Genome annotation for clinical genomic diagnostics: Strengths and weaknesses

Genome Medicine

Volumn 9, Issue 1, 2017, Pages

  Steward, Charles A ^a,b   Parker, Alasdair P J ^c   Minassian, Berge A ^d,e   Sisodiya, Sanjay M ^f,g   Frankish, Adam ^b,h   Harrow, Jennifer ^b,i  

^a Congenica Ltd ^*  (United Kingdom)

^b WELLCOME TRUST SANGER INSTITUTE   (United Kingdom)

^c UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^d UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

^e HOSPITAL FOR SICK CHILDREN   (Canada)

^f UNIVERSITY COLLEGE LONDON   (United Kingdom)

^g Chalfont Centre for Epilepsy   (United Kingdom)

^h EUROPEAN BIOINFORMATICS INSTITUTE   (United Kingdom)

ⁱ Illumina Ltd   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

LONG UNTRANSLATED RNA; MESSENGER RNA; MICRORNA; PIWI INTERACTING RNA; SMALL INTERFERING RNA; SMALL NUCLEOLAR RNA;

3' UNTRANSLATED REGION; 5' UNTRANSLATED REGION; COMPARATIVE GENE MAPPING; DIAGNOSTIC ACCURACY; DIAGNOSTIC TEST; DNA SEQUENCE; FALSE NEGATIVE RESULT; FALSE POSITIVE RESULT; FUNCTIONAL GENOMICS; GENE CONTROL; GENE FUNCTION; GENETIC CODE; GENETIC DISORDER; GENETIC VARIATION; GENOME ANALYSIS; GENOMIC ANNOTATION; HUMAN; HUMAN GENOME PROJECT; NEXT GENERATION SEQUENCING; NONHUMAN; NONSENSE MEDIATED MRNA DECAY; POLYADENYLATION; PRIORITY JOURNAL; PROMOTER REGION; PSEUDOGENE; REVIEW; RNA SPLICE SITE; WHOLE EXOME SEQUENCING; DIAGNOSTIC PROCEDURE; MOLECULAR GENETICS; PROCEDURES;

DIAGNOSTIC TECHNIQUES AND PROCEDURES; GENETIC VARIATION; HUMANS; MOLECULAR SEQUENCE ANNOTATION; PSEUDOGENES; SEQUENCE ANALYSIS, DNA;

EID: 85019973466     PISSN: None     EISSN: 1756994X     Source Type: Journal    
DOI: 10.1186/s13073-017-0441-1     Document Type: Review

References (204)

1. EpiPM Consortium. A roadmap for precision medicine in the epilepsies. Lancet Neurol. 2015;14:1219-28.
2. Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, et al. Initial sequencing and analysis of the human genome. Nature. 2001;409:860-921. Erratum in: Nature. 2001;411:720. Szustakowki, J [corrected to Szustakowski, J]. Nature 2001 Aug 2;412(6846):565.
3. International Human Genome Sequencing Consortium. Finishing the euchromatic sequence of the human genome. Nature. 2004;431:931-45.
4. Church DM, Schneider VA, Graves T, Auger K, Cunningham F, Bouk N, et al. Modernizing reference genome assemblies. PLoS Biol. 2011;9:e1001091.
5. GENCODE. Human GENCODE version 24. 2016. http://www.gencodegenes.org/stats/current.html. Accessed 14 Feb 2017.
6. Ensembl. Ensembl Human, release 83, GRC38. 2016. http://www.ensembl.org/Homo_sapiens/Info/Annotation. Accessed 14 Feb 2017.
7. Mullikin JC, Hunt SE, Cole CG, Mortimore BJ, Rice CM, Burton J, et al. An SNP map of human chromosome 22. Nature. 2000;407:516-20.
8. Firth HV, Wright CF. The Deciphering Developmental Disorders (DDD) study. Dev Med Child Neurol. 2011;53:702-3.
9. Deciphering Developmental Disorders Study. Prevalence and architecture of de novo mutations in developmental disorders. Nature. 2017;542:433-8.
10. Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977;74:5463-7.
11. Papandreou A, McTague A, Trump N, Ambegaonkar G, Ngoh A, Meyer E, et al. GABRB3 mutations: a new and emerging cause of early infantile epileptic encephalopathy. Dev Med Child Neurol. 2016;58:416-20.
12. Illumina. Illumina Inc. https://www.illumina.com/. Accessed 26 Apr 2017.
13. Bentley DR, Balasubramanian S, Swerdlow HP, Smith GP, Milton J, Brown CG, et al. Accurate whole human genome sequencing using reversible terminator chemistry. Nature. 2008;456:53-9.
14. McPherson JD. A defining decade in DNA sequencing. Nat Methods. 2014;110:1003-5.
15. 1000 Genomes Project Consortium, Abecasis GR, Altshuler D, Auton A, Brooks LD, Durbin RM, et al. A map of human genome variation from population-scale sequencing. Nature. 2010;467:1061-73.
16. 100K Genomes. Sequencing 100000 Genomes. 2014. http://www.genomicsengland.co.uk/. Accessed 14 Feb 2017.
17. Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25:1754-60.
18. Li H, Durbin R. Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics. 2010;26:589-95.
19. McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20:1297-303.
20. Cock PJ, Fields CJ, Goto N, Heuer ML, Rice PM. The Sanger FASTQ file format for sequences with quality scores, and the Solexa/Illumina FASTQ variants. Nucleic Acids Res. 2010;38:1767-71.
21. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009;25:2078-9.
22. Danecek P, Auton A, Abecasis G, Albers CA, Banks E, DePristo MA, et al. The variant call format and VCFtools. Bioinformatics. 2011;27:2156-8.
23. Chiang C, Scott AJ, Davis JR, Tsang EK, Li X, Kim Y, et al. The impact of structural variation on human gene expression. Nat Genet. 2017;9:692-9.
24. Sudmant PH, Rausch T, Gardner EJ, Handsaker RE, Abyzov A, Huddleston J, et al. An integrated map of structural variation in 2,504 human genomes. Nature. 2015;526:75-81.
25. Freeman JL, Perry GH, Feuk L, Redon R, McCarroll SA, Altshuler DM, et al. Copy number variation: new insights in genome diversity. Genome Res. 2006;16:949-61.
26. Frousios K, Iliopoulos CS, Schlitt T, Simpson MA. Predicting the functional consequences of non-synonymous DNA sequence variants--evaluation of bioinformatics tools and development of a consensus strategy. Genomics. 2013;102:223-8.
27. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24.
28. HGVS. HGVS nomenclature. 2017. http://www.hgvs.org/mutnomen. Accessed 24 Apr 2017.
29. Guigo R, Flicek P, Abril JF, Reymond A, Lagarde J, Denoeud F, et al. EGASP: the human ENCODE genome annotation assessment project. Genome Biol. 2006;7 Suppl. 1:S2. 1-31.
30. Pruitt KD, Brown GR, Hiatt SM, Thibaud-Nissen F, Astashyn A, Ermolaeva O, et al. RefSeq: an update on mammalian reference sequences. Nucleic Acids Res. 2014;42(Database issue):D756-63.
31. Bauters M, Frints SG, Van Esch H, Spruijt L, Baldewijns MM, de Die-Smulders CE, et al. Evidence for increased SOX3 dosage as a risk factor for X-linked hypopituitarism and neural tube defects. Am J Med Genet A. 2014;164A:1947-52.
32. Araujo PR, Yoon K, Ko D, Smith AD, Qiao M, Suresh U, et al. Before it gets started: regulating translation at the 5' UTR. Comp Funct Genomics. 2012;2012:475731.
33. Shiraki T, Kondo S, Katayama S, Waki K, Kasukawa T, Kawaji H, et al. Cap analysis gene expression for high-throughput analysis of transcriptional starting point and identification of promoter usage. Proc Natl Acad Sci U S A. 2003;100:15776-81.
34. Parihar R, Ganesh S. The SCN1A gene variants and epileptic encephalopathies. J Hum Genet. 2013;58:573-80.
35. Beaudoing E, Freier S, Wyatt JR, Claverie JM, Gautheret D. Patterns of variant polyadenylation signal usage in human genes. Genome Res. 2000;10:1001-10.
36. Kang MK, Han SJ. Post-transcriptional and post-translational regulation during mouse oocyte maturation. BMB Rep. 2011;44:147-57.
37. Black DL. Mechanisms of alternative pre-messenger RNA splicing. Annu Rev Biochem. 2003;72:291-336.
38. Burset M, Seledtsov IA, Solovyev VV. Analysis of canonical and non-canonical splice sites in mammalian genomes. Nucleic Acids Res. 2000;28:4364-75.
39. Gonzalez-Porta M, Frankish A, Rung J, Harrow J, Brazma A. Transcriptome analysis of human tissues and cell lines reveals one dominant transcript per gene. Genome Biol. 2013;14:R70.
40. Jaffe AE, Shin J, Collado-Torres L, Leek JT, Tao R, Li C, et al. Developmental regulation of human cortex transcription and its clinical relevance at single base resolution. Nat Neurosci. 2015;18:154-61.
41. Wang Z, Burge CB. Splicing regulation: from a parts list of regulatory elements to an integrated splicing code. RNA. 2008;14:802-13.
42. Lianoglou S, Garg V, Yang JL, Leslie CS, Mayr C. Ubiquitously transcribed genes use alternative polyadenylation to achieve tissue-specific expression. Genes Dev. 2013;27:2380-96.
43. Miura P, Shenker S, Andreu-Agullo C, Westholm JO, Lai EC, et al. Widespread and extensive lengthening of 3' UTRs in the mammalian brain. Genome Res. 2013;23:812-25.
44. Yap K, Lim ZQ, Khandelia P, Friedman B, Makeyev EV. Coordinated regulation of neuronal mRNA steady-state levels through developmentally controlled intron retention. Genes Dev. 2012;26:1209-23.
45. Braunschweig U, Barbosa-Morais NL, Pan Q, Nachman EN, Alipanahi B, Gonatopoulos-Pournatzis T, et al. Widespread intron retention in mammals functionally tunes transcriptomes. Genome Res. 2014;24:1774-86.
46. Reimand J, Wagih O, Bader GD. Evolutionary constraint and disease associations of post-translational modification sites in human genomes. PLoS Genet. 2015;11:e1004919.
47. Cheng J, Maquat LE. Nonsense codons can reduce the abundance of nuclear mRNA without affecting the abundance of pre-mRNA or the half-life of cytoplasmic mRNA. Mol Cell Biol. 1993;13:1892-902.
48. Nagy E, Maquat LE. A rule for termination-codon position within intron-containing genes: when nonsense affects RNA abundance. Trends Biochem Sci. 1998;23:198-9.
49. Zhao Y, Lin J, Xu B, Hu S, Zhang X, Wu L. MicroRNA-mediated repression of nonsense mRNAs. Elife. 2014;3:e03032.
50. Boutz PL, Bhutkar A, Sharp PA. Detained introns are a novel, widespread class of post-transcriptionally spliced introns. Genes Dev. 2015;29:63-80.
51. Nguyen LS, Jolly L, Shoubridge C, Chan WK, Huang L, Laumonnier F, et al. Transcriptome profiling of UPF3B/NMD-deficient lymphoblastoid cells from patients with various forms of intellectual disability. Mol Psychiatry. 2012;17:1103-15.
52. Adlakha YK, Saini N. Brain microRNAs and insights into biological functions and therapeutic potential of brain enriched miRNA-128. Mol Cancer. 2014;13:33.
53. Lin YS, Wang HY, Huang DF, Hsieh PF, Lin MY, Chou CH, et al. Neuronal splicing regulator RBFOX3 (NeuN) regulates adult hippocampal neurogenesis and synaptogenesis. PLoS One. 2016;11:e0164164.
54. Sundermeier T, Ge Z, Richards J, Dulebohn D, Karzai AW. Studying tmRNA-mediated surveillance and nonstop mRNA decay. Methods Enzymol. 2008;447:329-58.
55. Shoemaker CJ, Green R. Translation drives mRNA quality control. Nat Struct Mol Biol. 2012;19:594-601.
56. Frankish A, Harrow J. GENCODE pseudogenes. Methods Mol Biol. 2014;1167:129-55.
57. Vanin EF. Processed pseudogenes: characteristics and evolution. Annu Rev Genet. 1985;19:253-72.
58. Harrow J, Frankish A, Gonzalez JM, Tapanari E, Diekhans M, Kokocinski F, et al. GENCODE: the reference human genome annotation for The ENCODE Project. Genome Res. 2012;22:1760-74.
59. Pei B, Sisu C, Frankish A, Howald C, Habegger L, Mu XJ, et al. The GENCODE pseudogene resource. Genome Biol. 2012;13:R51.
60. MacArthur DG, Balasubramanian S, Frankish A, Huang N, Morris J, Walter K, et al. A systematic survey of loss-of-function variants in human protein-coding genes. Science. 2012;335:823-8.
61. International HapMap Consortium. A haplotype map of the human genome. Nature. 2005;437:1299-320.
62. Zook JM, Chapman B, Wang J, Mittelman D, Hofmann O, Hide W, et al. Integrating human sequence data sets provides a resource of benchmark SNP and indel genotype calls. Nat Biotechnol. 2014;32:246-51.
63. ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489:57-74.
64. Poliseno L, Salmena L, Zhang J, Carver B, Haveman WJ, Pandolfi PP. A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature. 2010;465:1033-8.
65. Poliseno L, Haimovic A, Christos PJ, Vega Y Saenz de Miera EC, Shapiro R, Pavlick A, et al. Deletion of PTENP1 pseudogene in human melanoma. J Invest Dermatol. 2011;131:2497-500.
66. Yu G, Yao W, Gumireddy K, Li A, Wang J, Xiao W, et al. Pseudogene PTENP1 functions as a competing endogenous RNA to suppress clear-cell renal cell carcinoma progression. Mol Cancer Ther. 2014;13:3086-97.
67. GTEX. GTEX. 2017. http://www.gtexportal.org/. Accessed 24 Apr 2017.
68. Atlas. Expression Atlas. https://www.ebi.ac.uk/gxa/home. Accessed 12 Feb 2017.
69. Wittkopp PJ, Kalay G. Cis-regulatory elements: molecular mechanisms and evolutionary processes underlying divergence. Nat Rev Genet. 2011;13:59-69.
70. Roadmap Epigenomics Consortium, Kundaje A, Meuleman W, Ernst J, Bilenky M, Yen A, et al. Integrative analysis of 111 reference human epigenomes. Nature. 2015;518:317-30.
71. Aken BL, Achuthan P, Akanni W, Amode MR, Bernsdorff F, Bhai J, et al. Ensembl 2017. Nucleic Acids Res. 2017;45(D1):D635-42.
72. McLaren W, Gil L, Hunt SE, Riat HS, Ritchie GR, Thormann A, et al. The Ensembl variant effect predictor. Genome Biol. 2016;17:122.
73. Khurana E, Fu Y, Colonna V, Mu XJ, Kang HM, Lappalainen T, et al. Integrative annotation of variants from 1092 humans: application to cancer genomics. Science. 2013;342:1235587.
74. Smedley D, Schubach M, Jacobsen JO, Köhler S, Zemojtel T, Spielmann M, et al. A whole-genome analysis framework for effective identification of pathogenic regulatory variants in Mendelian disease. Am J Hum Genet. 2016;99:595-606.
75. Morris KV, Mattick JS. The rise of regulatory RNA. Nat Rev Genet. 2014;15:423-37.
76. Barquist L, Burge SW, Gardner PP. Studying RNA homology and conservation with infernal: from single sequences to RNA families. Curr Protoc Bioinformatics. 2016;54:12.13.1-12.13.25.
77. Nawrocki EP, Burge SW, Bateman A, Daub J, Eberhardt RY, Eddy SR, et al. Rfam 12.0: updates to the RNA families database. Nucleic Acids Res. 2015;43(Database issue):D130-7.
78. Ambros V. The functions of animal microRNAs. Nature. 2004;431:350-5.
79. Henshall DC. MicroRNA and epilepsy: profiling, functions and potential clinical applications. Curr Opin Neurol. 2014;27:199-205.
80. Ren L, Zhu R, Li X. Silencing miR-181a produces neuroprotection against hippocampus neuron cell apoptosis post-status epilepticus in a rat model and in children with temporal lobe epilepsy. Genet Mol Res. 2016;15(1); doi: 10.4238/gmr.15017798.
81. Panjwani N, Wilson MD, Addis L, Crosbie J, Wirrell E, Auvin S, et al. A microRNA-328 binding site in PAX6 is associated with centrotemporal spikes of rolandic epilepsy. Ann Clin Transl Neurol. 2016;3:512-22.
82. Reschke CR, Silva LF, Norwood BA, Senthilkumar K, Morris G, Sanz-Rodriguez A, et al. Potent anti-seizure effects of locked nucleic acid antagomirs targeting miR-134 in multiple mouse and rat models of epilepsy. Mol Ther Nucleic Acids. 2017;6:45-56.
83. Ulitsky I, Bartel DP. lincRNAs: genomics, evolution, and mechanisms. Cell. 2013;154:26-46.
84. Wright MW. A short guide to long non-coding RNA gene nomenclature. Hum Genomics. 2014;8:7.
85. St Laurent G, Wahlestedt C, Kapranov P. The Landscape of long noncoding RNA classification. Trends Genet. 2015;31:239-51.
86. Nitsche A, Rose D, Fasold M, Reiche K, Stadler PF. Comparison of splice sites reveals that long noncoding RNAs are evolutionarily well conserved. RNA. 2015;21:801-12.
87. McHugh CA, Chen CK, Chow A, Surka CF, Tran C, McDonel P, et al. The Xist lncRNA interacts directly with SHARP to silence transcription through HDAC3. Nature. 2015;521:232-6.
88. Liu Z, Sun M, Lu K, Liu J, Zhang M, Wu W, et al. The long noncoding RNA HOTAIR contributes to cisplatin resistance of human lung adenocarcinoma cells via downregualtion of p21(WAF1/CIP1) expression. PLoS One. 2013;8:e77293.
89. Zhang X, Weissman SM, Newburger PE. Long intergenic non-coding RNA HOTAIRM1 regulates cell cycle progression during myeloid maturation in NB4 human promyelocytic leukemia cells. RNA Biol. 2014;11:777-87.
90. Lee DY, Moon J, Lee ST, Jung KH, Park DK, Yoo JS, et al. Dysregulation of long non-coding RNAs in mouse models of localization-related epilepsy. Biochem Biophys Res Commun. 2015;462:433-40.
91. Morris KV. The theory of RNA-mediated gene evolution. Epigenetics. 2015;10:1-5.
92. Vitiello M, Tuccoli A, Poliseno L. Long non-coding RNAs in cancer: implications for personalized therapy. Cell Oncol (Dordr). 2015;38:17-28.
93. Hsiao J, Yuan TY, Tsai MS, Lu CY, Lin YC, Lee ML, et al. Upregulation of haploinsufficient gene expression in the brain by targeting a long non-coding RNA improves seizure phenotype in a model of Dravet syndrome. EBioMedicine. 2016;9:257-77.
94. Zhang F, Lupski JR. Non-coding genetic variants in human disease. Hum Mol Genet. 2015;24(R1):R102-10.
95. Talkowski ME, Maussion G, Crapper L, Rosenfeld JA, Blumenthal I, Hanscom C, et al. Disruption of a large intergenic noncoding RNA in subjects with neurodevelopmental disabilities. Am J Hum Genet. 2012;91:1128-34.
96. Turner TN, Hormozdiari F, Duyzend MH, McClymont SA, Hook PW, Iossifov I, et al. Genome sequencing of autism-affected families reveals disruption of putative noncoding regulatory DNA. Am J Hum Genet. 2016;98:58-74.
97. Zhou W, Zhang F, Chen X, Shen Y, Lupski JR, Jin L. Increased genome instability in human DNA segments with self-chains: homology-induced structural variations via replicative mechanisms. Hum Mol Genet. 2013;22:2642-51.
98. Chen L, Zhou W, Zhang L, Zhang F. Genome architecture and its roles in human copy number variation. Genomics Inform. 2014;12:136-44.
99. Mefford HC, Zemel M, Geraghty E, Cook J, Clayton PT, Paul K, et al. Intragenic deletions of ALDH7A1 in pyridoxine-dependent epilepsy caused by Alu-Alu recombination. Neurology. 2015;85:756-62.
100. de Koning AP, Gu W, Castoe TA, Batzer MA, Pollock DD. Repetitive elements may comprise over two-thirds of the human genome. PLoS Genet. 2011;7:e1002384.
101. Bao W, Kojima KK, Kohany O. Repbase Update, a database of repetitive elements in eukaryotic genomes. Mob DNA. 2015;6:11.
102. Hubley R, Finn RD, Clements J, Eddy SR, Jones TA, Bao W, et al. The Dfam database of repetitive DNA families. Nucleic Acids Res. 2016;44(D1):D81-9.
103. Burge CB, Karlin S. Finding the genes in genomic DNA. Curr Opin Struct Biol. 1998;8:346-54.
104. Salamov AA, Solovyev VV. Ab initio gene finding in Drosophila genomic DNA. Genome Res. 2000;10:516-22.
105. Stanke M, Waack S. Gene prediction with a hidden Markov model and a new intron submodel. Bioinformatics. 2003;19 Suppl 2:ii215-25.
106. Mudge J, Harrow J. Methods for improving genome annotation. In: Alterovitz G, Ramoni MF, editors. Knowledge based bioinformatics: from analysis to interpretation. Chichester, West Sussex: John Wiley & Sons; 2010. p. 209-14.
107. Hattori M, Fujiyama A, Taylor TD, Watanabe H, Yada T, Park HS, et al. The DNA sequence of human chromosome 21. Nature. 2000;405:311-9. Erratum in: Nature. 2000;407:110.
108. Dunham I, Shimizu N, Roe BA, Chissoe S, Hunt AR, Collins JE, et al. The DNA sequence of human chromosome 22. Nature. 1999;402:489-95. Erratum in: Nature. 2000;404:904.
109. Karsch-Mizrachi I, Nakamura Y, Cochrane G. The international nucleotide sequence database collaboration. Nucleic Acids Res. 2012;40(Database issue):D33-7.
110. Yandell M, Ence D. A beginner's guide to eukaryotic genome annotation. Nat Rev Genet. 2012;13:329-42.
111. UniProt Consortium. Ongoing and future developments at the Universal Protein Resource. Nucleic Acids Res. 2011;39(Database issue):D214-9.
112. Harrow J, Denoeud F, Frankish A, Reymond A, Chen CK, Chrast J, et al. GENCODE: producing a reference annotation for ENCODE. Genome Biol. 2006;7 Suppl 1:S4. 1-9.
113. ENCODE Project Consortium, Birney E, Stamatoyannopoulos JA, Dutta A, Guigó R, et al. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature. 2007;447:799-816.
114. Frankish A, Uszczynska B, Ritchie GR, Gonzalez JM, Pervouchine D, Petryszak R, et al. Comparison of GENCODE and RefSeq gene annotation and the impact of reference geneset on variant effect prediction. BMC Genomics. 2015;16 Suppl 8:S2.
115. Pruitt KD, Harrow J, Harte RA, Wallin C, Diekhans M, Maglott DR, et al. The consensus coding sequence (CCDS) project: Identifying a common protein-coding gene set for the human and mouse genomes. Genome Res. 2009;19:1316-23.
116. Farrell CM, O'Leary NA, Harte RA, Loveland JE, Wilming LG, Wallin C, et al. Current status and new features of the Consensus Coding Sequence database. Nucleic Acids Res. 2014;42(Database issue):D865-72.
117. Mudge JM, Frankish A, Harrow J. Functional transcriptomics in the post-ENCODE era. Genome Res. 2013;23:1961-73.
118. SeqCap. SeqCap EZ Human Exome Library v3.0. 2014. http://sequencing.roche.com/products/nimblegen-seqcap-target-enrichment/seqcap-ez-system/seqcap-ez-exome-v3.html. Accessed 12 Feb 2017.
119. Chen R, Im H, Snyder M. Whole-exome enrichment with the agilent sureselect human all exon platform. Cold Spring Harb Protoc. 2015;2015:626-33.
120. Coffey AJ, Kokocinski F, Calafato MS, Scott CE, Palta P, Drury E, et al. The GENCODE exome: sequencing the complete human exome. Eur J Hum Genet. 2011;19:827-31.
121. Tyner C, Barber GP, Casper J, Clawson H, Diekhans M, Eisenhart C, et al. The UCSC Genome Browser database: 2017 update. Nucleic Acids Res. 2017;45(D1):D626-34.
122. Barcia G, Fleming MR, Deligniere A, Gazula VR, Brown MR, Langouet M, et al. De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. Nat Genet. 2012;44:1255-9.
123. Cooper GM, Stone EA, Asimenos G, NISC Comparative Sequencing Program, Green ED, Batzoglou S, et al. Distribution and intensity of constraint in mammalian genomic sequence. Genome Res. 2005;15:901-13.
124. Siepel A, Bejerano G, Pedersen JS, Hinrichs AS, Hou M, Rosenbloom K, et al. Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res. 2005;15:1034-50.
125. Howe K, Clark MD, Torroja CF, Torrance J, Berthelot C, Muffato M, et al. The zebrafish reference genome sequence and its relationship to the human genome. Nature. 2013;496:498-503. Erratum in: Nature. 2014;505:248.
126. Kalueff AV, Stewart AM, Gerlai R. Zebrafish as an emerging model for studying complex brain disorders. Trends Pharmacol Sci. 2014;35:63-75.
127. Deciphering Developmental Disorders Study. Large-scale discovery of novel genetic causes of developmental disorders. Nature. 2015;519:223-8.
128. Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, et al. A conditional knockout resource for the genome-wide study of mouse gene function. Nature. 2011;474:337-42.
129. Steward CA, Gonzalez JM, Trevanion S, Sheppard D, Kerry G, Gilbert JG, et al. The non-obese diabetic mouse sequence, annotation and variation resource: an aid for investigating type 1 diabetes. Database (Oxford). 2013;2013:bat032.
130. Church DM, Goodstadt L, Hillier LW, Zody MC, Goldstein S, She X, et al. Lineage-specific biology revealed by a finished genome assembly of the mouse. PLoS Biol. 2009;7:e1000112.
131. Hofker MH, Deursen JV. Transgenic mouse: methods and protocols. Methods in molecular biology. Totowa, NJ: Humana Press; 2003. p. 3741. xiii.
132. Pevzner P, Tesler G. Human and mouse genomic sequences reveal extensive breakpoint reuse in mammalian evolution. Proc Natl Acad Sci U S A. 2003;100:7672-7.
133. MGI. MGI-Mouse Vertebrate Homology. 2017. http://www.informatics.jax.org/homology.shtml. Accessed 24 Apr 2017.
134. Kearney JA, Plummer NW, Smith MR, Kapur J, Cummins TR, Waxman SG, et al. A gain-of-function mutation in the sodium channel gene Scn2a results in seizures and behavioral abnormalities. Neuroscience. 2001;102:307-17.
135. Henshall DC, Hamer HM, Pasterkamp RJ, Goldstein DB, Kjems J, Prehn JH, et al. MicroRNAs in epilepsy: pathophysiology and clinical utility. Lancet Neurol. 2016;15:1368-76.
136. Bult CJ, Eppig JT, Blake JA, Kadin JA, Richardson JE, Group MGD. Mouse genome database 2016. Nucleic Acids Res. 2016;44(D1):D840-7.
137. Ma X, Chen C, Veevers J, Zhou X, Ross RS, Feng W, et al. CRISPR/Cas9-mediated gene manipulation to create single-amino-acid-substituted and floxed mice with a cloning-free method. Sci Rep. 2017;7:42244.
138. Leiter EH, von Herrath M. Animal models have little to teach us about type 1 diabetes: 2. In opposition to this proposal. Diabetologia. 2004;47:1657-60.
139. Roep BO, Atkinson M. Animal models have little to teach us about type 1 diabetes: 1. In support of this proposal. Diabetologia. 2004;47:1650-6.
140. Voelkerding KV, Dames SA, Durtschi JD. Next-generation sequencing: from basic research to diagnostics. Clin Chem. 2009;55:641-58.
141. Steijger T, Abril JF, Engström PG, Kokocinski F, Hubbard TJ, Guigó R, et al. Assessment of transcript reconstruction methods for RNA-seq. Nat Methods. 2013;10:1177-84.
142. Gordon D, Huddleston J, Chaisson MJ, Hill CM, Kronenberg ZN, Munson KM, et al. Long-read sequence assembly of the gorilla genome. Science. 2016;352:aae0344.
143. Zheng GX, Lau BT, Schnall-Levin M, Jarosz M, Bell JM, Hindson CM, et al. Haplotyping germline and cancer genomes with high-throughput linked-read sequencing. Nat Biotechnol. 2016;34:303-11.
144. Gilissen C, Hehir-Kwa JY, Thung DT, van de Vorst M, van Bon BW, Willemsen MH, et al. Genome sequencing identifies major causes of severe intellectual disability. Nature. 2014;511:344-7.
145. Lupski JR, de Oca-Luna RM, Slaugenhaupt S, Pentao L, Guzzetta V, Trask BJ, et al. DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell. 1991;66:219-32.
146. Speevak MD, Farrell SA. Charcot-Marie-Tooth 1B caused by expansion of a familial myelin protein zero (MPZ) gene duplication. Eur J Med Genet. 2013;56:566-9.
147. Yuan B, Neira J, Gu S, Harel T, Liu P, Briceño I, et al. Nonrecurrent PMP22-RAI1 contiguous gene deletions arise from replication-based mechanisms and result in Smith-Magenis syndrome with evident peripheral neuropathy. Hum Genet. 2016;135:1161-74.
148. Corley SM, Canales CP, Carmona-Mora P, Mendoza-Reinosa V, Beverdam A, Hardeman EC, et al. RNA-Seq analysis of Gtf2ird1 knockout epidermal tissue provides potential insights into molecular mechanisms underpinning Williams-Beuren syndrome. BMC Genomics. 2016;17:450.
149. Batut P, Dobin A, Plessy C, Carninci P, Gingeras TR. High-fidelity promoter profiling reveals widespread alternative promoter usage and transposon-driven developmental gene expression. Genome Res. 2013;23:169-80.
150. Derti A, Garrett-Engele P, Macisaac KD, Stevens RC, Sriram S, Chen R, et al. A quantitative atlas of polyadenylation in five mammals. Genome Res. 2012;22:1173-83.
151. Zhang G, Annan RS, Carr SA, Neubert TA. Overview of peptide and protein analysis by mass spectrometry. Curr Protoc Protein Sci. 2010;Chapter 16:Unit16.1.
152. Ingolia NT. Ribosome profiling: new views of translation, from single codons to genome scale. Nat Rev Genet. 2014;15:205-13.
153. Lin MF, Jungreis I, Kellis M. PhyloCSF: a comparative genomics method to distinguish protein coding and non-coding regions. Bioinformatics. 2011;27:i275-82.
154. Jakovcevski M, Akbarian S. Epigenetic mechanisms in neurological disease. Nat Med. 2012;18:1194-204.
155. Henshall DC, Kobow K. Epigenetics and epilepsy. Cold Spring Harb Perspect Med. 2015;5(12); doi: 10.1101/cshperspect.a022731.
156. PacBio. Detecting DNA Base Modification. 2017. http://www.pacb.com/wp-content/uploads/2015/09/WP_Detecting_DNA_Base_Modifications_Using_SMRT_Sequencing.pdf. Accessed 24 Apr 2017.
157. Mifsud B, Tavares-Cadete F, Young AN, Sugar R, Schoenfelder S, Ferreira L, et al. Mapping long-range promoter contacts in human cells with high-resolution capture Hi-C. Nat Genet. 2015;47:598-606.
158. Fullwood MJ, Ruan Y. ChIP-based methods for the identification of long-range chromatin interactions. J Cell Biochem. 2009;107:30-9.
159. Guturu H, Chinchali S, Clarke SL, Bejerano G. Erosion of conserved binding sites in personal genomes points to medical histories. PLoS Comput Biol. 2016;12:e1004711.
160. Clark MB, Amaral PP, Schlesinger FJ, Dinger ME, Taft RJ, Rinn JL, et al. The reality of pervasive transcription. PLoS Biol. 2011;9:e1000625. discussion e1001102.
161. Bussotti G, Leonardi T, Clark MB, Mercer TR, Crawford J, Malquori L, et al. Improved definition of the mouse transcriptome via targeted RNA sequencing. Genome Res. 2016;26:705-16.
162. Frankish A, Mudge JM, Thomas M, Harrow J. The importance of identifying alternative splicing in vertebrate genome annotation. Database (Oxford). 2012;2012:bas014.
163. Djemie T, Weckhuysen S, von Spiczak S, Carvill GL, Jaehn J, Anttonen AK, et al. Pitfalls in genetic testing: the story of missed SCN1A mutations. Mol Genet Genomic Med. 2016;4:457-64.
164. Mercimek-Mahmutoglu S, Patel J, Cordeiro D, Hewson S, Callen D, Donner EJ, et al. Diagnostic yield of genetic testing in epileptic encephalopathy in childhood. Epilepsia. 2015;56:707-16.
165. Foo JN, Liu JJ, Tan EK. Whole-genome and whole-exome sequencing in neurological diseases. Nat Rev Neurol. 2012;8:508-17.
166. de la Hoya M, Soukarieh O, López-Perolio I, Vega A, Walker LC, van Ierland Y, et al. Combined genetic and splicing analysis of BRCA1 c.[594-2A > C; 641A > G] highlights the relevance of naturally occurring in-frame transcripts for developing disease gene variant classification algorithms. Hum Mol Genet. 2016;25:2256-68.
167. MacArthur JA, Morales J, Tully RE, Astashyn A, Gil L, Bruford EA, et al. Locus Reference Genomic: reference sequences for the reporting of clinically relevant sequence variants. Nucleic Acids Res. 2014;42(Database issue):D873-8.
168. Subaran RL, Conte JM, Stewart WC, Greenberg DA. Pathogenic EFHC1 mutations are tolerated in healthy individuals dependent on reported ancestry. Epilepsia. 2015;56:188-94.
169. Helbig I, Tayoun AA. Understanding genotypes and phenotypes in epileptic encephalopathies. Mol Syndromol. 2016;7:172-81.
170. Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285-91.
171. 1000 Genomes Project Consortium, Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, et al. A global reference for human genetic variation. Nature. 2015;526:68-74.
172. MacArthur DG, Manolio TA, Dimmock DP, Rehm HL, Shendure J, Abecasis GR, et al. Guidelines for investigating causality of sequence variants in human disease. Nature. 2014;508:469-76.
173. Hwang S, Kim E, Lee I, Marcotte EM. Systematic comparison of variant calling pipelines using gold standard personal exome variants. Sci Rep. 2015;5:17875.
174. Stenson PD, Mort M, Ball EV, Evans K, Hayden M, Heywood S, et al. The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. Hum Genet. 2017. doi: 10.1007/s00439-017-1779-6
175. Landrum MJ, Lee JM, Benson M, Brown G, Chao C, Chitipiralla S, et al. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res. 2016;44(D1):D862-8.
176. Congenica. Congenica Ltd. 2017. https://www.congenica.com/. Accessed 24 Apr 2017.
177. Sophia-Genetics. Sophia Genetics. 2017. http://www.sophiagenetics.com/home.html. Accessed 24 Apr 2017.
178. WuXi. WuXi NextCODE. https://www.wuxinextcode.com/. Accessed 7 Apr 2017.
179. Omicia. Omicia 2016. http://www.omicia.com/. Accessed 24 Apr 2017.
180. Barrie ES, Smith RM, Sanford JC, Sadee W. mRNA transcript diversity creates new opportunities for pharmacological intervention. Mol Pharmacol. 2012;81:620-30.
181. Buckanovich RJ, Yang YY, Darnell RB. The onconeural antigen Nova-1 is a neuron-specific RNA-binding protein, the activity of which is inhibited by paraneoplastic antibodies. J Neurosci. 1996;16:1114-22.
182. Boumil RM, Letts VA, Roberts MC, Lenz C, Mahaffey CL, Zhang ZW, et al. A missense mutation in a highly conserved alternate exon of dynamin-1 causes epilepsy in fitful mice. PLoS Genet. 2010;6. doi: 10.1371/journal.pgen.1001046
183. Paul SM, Mytelka DS, Dunwiddie CT, Persinger CC, Munos BH, Lindborg SR, et al. How to improve R&D productivity: the pharmaceutical industry's grand challenge. Nat Rev Drug Discov. 2010;9:203-14.
184. Arrowsmith J, Miller P. Trial watch: phase II and phase III attrition rates 2011-2012. Nat Rev Drug Discov. 2013;12:569.
185. Hay M, Thomas DW, Craighead JL, Economides C, Rosenthal J. Clinical development success rates for investigational drugs. Nat Biotechnol. 2014;32:40-51.
186. Vengoechea J, Parikh AS, Zhang S, Tassone F. De novo microduplication of the FMR1 gene in a patient with developmental delay, epilepsy and hyperactivity. Eur J Hum Genet. 2012;20:1197-200.
187. Lemke JR, Lal D, Reinthaler EM, Steiner I, Nothnagel M, Alber M, et al. Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes. Nat Genet. 2013;45:1067-72.
188. Epi4K Consortium. De novo mutations in SLC1A2 and CACNA1A are important causes of epileptic encephalopathies. Am J Hum Genet. 2016;99:287-98.
189. Bilguvar K, Oztürk AK, Louvi A, Kwan KY, Choi M, Tatli B, et al. Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature. 2010;467:207-10.
190. Coutinho AM, Oliveira G, Katz C, Feng J, Yan J, Yang C, et al. MECP2 coding sequence and 3'UTR variation in 172 unrelated autistic patients. Am J Med Genet B Neuropsychiatr Genet. 2007;144B:475-83.
191. Combi R, Dalprà L, Ferini-Strambi L, Tenchini ML. Frontal lobe epilepsy and mutations of the corticotropin-releasing hormone gene. Ann Neurol. 2005;58:899-904.
192. Ramser J, Abidi FE, Burckle CA, Lenski C, Toriello H, Wen G, et al. A unique exonic splice enhancer mutation in a family with X-linked mental retardation and epilepsy points to a novel role of the renin receptor. Hum Mol Genet. 2005;14:1019-27.
193. Elkon R, Ugalde AP, Agami R. Alternative cleavage and polyadenylation: extent, regulation and function. Nat Rev Genet. 2013;14:496-506.
194. Lynch DC, Revil T, Schwartzentruber J, Bhoj EJ, Innes AM, Lamont RE, et al. Disrupted auto-regulation of the spliceosomal gene SNRPB causes cerebro-costo-mandibular syndrome. Nat Commun. 2014;5:4483.
195. Qureshi IA, Mehler MF. Emerging roles of non-coding RNAs in brain evolution, development, plasticity and disease. Nat Rev Neurosci. 2012;13:528-41.
196. GENCODE. GENCODE annotation biotypes. https://www.gencodegenes.org/gencode_biotypes.html. Accessed 24 Apr 2017.
197. Kozak M. An analysis of 5'-noncoding sequences from 699 vertebrate messenger RNAs. Nucleic Acids Res. 1987;15:8125-48.
198. Ivanov IP, Firth AE, Michel AM, Atkins JF, Baranov PV, et al. Identification of evolutionarily conserved non-AUG-initiated N-terminal extensions in human coding sequences. Nucleic Acids Res. 2011;39:4220-34.
199. Brenner S, Barnett L, Katz ER, Crick FH. UGA: a third nonsense triplet in the genetic code. Nature. 1967;213:449-50.
200. Venters BJ, Pugh BF. Genomic organization of human transcription initiation complexes. Nature. 2013;502:53-8.
201. Mitchell PJ, Tjian R. Transcriptional regulation in mammalian cells by sequence-specific DNA binding proteins. Science. 1989;245:371-8.
202. Fatemi M, Pao MM, Jeong S, Gal-Yam EN, Egger G, Weisenberger DJ. Footprinting of mammalian promoters: use of a CpG DNA methyltransferase revealing nucleosome positions at a single molecule level. Nucleic Acids Res. 2005;33:e176.
203. Down TA, Hubbard TJ. Computational detection and location of transcription start sites in mammalian genomic DNA. Genome Res. 2002;12:458-61.
204. Matlin AJ, Clark F, Smith CW. Understanding alternative splicing: towards a cellular code. Nat Rev Mol Cell Biol. 2005;6:386-98.