Parallel Mapping and Simultaneous Sequencing Reveals Deletions in and Associated with Discrete Inherited Disorders in a Domestic Dog Breed
The domestic dog (Canis familiaris) segregates more naturally-occurring diseases and phenotypic variation than any other species and has become established as an unparalled model with which to study the genetics of inherited traits. We used a genome-wide association study (GWAS) and targeted resequencing of DNA from just five dogs to simultaneously map and identify mutations for two distinct inherited disorders that both affect a single breed, the Cavalier King Charles Spaniel. We investigated episodic falling (EF), a paroxysmal exertion-induced dyskinesia, alongside the phenotypically distinct condition congenital keratoconjunctivitis sicca and ichthyosiform dermatosis (CKCSID), commonly known as dry eye curly coat syndrome. EF is characterised by episodes of exercise-induced muscular hypertonicity and abnormal posturing, usually occurring after exercise or periods of excitement. CKCSID is a congenital disorder that manifests as a rough coat present at birth, with keratoconjunctivitis sicca apparent on eyelid opening at 10–14 days, followed by hyperkeratinisation of footpads and distortion of nails that develops over the next few months. We undertook a GWAS with 31 EF cases, 23 CKCSID cases, and a common set of 38 controls and identified statistically associated signals for EF and CKCSID on chromosome 7 (Praw 1.9×10−14; Pgenome = 1.0×10−5) and chromosome 13 (Praw 1.2×10−17; Pgenome = 1.0×10−5), respectively. We resequenced both the EF and CKCSID disease-associated regions in just five dogs and identified a 15,724 bp deletion spanning three exons of BCAN associated with EF and a single base-pair exonic deletion in FAM83H associated with CKCSID. Neither BCAN or FAM83H have been associated with equivalent disease phenotypes in any other species, thus demonstrating the ability to use the domestic dog to study the genetic basis of more than one disease simultaneously in a single breed and to identify multiple novel candidate genes in parallel.
Vyšlo v časopise:
Parallel Mapping and Simultaneous Sequencing Reveals Deletions in and Associated with Discrete Inherited Disorders in a Domestic Dog Breed. PLoS Genet 8(1): e32767. doi:10.1371/journal.pgen.1002462
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002462
Souhrn
The domestic dog (Canis familiaris) segregates more naturally-occurring diseases and phenotypic variation than any other species and has become established as an unparalled model with which to study the genetics of inherited traits. We used a genome-wide association study (GWAS) and targeted resequencing of DNA from just five dogs to simultaneously map and identify mutations for two distinct inherited disorders that both affect a single breed, the Cavalier King Charles Spaniel. We investigated episodic falling (EF), a paroxysmal exertion-induced dyskinesia, alongside the phenotypically distinct condition congenital keratoconjunctivitis sicca and ichthyosiform dermatosis (CKCSID), commonly known as dry eye curly coat syndrome. EF is characterised by episodes of exercise-induced muscular hypertonicity and abnormal posturing, usually occurring after exercise or periods of excitement. CKCSID is a congenital disorder that manifests as a rough coat present at birth, with keratoconjunctivitis sicca apparent on eyelid opening at 10–14 days, followed by hyperkeratinisation of footpads and distortion of nails that develops over the next few months. We undertook a GWAS with 31 EF cases, 23 CKCSID cases, and a common set of 38 controls and identified statistically associated signals for EF and CKCSID on chromosome 7 (Praw 1.9×10−14; Pgenome = 1.0×10−5) and chromosome 13 (Praw 1.2×10−17; Pgenome = 1.0×10−5), respectively. We resequenced both the EF and CKCSID disease-associated regions in just five dogs and identified a 15,724 bp deletion spanning three exons of BCAN associated with EF and a single base-pair exonic deletion in FAM83H associated with CKCSID. Neither BCAN or FAM83H have been associated with equivalent disease phenotypes in any other species, thus demonstrating the ability to use the domestic dog to study the genetic basis of more than one disease simultaneously in a single breed and to identify multiple novel candidate genes in parallel.
Zdroje
1. SutterNBOstranderEA 2004 Dog star rising: the canine genetic system. Nat Rev Genet 5 900 910
2. MellershC 2008 Give a dog a genome. Vet J 178 46 52
3. ParkerHGShearinALOstranderEA 2010 Man's best friend becomes biology's best in show: genome analyses in the domestic dog. Annu Rev Genet 44 309 336
4. PenderisJCalvinJAbramsonCJakobsCPettittL 2007 L-2-hydroxyglutaric aciduria: characterisation of the molecular defect in a spontaneous canine model. J Med Genet 44 334 340
5. MellershCSPettittLFormanOPVaudinMBarnettKC 2006 Identification of mutations in HSF4 in dogs of three different breeds with hereditary cataracts. Vet Ophthalmol 9 369 378
6. PeleMTiretLKesslerJLBlotSPanthierJJ 2005 SINE exonic insertion in the PTPLA gene leads to multiple splicing defects and segregates with the autosomal recessive centronuclear myopathy in dogs. Hum Mol Genet 14 1417 1427
7. PattersonEEMinorKMTchernatynskaiaAVTaylorSMSheltonGD 2008 A canine DNM1 mutation is highly associated with the syndrome of exercise-induced collapse. Nat Genet 40 1235 1239
8. Salmon HillbertzNHIsakssonMKarlssonEKHellmenEPielbergGR 2007 Duplication of FGF3, FGF4, FGF19 and ORAOV1 causes hair ridge and predisposition to dermoid sinus in Ridgeback dogs. Nat Genet 39 1318 1320
9. KarlssonEKBaranowskaIWadeCMSalmon HillbertzNHZodyMC 2007 Efficient mapping of mendelian traits in dogs through genome-wide association. Nat Genet 39 1321 1328
10. HerrtageMEPalmerAC 1983 Episodic falling in the cavalier King Charles spaniel. Vet Rec 112 458 459
11. WrightJABrownlieSESmythJBJonesDGWottonP 1986 Muscle hypertonicity in the cavalier King Charles spaniel–myopathic features. Vet Rec 118 511 512
12. WeberYGStorchAWuttkeTVBrockmannKKempfleJ 2008 GLUT1 mutations are a cause of paroxysmal exertion-induced dyskinesias and induce hemolytic anemia by a cation leak. J Clin Invest 118 2157 2168
13. TijssenMASchoemakerHCEdelbroekPJRoosRACohenAF 1997 The effects of clonazepam and vigabatrin in hyperekplexia. J Neurol Sci 149 63 67
14. ShiangRRyanSGZhuYZHahnAFO'ConnellP 1993 Mutations in the alpha 1 subunit of the inhibitory glycine receptor cause the dominant neurologic disorder, hyperekplexia. Nat Genet 5 351 358
15. ReesMILewisTMKwokJBMortierGRGovaertP 2002 Hyperekplexia associated with compound heterozygote mutations in the beta-subunit of the human inhibitory glycine receptor (GLRB). Hum Mol Genet 11 853 860
16. EulenburgVBeckerKGomezaJSchmittBBeckerCM 2006 Mutations within the human GLYT2 (SLC6A5) gene associated with hyperekplexia. Biochem Biophys Res Commun 348 400 405
17. ReesMIHarveyKWardHWhiteJHEvansL 2003 Isoform heterogeneity of the human gephyrin gene (GPHN), binding domains to the glycine receptor, and mutation analysis in hyperekplexia. J Biol Chem 278 24688 24696
18. BrodyIA 1969 Muscle contracture induced by exercise. A syndrome attributable to decreased relaxing factor. N Engl J Med 281 187 192
19. OdermattATaschnerPEKhannaVKBuschHFKarpatiG 1996 Mutations in the gene-encoding SERCA1, the fast-twitch skeletal muscle sarcoplasmic reticulum Ca2+ ATPase, are associated with Brody disease. Nat Genet 14 191 194
20. GeorgeALJrCrackowerMAAbdallaJAHudsonAJEbersGC 1993 Molecular basis of Thomsen's disease (autosomal dominant myotonia congenita). Nat Genet 3 305 310
21. KochMCSteinmeyerKLorenzCRickerKWolfF 1992 The skeletal muscle chloride channel in dominant and recessive human myotonia. Science 257 797 800
22. RhodesTHViteCHGigerUPattersonDFFahlkeC 1999 A missense mutation in canine C1C-1 causes recessive myotonia congenita in the dog. FEBS Lett 456 54 58
23. FinniganDFHannaWJPomaRBendallAJ 2007 A novel mutation of the CLCN1 gene associated with myotonia hereditaria in an Australian cattle dog. J Vet Intern Med 21 458 463
24. BarnettKC 2006 Congenital keratoconjunctivitis sicca and ichthyosiform dermatosis in the cavalier King Charles spaniel. J Small Anim Pract 47 524 528
25. CredilleKMBarnhartKFMinorJSDunstanRW 2005 Mild recessive epidermolytic hyperkeratosis associated with a novel keratin 10 donor splice-site mutation in a family of Norfolk terrier dogs. Br J Dermatol 153 51 58
26. CredilleKMMinorJSBarnhartKFLeeECoxML 2009 Transglutaminase 1-deficient recessive lamellar ichthyosis associated with a LINE-1 insertion in Jack Russell terrier dogs. Br J Dermatol 161 265 272
27. SkinnerBAGreistMCNorinsAL 1981 The keratitis, ichthyosis, and deafness (KID) syndrome. Arch Dermatol 117 285 289
28. RichardGRouanFWilloughbyCEBrownNChungP 2002 Missense mutations in GJB2 encoding connexin-26 cause the ectodermal dysplasia keratitis-ichthyosis-deafness syndrome. Am J Hum Genet 70 1341 1348
29. van SteenselMAKoedamMISwinkelsOQRietveldFSteijlenPM 2001 Woolly hair, premature loss of teeth, nail dystrophy, acral hyperkeratosis and facial abnormalities: possible new syndrome in a Dutch kindred. Br J Dermatol 145 157 161
30. AstleWBaldingDJ 2009 Population Structure and Cryptic Relatedness in Genetic Association Studies. Statistical Science 24 451 471
31. BonfieldJKSmithKStadenR 1995 A new DNA sequence assembly program. Nucleic Acids Res 23 4992 4999
32. YamadaHWatanabeKShimonakaMYamaguchiY 1994 Molecular cloning of brevican, a novel brain proteoglycan of the aggrecan/versican family. J Biol Chem 269 10119 10126
33. BekkuYRauchUNinomiyaYOohashiT 2009 Brevican distinctively assembles extracellular components at the large diameter nodes of Ranvier in the CNS. J Neurochem 108 1266 1276
34. BekkuYVargovaLGotoYVorisekIDmytrenkoL 2010 Bral1: its role in diffusion barrier formation and conduction velocity in the CNS. J Neurosci 30 3113 3123
35. BrakebuschCSeidenbecherCIAsztelyFRauchUMatthiesH 2002 Brevican-deficient mice display impaired hippocampal CA1 long-term potentiation but show no obvious deficits in learning and memory. Mol Cell Biol 22 7417 7427
36. RusbridgeC 2005 Neurological diseases of the Cavalier King Charles spaniel. J Small Anim Pract 46 265 272
37. GillJLTsaiKLKreyCNooraiREVanbellinghenJF 2011 A canine BCAN microdeletion associated with episodic falling syndrome. Neurobiol Dis
38. KimJWLeeSKLeeZHParkJCLeeKE 2008 FAM83H mutations in families with autosomal-dominant hypocalcified amelogenesis imperfecta. Am J Hum Genet 82 489 494
39. UrzuaBOrtega-PintoAMorales-BozoIRojas-AlcayagaGCifuentesV 2010 Defining a new candidate gene for amelogenesis imperfecta: from molecular genetics to biochemistry. Biochem Genet 49 104 121
40. PurcellSNealeBTodd-BrownKThomasLFerreiraMA 2007 PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81 559 575
41. LiHDurbinR 2009 Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25 1754 1760
42. McKennaAHannaMBanksESivachenkoACibulskisK 2010 The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20 1297 1303
43. YeKSchulzMHLongQApweilerRNingZ 2009 Pindel: a pattern growth approach to detect break points of large deletions and medium sized insertions from paired-end short reads. Bioinformatics 25 2865 2871
44. RobinsonJTThorvaldsdottirHWincklerWGuttmanMLanderES 2011 Integrative genomics viewer. Nat Biotechnol 29 24 26
45. RozenSSkaletskyH 2000 Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol 132 365 386
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2012 Číslo 1
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