S, Al-Chalabi A, Leigh PN, Blair IP, Nicholson G, de Belleroche J, Gallo JM, Miller CC, Shaw CE. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science. 2009 Feb 27;323(5918):1208–11
28. Lai SL, Abramzon Y, Schymick JC, Stephan DA, Dunckley T, Dillman A, Cookson M, Calvo A, Battistini S, Giannini F, Caponnetto C, Mancardi GL, Spataro R, Monsurro MR, 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 BJ. FUS mutations in sporadic amyotrophic lateral sclerosis. Neurobiol Aging. 2011 Mar;32(3):550.e1–4
29. Sabatelli M, Moncada A, Conte A, Lattante S, Marangi G, Luigetti M, Lucchini M, Mirabella M, Romano A, Del Grande A, Bisogni G, Doronzio PN, Rossini PM, 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
Chapter 17
1. Johnson JM, Castle J, Garrett-Engele P, Kan Z, Loerch PM, Armour CD, Santos R, Schadt EE, 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
2. 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
3. These steps are laid out very clearly in some reviews e.g. Wang GS, Cooper TA. Splicing in disease: disruption of the splicing code and the decoding machinery. Nat Rev Genet. 2007 Oct;8(10):749–61
4. 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
6. Vithana EN, Abu-Safieh L, Allen MJ, Carey A, Papaioannou M, Chakarova C, Al-Maghtheh M, Ebenezer ND, Willis C, Moore AT, Bird AC, Hunt DM, Bhattacharya SS. 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
7. McKie AB, McHale JC, Keen TJ, Tarttelin EE, Goliath R, van Lith-Verhoeven JJ, Greenberg J, Ramesar RS, Hoyng CB, Cremers FP, Mackey DA, Bhattacharya SS, Bird AC, Markham AF, Inglehearn CF. 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
8. Chakarova CF, Hims MM, Bolz H, Abu-Safieh L, Patel RJ, Papaioannou MG, Inglehearn CF, Keen TJ, Willis C, Moore AT, Rosenberg T, Webster AR, Bird AC, Gal A, Hunt D, Vithana EN, Bhattacharya SS. 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
9. Maita H, Kitaura H, Keen TJ, Inglehearn CF, Ariga H, Iguchi-Ariga SM. 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
11. He H, Liyanarachchi S, Akagi K, Nagy R, Li J, Dietrich RC, Li W, Sebastian N, Wen B, Xin B, Singh J, Yan P, Alder H, Haan E, Wieczorek D, Albrecht B, Puffenberger E, Wang H, Westman JA, Padgett RA, Symer DE, de la Chapelle A. Mutations in U4atac snRNA, a component of the minor spliceosome, in the developmental disorder MOPD I. Science. 2011 Apr 8;332(6026):238–40
12. Padgett RA. New connections between splicing and human disease. Trends Genet. 2012 Apr;28(4): 147–54
13. Haas JT, Winter HS, Lim E, Kirby A, Blumenstiel B, DeFelice M, Gabriel S, Jalas C, Branski D, Grueter CA, Toporovski MS, Walther TC, Daly MJ, Farese RV Jr. DGAT1 mutation is linked to a congenital diarrheal disorder. J Clin Invest. 2012 Dec 3;122(12):4680–4
14. Byun M, Abhyankar A, Lelarge V, Plancoulaine S, Palanduz A, Telhan L, Boisson B, Picard C, Dewell S, Zhao C, Jouanguy E, Feske S, Abel L, Casanova JL. Whole-exome sequencing-based discovery of STIM1 deficiency in a child with fatal classic Kaposi sarcoma. J Exp Med. 2010 Oct 25;207(11):2307–12
16. Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, Erdos MR, Robbins CM, Moses TY, Berglund P, Dutra A, Pak E, Durkin S, Csoka AB, Boehnke M, Glover TW, Collins FS. Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature. 2003 May 15;423(6937):293–8
2. For a more detailed description of classes of smallRNAs, see Castel SE, Martienssen RA. RNA interference in the nucleus: roles for small RNAs in transcription, epigenetics and beyond. Nat Rev Genet. 2013 Feb;14(2):100–12
3. Kang SG, Liu WH, Lu P, Jin HY, Lim HW, Shepherd J, Fremgen D, Verdin E, Oldstone MB, Qi H, Teijaro JR, Xiao C. MicroRNAs of the miR-17~92 family are critical regulators of T(FH) differentiation. Nat Immunol. 2013 Aug;14(8):849–57
4. Baumjohann D, Kageyama R, Clingan JM, Morar MM, Patel S, de Kouchkovsky D, Bannard O, Bluestone JA, Matloubian M, Ansel KM, Jeker LT. The microRNA cluster miR-17~92 promotes TFH cell differentiation and represses subset-inappropriate gene expression. Nat Immunol. 2013 Aug;14(8):840–8
5. Tassano E, Di Rocco M, Signa S, Gimelli G. De novo 13q31.1-q32.1 interstitial deletion encompassing the miR-17-92 cluster in a patient with Feingold syndrome-2. Am J Med Genet A. 2013 Apr;161A(4):894–6
7. Han YC, Ventura A. Control of T(FH) differentiation by a microRNA cluster. Nat Immunol. 2013 Aug;14(8):770–1
8. Reviewed in Koerner MV, Pauler FM, Huang R, Barlow DP. The function of non-coding RNAs in genomic imprinting. Development. 2009 Jun;136(11):1771–83
9. Rogler LE, Kosmyna B, Moskowitz D, Bebawee R, Rahimzadeh J, Kutchko K, Laederach A, Notarangelo LD, Giliani S, Bouhassira E, Frenette P, Roy-Chowdhury J, Rogler CE. Small RNAs derived from lncRNA RNase MRP have gene-silencing activity relevant to human cartilage-hair hypoplasia. Hum Mol Genet. 2014 Jan 15;23(2):368–82
10. Subramanyam D, Lamouille S, Judson RL, Liu JY, Bucay N, Derynck R, Blelloch R. Multiple targets of miR-302 and miR-372 promote reprogramming of human fibroblasts to induced pluripotent stem cells. Nat Biotechnol. 2011 May;29(5):443–8
11. Li Z, Yang CS, Nakashima K, Rana TM. Small RNA-mediated regulation of iPS cell generation. EMBO J. 2011 Mar 2;30(5):823–34
13. Huang TC, Sahasrabuddhe NA, Kim MS, Getnet D, Yang Y, Peterson JM, Ghosh B, Chaerkady R, Leach SD, Marchionni L, Wong GW, Pandey A. Regulation of lipid metabolism by Dicer revealed through SILAC mice. J Proteome Res. 2012 Apr 6;11(4):2193–205
14. Yi R, O’Carroll D, Pasolli HA, Zhang Z, Dietrich FS, Tarakhovsky A, Fuchs E. Morphogenesis in skin is governed by discrete sets of differentially expressed microRNAs. Nat Genet. 2006 Mar;38(3):356–62
15. Crist CG, Montarras D, Pallafacchina G, Rocancourt D, Cumano A, Conway SJ, Buckingham M. Muscle stem cell behavior is modified by microRNA-27 regulation of Pax3 expression. Proc Natl Acad Sci U S A. 2009 Aug 11;106(32):13383–7
16. Chen JF, Tao Y, Li J, Deng Z, Yan Z, Xiao X, Wang DZ. microRNA-1 and microRNA-206 regulate skeletal muscle satellite cell proliferation and differentiation by repressing Pax7. J Cell Biol. 2010 Sep 6;190(5):867–79
17. da Costa Martins PA, Bourajjaj M, Gladka M, Kortland M, van Oort RJ, Pinto YM, Molkentin JD, De Windt LJ. Conditional dicer gene deletion in the postnatal myocardium provokes spontaneous cardiac remodeling. Circulation. 2008 Oct 7;118(15):1567–76
18. de Chevigny A, Coré N, Follert P, Gaudin M, Barbry P, Béclin C, Cremer H. miR-7a regulation of Pax6 controls spatial origin of forebrain dopaminergic neurons. Nat Neurosci. 2012 Jun 24; 15(8): 1120–6
19. Konopka W, Kiryk A, Novak M, Herwerth M, Parkitna JR, Wawrzyniak M, Kowarsch A, Michaluk P, Dzwonek J, Arnsperger T, Wilczynski G, Merkenschlager M, Theis FJ, Köhr G, Kaczmarek L, Schütz G. MicroRNA loss enhances learning and memory in mice. J Neurosci. 2010 Nov 3;30(44):14835–42
20. Schaefer A, O’Carroll D, Tan CL, Hillman D, Sugimori M, Llinas R, Greengard P. Cerebellar neurodegeneration in the absence of microRNAs. J Exp Med. 2007 Jul 9;204(7): 1553–8
21. Pietrzykowski AZ, Friesen RM, Martin GE, Puig SI, Nowak CL, Wynne PM, Siegelmann HT, Treistman SN. Posttranscriptional regulation of BK channel splice variant stability by miR-9 underlies neuroadaptation to alcohol. Neuron. 2008 Jul 31;59(2):274–87
22. Hollander JA, Im HI, Amelio AL, Kocerha J, Bali P, Lu Q, Willoughby D, Wahlestedt C, Conkright MD, Kenny PJ. Striatal microRNA controls cocaine intake through CREB signalling. Nature. 2010 Jul 8;466(7303):197–202
23. Fernández-Hernando C, Baldán A. MicroRNAs and Cardiovascular Disease. Curr Genet Med Rep. 2013 Mar; 1(1):30–38
24. For a review, see for example Suzuki H, Maruyama R, Yamamoto E, Kai M. Epigenetic alteration and microRNA dysregulation in cancer. Front Genet. 2013 Dec 3;4:258. eCollection 2013
25. Kleinman CL, Gerges N, Papillon-Cavanagh S, Sin-Chan P, Pramatarova A, Quang DA, Adoue V, Busche S, Caron M, Djambazian H, Bemmo A, Fontebasso AM, 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 PP, Dong Z, Siegel PM, Duchaine T, Perotti C, Fleming A, Faury D, Remke M, Gallo M, Dirks P, Taylor MD, Sladek R, Pastinen T, Chan JA, 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
26. Song SJ, Poliseno L, Song MS, Ala U, Webster K, Ng C, Beringer G, Brikbak NJ, Yuan X, Cantley LC, Richardson AL, Pandolfi PP. MicroRNA-antagonism regulates breast cancer stemness and metastasis via TET-family-dependent chromatin remodeling. Cell. 2013 Jul 18;154(2):311–24
27. For an extensive review of this approach, see Schwarzenbach H, Nishida N, Calin GA, Pantel K. Clinical relevance of circulating cell-free microRNAs in cancer. Nat Rev Clin Oncol. 2014 Mar; 11(3): 145–56
28. Chen W, Cai F, Zhang B, Barekati Z, Zhong XY. The level of circulating miRNA-10b and miRNA-373 in detecting lymph node metastasis of breast cancer: potential biomarkers. Tumour Biol. 2013 Feb;34(1):455–62
29. Hong F, Li Y, Xu Y, Zhu L. Prognostic significance of serum microRNA-221 expression in human epithelial ovarian cancer. J Int Med Res. 2013 Feb;41(1):64–71
30. Shen J, Liu Z, Todd NW, Zhang H, Liao J, Yu L, Guarnera MA, Li R, Cai L, Zhan M, Jiang F. Diagnosis of lung cancer in individuals with solitary pulmonary nodules by plasma microRNA biomarkers. BMC Cancer. 2011 Aug 24;11:374
32. Trobaugh DW, Gardner CL, Sun C, Haddow AD, Wang E, Chapnik E, Mildner A, Weaver SC, Ryman KD, Klimstra WB. RNA viruses can hijack vertebrate microRNAs to suppress innate immunity. Nature. 2014 Feb 13;506(7487):245–8
33. Jopling CL, Yi M, Lancaster AM, Lemon SM, Sarnow P. Modulation of hepatitis C virus RNA abundance by a liver-specific MicroRNA. Science. 2005 Sep 2;309(5740):1577–81
6. Koval ED, Shaner C, Zhang P, du Maine X, Fischer K, Tay J, Chau BN, Wu GF, Miller TM. Method for widespread microRNA-155 inhibition prolongs survival in ALS-model mice. Hum Mol Genet. 2013 Oct 15;22(20):4127–35
7. Ozsolak F, Kapranov P, Foissac S, Kim SW, Fishilevich E, Monaghan AP, John B, Milos PM. Comprehensive polyadenylation site maps in yeast and human reveal pervasive alternative polyadenylation. Cell. 2010 Dec 10;143(6):1018–29
8. A very good review of how antisense expression can regulate genes is Pelechano V, Steinmetz LM. Gene regulation by antisense transcription. Nat Rev Genet. 2013 Dec;14(12):880–93
1. 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 SM, Miller DG, Tawil R, Filippova GN, Tapscott SJ. Facioscapulohumeral muscular dystrophy: consequences of chromatin relaxation. Curr Opin Neurol. 2012 Oct;25(5):614–20
2. This is a distinction, and a terminology, first coined by Sidney Brenner.