Junk DNA: A Journey Through the Dark Matter of the Genome (49 page)

  
5
. Updates on this programme can be found at
http://mirnarx.com/pipeline/mirna-MRX34.html

  
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

  
9
.
http://www.drugs.com/cons/fomivirsen-intraocular.html

10
.
https://www.bhf.org.uk/heart-matters-online/august-september-2012/medical/familial-hypercholesterolaemia.aspx

11
.
http://www.medscape.com/viewarticle/804574_5

12
.
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm337195.htm

13
.
http://www.medscape.com/viewarticle/781317

14
.
http://www.nature.com/nrd/journal/v12/n3/full/nrd3963.html

15
. Lindow M, Kauppinen S. Discovering the first microRNA-targeted drug.
J Cell Biol
. 2012 Oct 29;199(3):407–12

16
.
http://www.fiercebiotech.com/story/merck-writes-rnai-punts-sirnaalnylam-175m/2014-01-13

17
.
http://www.fiercebiotech.com/press-releases/rana-therapeutics-raises-207-million-harness-potential-long-non-coding-rna

18
.
http://www.bostonglobe.com/business/2014/01/30/dicerna-shares-soar-first-day-trading-after-biotech-raises-million-initial-public-offering/mbwMnXBSPsVCUVkGQLc64I/story.html

19
.
http://www.dicerna.com/pipeline.php
as of 14 April 2014

20
.
http://www.fiercebiotech.com/story/breaking-novartis-slams-brakes-rnai-development-efforts/2014-04-14

Chapter 20

  
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.

Appendix

List of Human Diseases cited in the main text, in which Junk DNA Has Been Implicated

Alzheimer’s disease
May involve over-expression of an antisense RNA that binds to and stabilises the critical BACE1 mRNA.

Angelman syndrome
A condition caused by abnormal imprinting. Junk DNA is vital in control of imprinting, including the involvement of imprinting control regions, promoters, long non-coding RNAs and cross-talk with the epigenetic systems.

Aplastic anaemia
Around 5 per cent of cases are caused by mutations in some of the critical genes that maintain the lengths of telomeres, the junk regions at the ends of chromosomes.

Basal cell carcinoma
A small number of cases are caused by mutations in the non-protein-coding region at the beginning of a gene, which result in decreased expression of the RNA from that gene.

Beckwith-Wiedemann syndrome
A condition caused by abnormal imprinting. Junk DNA is vital in control of imprinting, including the involvement of imprinting control regions, promoters, long non-coding RNAs and cross-talk with the epigenetic systems.

Burkitt’s lymphoma
Caused when the Myc oncogene from chromosome 8 gets translocated to chromosome 14 and placed under the control of the immunoglobulin promoter.

Cancer
Junk DNA has been implicated at a number of levels in cancer, such as over-expression of certain long non-coding RNAs in specific cancer types. In most cases, the evidence isn’t yet strong enough to determine how significant a role these play in human pathology. However, over-expression of the proteins that maintain the lengths of telomeres, the junk regions at the ends of chromosomes, are now generally accepted as having a causal role in the progression of some tumours. Mis-targeting of epigenetic enzymes to the wrong genes because of abnormal expression of long non-coding RNAs is also under active investigation as another method by which cancer cells proliferate abnormally.

Cartilage-hair hypoplasia
Caused by mutations which affect smallRNAs embedded within long non-coding RNAs.

Congenital diarrhoea disorder
Caused by a mutation in a splicing signal in a gene.

Cornelia de Lange syndrome
Caused by defects in a protein required for the junk-mediated higher-order structuring of DNA.

Down’s syndrome
Caused by uneven distribution of chromosome 21 to developing gametes, a process dependent on a junk region called the centromere.

Duchenne muscular dystrophy
Some cases are caused by mutations which result in abnormal splicing of the dystrophin RNA molecule.

Dyskeratosis congenita
Can be caused by mutations in a number of different genes, each of which is involved in maintaining the lengths of telomeres, the junk regions at the ends of chromosomes.

Edward’s syndrome
Caused by uneven distribution of chromosome 18 to developing gametes, a process dependent on a junk region called the centromere.

ETMR paediatric brain tumour
Caused by rearrangement and amplification of a smallRNA cluster.

Extra digits
Caused by single base changes in an enhancer for a morphogen.

Facioscapulohumeral muscular dystrophy
Caused by the interactions of a combination of junk DNA elements, leading to abnormal expression of a retroviral sequence.

Feingold syndrome
Some cases are caused by the loss of a cluster of smallRNAs.

Fragile X syndrome of mental retardation
Caused by the expansion of a CCG repeat in a non-protein-coding region at the beginning of a gene. The repeat prevents expression of the gene by making it difficult for the cell to copy the DNA into RNA.

Friedreich’s ataxia
Caused by the expansion of a GAA repeat in a non-protein-coding region within a gene. The repeat prevents expression of the gene by making it difficult for the cell to copy the DNA into RNA.

Hepatitis C virus
A smallRNA produced by human liver cells binds to the viral RNA, stabilising it and promoting viral productivity.

HHV-8 susceptibility
Can be caused by mutation in a splicing signal in a gene.

Holoprosencephaly
Some cases have been shown to be caused by mutations in an enhancer region for a morphogen.

Hutchinson-Gilford progeria
Caused by a mutation which creates an extra splicing signal in a gene.

Idiopathic pulmonary fibrosis
Can be caused by mutations in a number of different genes, each of which is involved in maintaining the lengths of telomeres, the junk regions at the ends of chromosomes.

IPEX autoimmune disorder
Caused by a mutation in the non-protein-coding region at the end of a gene, which prevents correct processing of the mRNA.

Malignant melanoma
A small number of cases are caused by mutations in the non-protein-coding region at the beginning of a gene, which result in the insertion of extra amino acids into the protein.

Myotonic dystrophy
Caused by the expansion of a CTG repeat in a non-protein-coding region at the end of a gene. The repeat is copied into RNA, and mops up RNA-binding proteins, resulting in mis-regulation of a large number of other mRNA molecules.

Neuropathic pain
May involve over-expression of a long non-coding RNA that regulates expression of a key ion channel.

North American eastern equine encephalitis virus
A smallRNA produced by human immune cells binds to the viral genome and prevents the immune system from recognising that the body is under attack.

Ohio Amish dwarfism
Caused by a mutation in a non-coding RNA required for the proper functioning of the splicing machinery.

Opitz-Kaveggia syndrome
Caused by defects in a protein that is critical for interaction with long non-coding RNAs in the Mediator complex.

Osteogenesis imperfecta (brittle bone disease)
A small number of cases are caused by mutations in the non-protein-coding region at the beginning of a gene, which result in the insertion of extra amino acids into the protein.

Pancreatic agenesis
Some cases have been shown to be caused by mutations in enhancer sequences.

Patau’s syndrome
Caused by uneven distribution of chromosome 13 to developing gametes, a process dependent on a junk region called the centromere.

Prader-Willi syndrome
A condition caused by abnormal imprinting. Junk DNA is vital in control of imprinting, including the involvement of imprinting control regions, promoters, long non-coding RNAs and cross-talk with the epigenetic systems.

Retinitis pigmentosa
Some cases are caused by a defect in a protein which is required to ensure normal splicing and removal of junk DNA from mRNA molecules.

Roberts syndrome
Caused by defects in a protein required for the junk-mediated higher-order structuring of DNA.

Silver-Russell syndrome
A condition caused by abnormal imprinting. Junk DNA is vital in control of imprinting, including the involvement of imprinting control regions, promoters, long non-coding RNAs and cross-talk with the epigenetic systems.

Spinal muscular atrophy
The SMN2 gene is unable to compensate for mutations in the closely related SMN1 gene, because of a variant base pair which prevents normal splicing of SMN2 mRNA into functional protein.

X0 syndrome (Turner’s syndrome)
Women with only one X chromosome, caused by uneven distribution of X chromosomes to developing gametes, a process dependent on a junk region called the centromere.

XXX syndrome
Women with three X chromosomes, caused by uneven distribution of X chromosomes to developing gametes, a process dependent on a junk region called the centromere.

XXY syndrome (Klinefelter’s syndrome)
Men with two X chromosomes, caused by uneven distribution of X chromosomes to developing gametes, a process dependent on a junk region called the centromere.

Index

11-FINGERS protein
178
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9
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286