Integrated genome and transcriptome sequencing identifies a noncoding mutation in the genome replication factor DONSON as the cause of microcephaly-micromelia syndrome

Genome Research

Volumn 27, Issue 8, 2017, Pages 1323-1335

  Evrony, Gilad D ^a,b,c   Cordero, Dwight R ^d   Shen, Jun ^d,e   Partlow, Jennifer N ^a,b,c   Yu, Timothy W ^a,b,c   Rodin, Rachel E ^a,b,c   Hill, R Sean ^a,b,c   Coulter, Michael E ^a,b,c   Lam, Anh Thu N ^a,b,c   Jayaraman, Divya ^a,b,c   Gerrelli, Dianne ^f   Diaz, Diana G ^f   Santos, Chloe ^f   Morrison, Victoria ^f   Galli, Antonella ^g   Tschulena, Ulrich ^h   Wiemann, Stefan ^h   Martel, M Jocelyne ⁱ   Spooner, Betty ⁱ   Ryu, Steven C ^a,b,c   Elhosary, Princess C ^a,b,c   Richardson, Jillian M ^a,b,c   Tierney, Danielle ^a,b,c   Robinson, Christopher A ^j   Chibbar, Rajni ^j   Diudea, Dana ^j   Folkerth, Rebecca ^d   Wiebe, Sheldon ^j   Barkovich, A James ^k   Mochida, Ganeshwaran H ^a,b,c,l   Irvine, James ^i,m   Lemire, Edmond G ^j   Blakley, Patricia ^j   Walsh, Christopher A ^a,b,c   more..

^a BOSTON CHILDREN S HOSPITAL   (United States)

^b HARVARD MEDICAL SCHOOL   (United States)

^c BROAD INSTITUTE OF MIT AND HARVARD   (United States)

^d BRIGHAM AND WOMEN S HOSPITAL   (United States)

^e Partners Center for Personalized Genomic Medicine   (United States)

^f UNIVERSITY COLLEGE LONDON   (United Kingdom)

^g WELLCOME TRUST SANGER INSTITUTE   (United Kingdom)

^h GERMAN CANCER RESEARCH CENTER DKFZ   (Germany)

ⁱ UNIVERSITY OF SASKATCHEWAN   (Canada)

^j ROYAL UNIVERSITY HOSPITAL   (Canada)

^k UNIVERSITY OF CALIFORNIA   (United States)

^l MASSACHUSETTS GENERAL HOSPITAL   (United States)

^m Athabasca Hlth Authority Keewatin Yatthe Health Region and Mamawetan Churchill River Health Region   (Canada)

more..

Author keywords

[No Author keywords available]

Indexed keywords

MESSENGER RNA; TRANSCRIPTOME; DNA BINDING PROTEIN;

ARTICLE; BONE DYSPLASIA; CHROMOSOME 21; CONTROLLED STUDY; CRANIOFACIAL MALFORMATION; DNA REPLICATION; DNA SEQUENCE; DONSON GENE; EMBRYO DEVELOPMENT; FEASIBILITY STUDY; FIRST NATION; GENE; GENE MUTATION; GENE REPLICATION; HUMAN; INTRAUTERINE GROWTH RETARDATION; LETHALITY; LINKAGE ANALYSIS; MICROCEPHALY; MICROCEPHALY MICROMELIA SYNDROME; MICROMELIA; MOUSE; NONHUMAN; PEDIGREE; PRIORITY JOURNAL; RNA SEQUENCE; TRANSCRIPTOMICS; WHOLE GENOME SEQUENCING; ANIMAL; CHONDRODYSPLASIA; CHROMOSOMAL MAPPING; FEMALE; GENETIC LINKAGE; GENETICS; GENOMIC INSTABILITY; HIGH THROUGHPUT SEQUENCING; KNOCKOUT MOUSE; MALE; METABOLISM; MUTATION; PATHOLOGY; PREGNANCY; RNA SPLICING; SEQUENCE ANALYSIS;

ANIMALS; CHROMOSOME MAPPING; DNA REPLICATION; DNA-BINDING PROTEINS; FEMALE; GENETIC LINKAGE; GENOMIC INSTABILITY; HIGH-THROUGHPUT NUCLEOTIDE SEQUENCING; HUMANS; MALE; MICE; MICE, KNOCKOUT; MICROCEPHALY; MUTATION; OSTEOCHONDRODYSPLASIAS; PEDIGREE; PREGNANCY; RNA SPLICING; SEQUENCE ANALYSIS, RNA; TRANSCRIPTOME; WHOLE GENOME SEQUENCING;

EID: 85026643052     PISSN: 10889051     EISSN: 15495469     Source Type: Journal    
DOI: 10.1101/gr.219899.116     Document Type: Article

References (73)

1. The 1000 Genomes Project Consortium. 2015. A global reference for human genetic variation. Nature 526: 68-74.
2. Abecasis GR, Cherny SS, Cookson WO, Cardon LR. 2002. Merlin-rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 30: 97-101.
3. Bandura JL. 2005. "Humpty dumpty defines a new gene family required for S phase." PhD thesis, University of Pennsylvania.
4. Bandura JL, Beall EL, Bell M, Silver HR, Botchan MR, Calvi BR. 2005. humpty dumpty is required for developmental DNA amplification and cell proliferation in Drosophila. Curr Biol 15: 755-759.
5. Barash Y, Calarco JA, GaoW, Pan Q, Wang X, Shai O, Blencowe BJ, Frey BJ. 2010. Deciphering the splicing code. Nature 465: 53-59.
6. Bell TJ, Miyashiro KY, Sul JY, Buckley PT, Lee MT, McCullough R, Jochems J, Kim J, Cantor CR, Parsons TD, et al. 2010. Intron retention facilitates splice variant diversity in calcium-activated big potassium channel populations. Proc Natl Acad Sci 107: 21152-21157.
7. Bermudez VP, Maniwa Y, Tappin I, Ozato K, Yokomori K, Hurwitz J. 2003. The alternative Ctf18-Dcc1-Ctf8-replication factor C complex required for sister chromatid cohesion loads proliferating cell nuclear antigen onto DNA. Proc Natl Acad Sci 100: 10237-10242.
8. Bicknell LS, Bongers EM, Leitch A, Brown S, Schoots J, Harley ME, Aftimos S, Al-Aama JY, Bober M, Brown PA, et al. 2011. Mutations in the pre-replication complex cause Meier-Gorlin syndrome. Nat Genet 43: 356-359.
9. Boutz PL, Bhutkar A, Sharp PA. 2015. Detained introns are a novel, widespread class of post-transcriptionally spliced introns. Genes Dev 29: 63-80.
10. Bowman GD, O'Donnell M, Kuriyan J. 2004. Structural analysis of a eukaryotic sliding DNA clamp-clamp loader complex. Nature 429: 724-730.
11. Braunschweig U, Barbosa-Morais NL, Pan Q, Nachman EN, Alipanahi B, Gonatopoulos-Pournatzis T, Frey B, Irimia M, Blencowe BJ. 2014. Widespread intron retention in mammals functionally tunes transcriptomes. Genome Res 24: 1774-1786.
12. Burrage LC, Charng WL, Eldomery MK, Willer JR, Davis EE, Lugtenberg D, ZhuW, Leduc MS, Akdemir ZC, Azamian M, et al. 2015. De novoGMNN mutations cause autosomal-dominant primordial dwarfism associated with Meier-Gorlin syndrome. Am J Hum Genet 97: 904-913.
13. Cartegni L, Chew SL, Krainer AR. 2002. Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat Rev Genet 3: 285-298.
14. Chandrasekharappa SC, Lach FP, Kimble DC, Kamat A, Teer JK, Donovan FX, Flynn E, Sen SK, Thongthip S, Sanborn E, et al. 2013. Massively parallel sequencing, aCGH, and RNA-Seq technologies provide a comprehensive molecular diagnosis of Fanconi anemia. Blood 121: e138-e148.
15. Chatr-Aryamontri A, Breitkreutz BJ, Oughtred R, Boucher L, Heinicke S, Chen D, Stark C, Breitkreutz A, Kolas N, O'Donnell L, et al. 2015. The BioGRID interaction database: 2015 update. Nucleic Acids Res 43: D470-D478.
16. Cooper GM, Shendure J. 2011. Needles in stacks of needles: finding diseasecausal variants in a wealth of genomic data. Nat Rev Genet 12: 628-640.
17. de Klerk E, 't Hoen PA. 2015. Alternative mRNA transcription, processing, and translation: insights from RNA sequencing. Trends Genet 31: 128-139.
18. Drmanac R, Sparks AB, Callow MJ, Halpern AL, Burns NL, Kermani BG, Carnevali P, Nazarenko I, Nilsen GB, Yeung G, et al. 2010. Human genome sequencing using unchained base reads on self-assembling DNA nanoarrays. Science 327: 78-81.
19. Dvinge H, Bradley RK. 2015. Widespread intron retention diversifies most cancer transcriptomes. Genome Med 7: 45.
20. Edwards CR, RitchieW, Wong JJ, Schmitz U, Middleton R, An X, Mohandas N, Rasko JE, Blobel GA. 2016. A dynamic intron retention program in the mammalian megakaryocyte and erythrocyte lineages. Blood doi: 10.1182/blood-2016-01-692764.
21. Faustino NA, Cooper TA. 2003. Pre-mRNA splicing and human disease. Genes Dev 17: 419-437.
22. Fenwick AL, Kliszczak M, Cooper F, Murray J, Sanchez-Pulido L, Twigg SR, Goriely A, McGowan SJ, Miller KA, Taylor IB, et al. 2016. Mutations in CDC45, encoding an essential component of the pre-initiation complex, cause Meier-Gorlin syndrome and craniosynostosis. Am J Hum Genet 99: 125-138.
23. Fuchs F, Pau G, Kranz D, Sklyar O, Budjan C, Steinbrink S, Horn T, Pedal A, Huber W, Boutros M. 2010. Clustering phenotype populations by genome-wide RNAi and multiparametric imaging. Mol Syst Biol 6: 370.
24. Galante PA, Sakabe NJ, Kirschbaum-Slager N, de Souza SJ. 2004. Detection and evaluation of intron retention events in the human transcriptome. RNA 10: 757-765.
25. Ge Y, Porse BT. 2014. The functional consequences of intron retention: alternative splicing coupled to NMD as a regulator of gene expression. Bioessays 36: 236-243.
26. Guigo R, Valcarcel J. 2015. RNA. Prescribing splicing. Science 347: 124-125.
27. Guruharsha KG, Rual JF, Zhai B, Mintseris J, Vaidya P, Vaidya N, Beekman C, Wong C, Rhee DY, Cenaj O, et al. 2011. A protein complex network of Drosophila melanogaster. Cell 147: 690-703.
28. Higa LA, Banks D,WuM, Kobayashi R, Sun H, Zhang H. 2006. L2DTL/CDT2 interacts with the CUL4/DDB1 complex and PCNA and regulates CDT1 proteolysis in response to DNA damage. Cell Cycle 5: 1675-1680.
29. Homesley L, Lei M, Kawasaki Y, Sawyer S, Christensen T, Tye BK. 2000. Mcm10 and the MCM2-7 complex interact to initiate DNA synthesis and to release replication factors from origins. Genes Dev 14: 913-926.
30. Ives EJ, Houston CS. 1980. Autosomal recessive microcephaly and micromelia in Cree Indians. Am J Med Genet 7: 351-360.
31. Jian X, Boerwinkle E, Liu X. 2014. In silico tools for splicing defect prediction: a survey from the viewpoint of end users. Genet Med 16: 497-503.
32. Jung H, Lee D, Lee J, Park D, Kim YJ, Park WY, Hong D, Park PJ, Lee E. 2015. Intron retention is a widespread mechanism of tumor-suppressor inactivation. Nat Genet 47: 1242-1248.
33. Kallabi F, Ben Rhouma B, Baklouti S, Ghorbel R, Felhi R, Keskes L, Kamoun H. 2016. Splicing defects in the AAAS gene leading to both exon skipping and partial intron retention in a Tunisian patient with Allgrove syndrome. Horm Res Paediatr 86: 90-93.
34. Kang HJ, Kawasawa YI, Cheng F, Zhu Y, Xu X, Li M, Sousa AM, Pletikos M, Meyer KA, Sedmak G, et al. 2011. Spatio-temporal transcriptome of the human brain. Nature 478: 483-489.
35. Khetarpal P, Das S, Panigrahi I, Munshi A. 2016. Primordial dwarfism: overview of clinical and genetic aspects. Mol Genet Genomics 291: 1-15.
36. Kim D, Langmead B, Salzberg SL. 2015. HISAT: a fast spliced aligner with low memory requirements. Nat Methods 12: 357-360.
37. Klingseisen A, Jackson AP. 2011. Mechanisms and pathways of growth failure in primordial dwarfism. Genes Dev 25: 2011-2024.
38. Lee Y, Rio DC. 2015. Mechanisms and regulation of alternative pre-mRNA splicing. Annu Rev Biochem 84: 291-323.
39. Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, O'Donnell-Luria AH, Ware JS, Hill AJ, Cummings BB, et al. 2016. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536: 285-291.
40. Lewandowska MA. 2013. The missing puzzle piece: splicing mutations. Int J Clin Exp Pathol 6: 2675-2682.
41. Lim KH, Ferraris L, Filloux ME, Raphael BJ, Fairbrother WG. 2011. Using positional distribution to identify splicing elements and predict premRNA processing defects in human genes. Proc Natl Acad Sci 108: 11093-11098.
42. Lopez-Bigas N, Audit B, Ouzounis C, Parra G, Guigo R. 2005. Are splicing mutations the most frequent cause of hereditary disease? FEBS Lett 579: 1900-1903.
43. MacArthur DG, Manolio TA, Dimmock DP, Rehm HL, Shendure J, Abecasis GR, Adams DR, Altman RB, Antonarakis SE, Ashley EA, et al. 2014. Guidelines for investigating causality of sequence variants in human disease. Nature 508: 469-476.
44. Miller AC, Obholzer ND, Shah AN, Megason SG, Moens CB. 2013. RNA-seqbased mapping and candidate identification of mutations from forward genetic screens. Genome Res 23: 679-686.
45. Miller JA, Ding SL, Sunkin SM, Smith KA, Ng L, Szafer A, Ebbert A, Riley ZL, Royall JJ, Aiona K, et al. 2014. Transcriptional landscape of the prenatal human brain. Nature 508: 199-206.
46. Morin RD, Mungall K, Pleasance E, Mungall AJ, Goya R, Huff R, Scott DW, Ding J, Roth A, Chiu R, et al. 2013. Mutational and structural analysis of diffuse large B-cell lymphoma using whole genome sequencing. Blood 122: 1256-1265.
47. Mudvari P, Movassagh M, Kowsari K, Seyfi A, Kokkinaki M, Edwards NJ, Golestaneh N, Horvath A. 2015. SNPlice: variants that modulate Intron retention from RNA-sequencing data. Bioinformatics 31: 1191-1198.
48. Nadeau NJ, Pardo-Diaz C, Whibley A, SuppleMA, Saenko SV, WallbankRW, WuGC, Maroja L, Ferguson L, Hanly JJ, et al. 2016. The gene cortex controls mimicry and crypsis in butterflies and moths. Nature 534: 106-110.
49. Ni T, Yang W, Han M, Zhang Y, Shen T, Nie H, Zhou Z, Dai Y, Yang Y, Liu P, et al. 2016. Global intron retention mediated gene regulation during CD4+ T cell activation. Nucleic Acids Res doi: 10.1093/nar/gkw591.
50. Okamura Y, Aoki Y, Obayashi T, Tadaka S, Ito S, Narise T, Kinoshita K. 2015. COXPRESdb in 2015: coexpression database for animal species by DNA-microarray and RNAseq-based expression data with multiple quality assessment systems. Nucleic Acids Res 43: D82-D86.
51. Ortega-Recalde O, Moreno MB, Vergara JI, Fonseca DJ, Rojas RF, Mosquera H, Medina CL, Restrepo CM, Laissue P. 2015. A novel TGM1 mutation, leading to multiple splicing rearrangements, is associated with autosomal recessive congenital ichthyosis. Clin Exp Dermatol 40: 757-760.
52. Pagani F, Baralle FE. 2004. Genomic variants in exons and introns: identifying the splicing spoilers. Nat Rev Genet 5: 389-396.
53. Pan Q, Shai O, Lee LJ, Frey BJ, Blencowe BJ. 2008. Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat Genet 40: 1413-1415.
54. Pierron G, Tirode F, Lucchesi C, Reynaud S, Ballet S, Cohen-Gogo S, PerrinV, Coindre JM, Delattre O. 2012. A new subtype of bone sarcoma defined by BCOR-CCNB3 gene fusion. Nat Genet 44: 461-466.
55. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, et al. 2007. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81: 559-575.
56. Reynolds JJ, Bicknell LS, Carroll P, Higgs MR, Shaheen R, Murray JE, Papadopoulos DK, Leitch A, Murina O, Tarnauskaite Z, et al. 2017. Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism. Nat Genet 49: 537-549.
57. Ricke RM, Bielinsky AK. 2004. Mcm10 regulates the stability and chromatin association of DNA polymerase-α. Mol Cell 16: 173-185.
58. Seifert W, Holder-Espinasse M, Spranger S, Hoeltzenbein M, Rossier E, Dollfus H, Lacombe D, Verloes A, Chrzanowska KH, Maegawa GH, et al. 2006. Mutational spectrum of COH1 and clinical heterogeneity in Cohen syndrome. J Med Genet 43: e22.
59. Tanackovic G, Ransijn A, Ayuso C, Harper S, Berson EL, Rivolta C. 2011. A missense mutation in PRPF6 causes impairment of pre-mRNA splicing and autosomal-dominant retinitis pigmentosa. Am J Hum Genet 88: 643-649.
60. Tennessen JA, Bigham AW,O'Connor TD, FuW, Kenny EE, Gravel S, McGee S, Do R, Liu X, Jun G, et al. 2012. Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science 337: 64-69.
61. Van der Auwera GA, Carneiro MO, Hartl C, Poplin R, Del Angel G, Levy-Moonshine A, Jordan T, Shakir K, Roazen D, Thibault J, et al. 2013. From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline. Curr Protoc Bioinformatics 43: 11.10.1-33.
62. Vermeulen K, Van Bockstaele DR, Berneman ZN. 2003. The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell Prolif 36: 131-149.
63. Volk A, Crispino JD. 2015. The role of the chromatin assembly complex (CAF-1) and its p60 subunit (CHAF1b) in homeostasis and disease. Biochim Biophys Acta 1849: 979-986.
64. Wang Z, Gerstein M, Snyder M. 2009. RNA-Seq: a revolutionary tool for transcriptomics. Nat Rev Genet 10: 57-63.
65. Wang K, Li M, Hakonarson H. 2010. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38: e164.
66. Wang K, Kim C, Bradfield J, Guo Y, Toskala E, Otieno FG, Hou C, Thomas K, Cardinale C, Lyon GJ, et al. 2013. Whole-genome DNA/RNA sequencing identifies truncating mutations in RBCK1 in a novel Mendelian disease with neuromuscular and cardiac involvement. Genome Med 5: 67.
67. White JK, Gerdin AK, Karp NA, Ryder E, Buljan M, Bussell JN, Salisbury J, Clare S, Ingham NJ, Podrini C, et al. 2013. Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes. Cell 154: 452-464.
68. Whitfield ML, Sherlock G, Saldanha AJ, Murray JI, Ball CA, Alexander KE, Matese JC, Perou CM, Hurt MM, Brown PO, et al. 2002. Identification of genes periodically expressed in the human cell cycle and their expression in tumors. Mol Biol Cell 13: 1977-2000.
69. Wong JJ, Ritchie W, Ebner OA, Selbach M, Wong JW, Huang Y, Gao D, Pinello N, Gonzalez M, Baidya K, et al. 2013. Orchestrated intron retention regulates normal granulocyte differentiation. Cell 154: 583-595.
70. Wong JJ, Au AY, Ritchie W, Rasko JE. 2016. Intron retention in mRNA: no longer nonsense: known and putative roles of intron retention in normal and disease biology. Bioessays 38: 41-49.
71. Xiong HY, Alipanahi B, Lee LJ, Bretschneider H, Merico D, Yuen RK, Hua Y, Gueroussov S, Najafabadi HS, Hughes TR, et al. 2015. RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. Science 347: 1254806.
72. Yang YJ, Baltus AE, Mathew RS, Murphy EA, Evrony GD, Gonzalez DM, Wang EP, Marshall-Walker CA, Barry BJ, Murn J, et al. 2012. Microcephaly gene links trithorax and REST/NRSF to control neural stem cell proliferation and differentiation. Cell 151: 1097-1112.
73. Yap K, Lim ZQ, Khandelia P, Friedman B, Makeyev EV. 2012. Coordinated regulation of neuronal mRNA steady-state levels through developmentally controlled intron retention. Genes Dev 26: 1209-1223.