A Nonsense Mutation in Encoding a Nondescript Transmembrane Protein Causes Idiopathic Male Subfertility in Cattle

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Genetic variants underlying reduced male reproductive performance have been identified in humans and model organisms, most of them compromising semen quality. Occasionally, male fertility is severely compromised although semen analysis remains without any apparent pathological findings (i.e., idiopathic subfertility). Artificial insemination (AI) in most cattle populations requires close examination of all ejaculates before insemination. Although anomalous ejaculates are rejected, insemination success varies considerably among AI bulls. In an attempt to identify genetic causes of such variation, we undertook a genome-wide association study (GWAS). Imputed genotypes of 652,856 SNPs were available for 7962 AI bulls of the Fleckvieh (FV) population. Male reproductive ability (MRA) was assessed based on 15.3 million artificial inseminations. The GWAS uncovered a strong association signal on bovine chromosome 19 (P = 4.08×10⁻⁵⁹). Subsequent autozygosity mapping revealed a common 1386 kb segment of extended homozygosity in 40 bulls with exceptionally poor reproductive performance. Only 1.7% of 35,671 inseminations with semen samples of those bulls were successful. None of the bulls with normal reproductive performance was homozygous, indicating recessive inheritance. Exploiting whole-genome re-sequencing data of 43 animals revealed a candidate causal nonsense mutation (rs378652941, c.483C>A, p.Cys161X) in the transmembrane protein 95 encoding gene TMEM95 which was subsequently validated in 1990 AI bulls. Immunohistochemical investigations evidenced that TMEM95 is located at the surface of spermatozoa of fertile animals whereas it is absent in spermatozoa of subfertile animals. These findings imply that integrity of TMEM95 is required for an undisturbed fertilisation. Our results demonstrate that deficiency of TMEM95 severely compromises male reproductive performance in cattle and reveal for the first time a phenotypic effect associated with genomic variation in TMEM95.

Vyšlo v časopise: A Nonsense Mutation in Encoding a Nondescript Transmembrane Protein Causes Idiopathic Male Subfertility in Cattle. PLoS Genet 10(1): e32767. doi:10.1371/journal.pgen.1004044
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004044

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Zdroje

1. IrvineDS (1998) Epidemiology and aetiology of male infertility. Hum Reprod 13 Suppl 1 : 33–44.

2. De KretserD (1997) Male infertility. The Lancet 349 : 787–790.

3. GurunathS, PandianZ, AndersonRA, BhattacharyaS (2011) Defining infertility–a systematic review of prevalence studies. Hum Reprod Update 17 : 575–588.

4. BhasinS, de KretserDM, BakerHW (1994) Clinical review 64: Pathophysiology and natural history of male infertility. J Clin Endocrinol Metab 79 : 1525–1529.

5. GuzickDS, OverstreetJW, Factor-LitvakP, BrazilCK, NakajimaST, CoutifarisC, CarsonSA, CisnerosP, SteinkampfMP, HillJA, XuD, VogelDL (2001) Sperm morphology, motility, and concentration in fertile and infertile men. N Engl J Med 345 : 1388–1393.

6. MundyAJ, RyderTA, EdmondsDK (1995) Asthenozoospermia and the human sperm mid-piece. Hum Reprod 10 : 116–119.

7. TomarR, MishraAK, MohantyNK, JainAK (2012) Altered Expression of Succinic Dehydrogenase in Asthenozoospermia Infertile Male. Am J Reprod Immunol

8. Effectiveness and treatment for unexplained infertility. Fertil Steril 86: S111–114.

9. QuaasA, DokrasA (2008) Diagnosis and Treatment of Unexplained Infertility. Rev Obstet Gynecol 1 : 69–76.

10. DruetT, FritzS, SellemE, BassoB, GérardO, Salas-CortesL, HumblotP, DruartX, EggenA (2009) Estimation of genetic parameters and genome scan for 15 semen characteristics traits of Holstein bulls. J Anim Breed Genet 126 : 269–277.

11. FerlinA, RaicuF, GattaV, ZuccarelloD, PalkaG, ForestaC (2007) Male infertility: role of genetic background. Reproductive BioMedicine Online 14 : 734–745.

12. O'Flynn O'BrienKL, VargheseAC, AgarwalA (2010) The genetic causes of male factor infertility: a review. Fertil Steril 93 : 1–12.

13. HarrisT, MarquezB, SuarezS, SchimentiJ (2007) Sperm Motility Defects and Infertility in Male Mice with a Mutation in Nsun7, a Member of the Sun Domain-Containing Family of Putative RNA Methyltransferases. Biol Reprod 77 : 376–382.

14. SironenA, UimariP, VenhorantaH, AnderssonM, VilkkiJ (2011) An exonic insertion within Tex14 gene causes spermatogenic arrest in pigs. BMC Genomics 12 : 591.

15. TollnerTL, VennersSA, HolloxEJ, YudinAI, LiuX, TangG, XingH, KaysRJ, LauT, OverstreetJW, XuX, BevinsCL, CherrGN (2011) A common mutation in the defensin DEFB126 causes impaired sperm function and subfertility. Sci Transl Med 3 : 92ra65.

16. WuW, ShenO, QinY, NiuX, LuC, XiaY, SongL, WangS, WangX (2010) Idiopathic Male Infertility Is Strongly Associated with Aberrant Promoter Methylation of Methylenetetrahydrofolate Reductase (MTHFR). PLoS ONE 5: e13884.

17. CarrellDT, AstonKI (2011) The search for SNPs, CNVs, and epigenetic variants associated with the complex disease of male infertility. Syst Biol Reprod Med 57 : 17–26.

18. KastelicJP, ThundathilJC (2008) Breeding soundness evaluation and semen analysis for predicting bull fertility. Reprod Domest Anim 43 Suppl 2 : 368–373.

19. BlaschekM, KayaA, ZwaldN, MemiliE, KirkpatrickBW (2011) A whole-genome association analysis of noncompensatory fertility in Holstein bulls. J Dairy Sci 94 : 4695–4699.

20. HuangW, KirkpatrickBW, RosaGJM, KhatibH (2010) A genome-wide association study using selective DNA pooling identifies candidate markers for fertility in Holstein cattle. Anim Genet 41 : 570–578.

21. PeñagaricanoF, WeigelKA, KhatibH (2012) Genome-wide association study identifies candidate markers for bull fertility in Holstein dairy cattle. Anim Genet 43 Suppl 1 : 65–71.

22. LanXY, PeñagaricanoF, DejungL, WeigelKA, KhatibH (2013) Short communication: A missense mutation in the PROP1 (prophet of Pit 1) gene affects male fertility and milk production traits in the US Holstein population. J Dairy Sci 96 : 1255–1257.

23. JansenS, AignerB, PauschH, WysockiM, EckS, Benet-PagèsA, GrafE, WielandT, StromTM, MeitingerT, FriesR (2013) Assessment of the genomic variation in a cattle population by re-sequencing of key animals at low to medium coverage. BMC Genomics 14 : 446.

24. FloreaL, SouvorovA, KalbfleischTS, SalzbergSL (2011) Genome Assembly Has a Major Impact on Gene Content: A Comparison of Annotation in Two Bos Taurus Assemblies. PLoS ONE 6: e21400.

25. Daetwyler HD, Capitan A, Pausch H, Stothard P, van Binsbergen R, Brøndrum RF, Liao X, Djari A, Rodriguez SC, Grohs C, Jung S, Esquerré D, Bouchez O, Gollnick NS, Rossignol M-N, Klopp C, Rocha D, Fritz S, Eggen A, Bowman PJ, Coote D, Chamberlain AJ, VanTassel CP, Hulsegge I, Goddard ME, Guldbrandtsen B, Lund MS, Veerkam RF, Boichard DA, Fries R, Hayes BJ (2013) The 1000 bull genomes project. submitted.

26. DaviesMJ, deLaceySL, NormanRJ (2005) Towards less confusing terminology in reproductive medicine Clarifying medical ambiguities to the benefit of all. Hum Reprod 20 : 2669–2671.

27. VisscherPM, WoolliamsJA, SmithD, WilliamsJL (2002) Estimation of Pedigree Errors in the UK Dairy Population using Microsatellite Markers and the Impact on Selection. J Dairy Sci 85 : 2368–2375.

28. RobertsonA, RendelJM (1950) The use of progeny testing with artificial insemination in dairy cattle. Journ. of Genetics 50 : 21–31.

29. Gonzaga-JaureguiC, LupskiJR, GibbsRA (2012) Human Genome Sequencing in Health and Disease. Annual Review of Medicine 63 : 35–61.

30. ArnoldCN, XiaY, LinP, RossC, SchwanderM, SmartNG, MullerU, BeutlerB (2011) Rapid Identification of a Disease Allele in Mouse Through Whole Genome Sequencing and Bulk Segregation Analysis. Genetics 187 : 633–641.

31. FormanOP, PenderisJ, HartleyC, HaywardLJ, RickettsSL, MellershCS (2012) Parallel Mapping and Simultaneous Sequencing Reveals Deletions in BCAN and FAM83H Associated with Discrete Inherited Disorders in a Domestic Dog Breed. PLoS Genet 8: e1002462.

32. CharlierC, AgerholmJS, CoppietersW, Karlskov-MortensenP, LiW, de JongG, FasquelleC, KarimL, CireraS, CambisanoN, AharizN, MullaartE, GeorgesM, FredholmM (2012) A Deletion in the Bovine FANCI Gene Compromises Fertility by Causing Fetal Death and Brachyspina. PLoS ONE 7: e43085.

33. SonstegardTS, ColeJB, VanradenPM, Van TassellCP, NullDJ, SchroederSG, BickhartD, McClureMC (2013) Identification of a Nonsense Mutation in CWC15 Associated with Decreased Reproductive Efficiency in Jersey Cattle. PLoS ONE 8: e54872.

34. FritzS, CapitanA, DjariA, RodriguezSC, BarbatA, BaurA, GrohsC, WeissB, BoussahaM, EsquerréD, KloppC, RochaD, BoichardD (2013) Detection of Haplotypes Associated with Prenatal Death in Dairy Cattle and Identification of Deleterious Mutations in GART, SHBG and SLC37A2. PLoS ONE 8: e65550.

35. SuriA (2004) Sperm specific proteins-potential candidate molecules for fertility control. Reproductive Biology and Endocrinology 2 : 10.

36. WangH, LiuJ, ChoK-H, RenD (2009) A Novel, Single, Transmembrane Protein CATSPERG Is Associated with CATSPER1 Channel Protein. Biol Reprod 81 : 539–544.

37. SingsonA, MercerKB, L'HernaultSW (1998) The C. elegans spe-9 Gene Encodes a Sperm Transmembrane Protein that Contains EGF-like Repeats and Is Required for Fertilization. Cell 93 : 71–79.

38. ChatterjeeI, RichmondA, PutiriE, ShakesDC, SingsonA (2005) The Caenorhabditis elegans spe-38 gene encodes a novel four-pass integral membrane protein required for sperm function at fertilization. Development 132 : 2795–2808.

39. ChangY-F, ImamJS, WilkinsonMF (2007) The nonsense-mediated decay RNA surveillance pathway. Annu Rev Biochem 76 : 51–74.

40. QiH, MoranMM, NavarroB, ChongJA, KrapivinskyG, KrapivinskyL, KirichokY, RamseyIS, QuillTA, ClaphamDE (2007) All four CatSper ion channel proteins are required for male fertility and sperm cell hyperactivated motility. PNAS 104 : 1219–1223.

41. Rodriguez-MartinezH, BarthAD (2007) In vitro evaluation of sperm quality related to in vivo function and fertility. Soc Reprod Fertil Suppl 64 : 39–54.

42. BedfordJM, MooreHDM, FranklinLE (1979) Significance of the equatorial segment of the acrosome of the spermatozoon in eutherian mammals. Experimental Cell Research 119 : 119–126.

43. PalermoGD, ColomberoLT, RosenwaksZ (1997) The human sperm centrosome is responsible for normal syngamy and early embryonic development. Rev Reprod 2 : 19–27.

44. Ruiz-PesiniE, DiezC, LapeñaAC, Pérez-MartosA, MontoyaJ, AlvarezE, ArenasJ, López-PérezMJ (1998) Correlation of sperm motility with mitochondrial enzymatic activities. Clin Chem 44 : 1616–1620.

45. RameyNA, ParkCY, GehlbachPL, ChuckRS (2007) Imaging mitochondria in living corneal endothelial cells using autofluorescence microscopy. Photochem Photobiol 83 : 1325–1329.

46. EckersE, DeponteM (2012) No Need for Labels: The Autofluorescence of Leishmania tarentolae Mitochondria and the Necessity of Negative Controls. PLoS ONE 7: e47641.

47. AnwerAG, GosnellME, PerincherySM, InglisDW, GoldysEM (2012) Visible 532 nm laser irradiation of human adipose tissue-derived stem cells: Effect on proliferation rates, mitochondria membrane potential and autofluorescence. Lasers Surg Med 44 : 769–778.

48. HerreraJ, FierroR, ZayasH, ConejoJ, JiménezI, GarcíaA, BetancourtM (2002) Acrosome reaction in fertile and subfertile boar sperm. Arch Androl 48 : 133–139.

49. BrinskoSP, LoveCC, BauerJE, MacphersonML, VarnerDD (2007) Cholesterol-to-phospholipid ratio in whole sperm and seminal plasma from fertile stallions and stallions with unexplained subfertility. Anim Reprod Sci 99 : 65–71.

50. Lopes-SantiagoB, MonteiroG, BittencourtR, ArduinoF, OvidioP, Jordão-JuniorA, AraújoJ, LopesM (2012) Evaluation of Sperm DNA Peroxidation in Fertile and Subfertile Dogs. Reproduction in Domestic Animals 47 : 208–209.

51. MacArthurDG, BalasubramanianS, FrankishA, HuangN, MorrisJ, WalterK, JostinsL, HabeggerL, PickrellJK, MontgomerySB, AlbersCA, ZhangZD, ConradDF, LunterG, ZhengH, AyubQ, DePristoMA, BanksE, HuM, HandsakerRE, RosenfeldJA, FromerM, JinM, MuXJ, KhuranaE, YeK, KayM, SaundersGI, SunerM-M, HuntT, BarnesIHA, AmidC, Carvalho-SilvaDR, BignellAH, SnowC, YngvadottirB, BumpsteadS, CooperDN, XueY, RomeroIG, WangJ, LiY, GibbsRA, McCarrollSA, DermitzakisET, PritchardJK, BarrettJC, HarrowJ, HurlesME, GersteinMB, Tyler-SmithC (2012) A Systematic Survey of Loss-of-Function Variants in Human Protein-Coding Genes. Science 335 : 823–828.

52. Consortium T 1000 GP (2012) An integrated map of genetic variation from 1,092 human genomes. Nature 491 : 56–65.

53. DrögemüllerC, ReichartU, SeuberlichT, OevermannA, BaumgartnerM, Kühni BoghenborK, StoffelMH, SyringC, MeylanM, MüllerS, MüllerM, GredlerB, SölknerJ, LeebT (2011) An Unusual Splice Defect in the Mitofusin 2 Gene (MFN2) Is Associated with Degenerative Axonopathy in Tyrolean Grey Cattle. PLoS ONE 6: e18931.

54. SarteletA, DruetT, MichauxC, FasquelleC, GéronS, TammaN, ZhangZ, CoppietersW, GeorgesM, CharlierC (2012) A Splice Site Variant in the Bovine RNF11 Gene Compromises Growth and Regulation of the Inflammatory Response. PLoS Genet 8: e1002581.

55. GredlerB, FuerstC, Fuerst-WaltlB, SchwarzenbacherH, SölknerJ (2007) Genetic Parameters for Semen Production Traits in Austrian Dual-Purpose Simmental Bulls. Reproduction in Domestic Animals 42 : 326–328.

56. MathevonM, BuhrMM, DekkersJCM (1998) Environmental, Management, and Genetic Factors Affecting Semen Production in Holstein Bulls. Journal of Dairy Science 81 : 3321–3330.

57. FürstC, GredlerB (2009) Genetic Evaluation for Fertility Traits in Austria and Germany. Interbull Bulletin 40 : 3–9.

58. ZiminAV, DelcherAL, FloreaL, KelleyDR, SchatzMC, PuiuD, HanrahanF, PerteaG, Van TassellCP, SonstegardTS, MarçaisG, RobertsM, SubramanianP, YorkeJA, SalzbergSL (2009) A whole-genome assembly of the domestic cow, Bos taurus. Genome Biol 10: R42–R42.

59. PurcellS, NealeB, Todd-BrownK, ThomasL, FerreiraMAR, BenderD, MallerJ, SklarP, de BakkerPIW, DalyMJ, ShamPC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81 : 559–575.

60. HayesB, BowmanP, ChamberlainA, VerbylaK, GoddardM (2009) Accuracy of genomic breeding values in multi-breed dairy cattle populations. Genetics Selection Evolution 41 : 51.

61. ColeJ (2007) PyPedal: A computer program for pedigree analysis. Computers and Electronics in Agriculture 57 : 107–113.

62. BrowningBL, BrowningSR (2009) A Unified Approach to Genotype Imputation and Haplotype-Phase Inference for Large Data Sets of Trios and Unrelated Individuals. The American Journal of Human Genetics 84 : 210–223.

63. HowieB, FuchsbergerC, StephensM, MarchiniJ, AbecasisGR (2012) Fast and accurate genotype imputation in genome-wide association studies through pre-phasing. Nature Genetics 44 : 955–959.

64. PauschH, AignerB, EmmerlingR, EdelC, GötzK-U, FriesR (2013) Imputation of high-density genotypes in the Fleckvieh cattle population. Genet Sel Evol 45 : 3.

65. KangHM, SulJH, ServiceSK, ZaitlenNA, KongS, FreimerNB, SabattiC, EskinE (2010) Variance component model to account for sample structure in genome-wide association studies. Nat Genet 42 : 348–354.

66. EckS, Benet-PagesA, FlisikowskiK, MeitingerT, FriesR, StromT (2009) Whole genome sequencing of a single Bos taurus animal for SNP discovery. Genome Biology 10: R82.

67. LiH, DurbinR (2009) Fast and accurate short read alignment with Burrows–Wheeler transform. Bioinformatics 25 : 1754–1760.

68. LiH, HandsakerB, WysokerA, FennellT, RuanJ, HomerN, MarthG, AbecasisG, DurbinR (2009) The Sequence Alignment/Map format and SAMtools. Bioinformatics 25 : 2078–2079.

69. LiY, SidoreC, KangHM, BoehnkeM, AbecasisGR (2011) Low-coverage sequencing: Implications for design of complex trait association studies. Genome Res 21 : 940–951.

70. DePristoMA, BanksE, PoplinR, GarimellaKV, MaguireJR, HartlC, PhilippakisAA, del AngelG, RivasMA, HannaM, McKennaA, FennellTJ, KernytskyAM, SivachenkoAY, CibulskisK, GabrielSB, AltshulerD, DalyMJ (2011) A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet 43 : 491–498.

71. ViklundH, BernselA, SkwarkM, ElofssonA (2008) SPOCTOPUS: a combined predictor of signal peptides and membrane protein topology. Bioinformatics 24 : 2928–2929.

72. KällL, KroghA, SonnhammerELL (2004) A combined transmembrane topology and signal peptide prediction method. J Mol Biol 338 : 1027–1036.

73. HirokawaT, Boon-ChiengS, MitakuS (1998) SOSUI: classification and secondary structure prediction system for membrane proteins. Bioinformatics 14 : 378–379.

74. ThompsonJD, HigginsDG, GibsonTJ (1994) CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 22 : 4673–4680.

75. AdzhubeiIA, SchmidtS, PeshkinL, RamenskyVE, GerasimovaA, BorkP, KondrashovAS, SunyaevSR (2010) A method and server for predicting damaging missense mutations. Nat. Methods 7 : 248–249.