Conserved Genetic Interactions between Ciliopathy Complexes Cooperatively Support Ciliogenesis and Ciliary Signaling

English version České info

Ciliopathies, diseases arising from defects in the functions of primary cilia, have many different manifestations and vary dramatically in severity. How genetics influence ciliopathy phenotypes is poorly understood. Building off of our increasing knowledge of how different biochemical complexes contribute to ciliary function, we investigated how ciliopathy-associated genes interact to support ciliogenesis. Using a combination of nematode and mouse genetics, we found that genes encoding components of different biochemical complexes interact, whereas genes encoding different components within a single complex do not. These results revealed overlapping ciliary functions of biochemically distinct proteins complexes such as the BBSome, the transition zone MKS complex and the transition zone NPHP complex. This work indicates the genetic interactions that may alter the phenotypic consequences of human ciliopathy mutations.

Vyšlo v časopise: Conserved Genetic Interactions between Ciliopathy Complexes Cooperatively Support Ciliogenesis and Ciliary Signaling. PLoS Genet 11(11): e32767. doi:10.1371/journal.pgen.1005627
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005627

Souhrn

Zdroje

1. Morell RJ, Brewer CC, Ge D, Snieder H, Zalewski CK, King KA, et al. A twin study of auditory processing indicates that dichotic listening ability is a strongly heritable trait. Hum Genet. 2007;122(1):103–11. doi: 10.1007/s00439-007-0384-5 17533509.

2. Adato A, Kalinski H, Weil D, Chaib H, Korostishevsky M, Bonne-Tamir B. Possible interaction between USH1B and USH3 gene products as implied by apparent digenic deafness inheritance. Am J Hum Genet. 1999;65(1):261–5. doi: 10.1086/302438 10364543; PubMed Central PMCID: PMCPMC1378101.

3. Floeth M, Bruckner-Tuderman L. Digenic junctional epidermolysis bullosa: mutations in COL17A1 and LAMB3 genes. Am J Hum Genet. 1999;65(6):1530–7. doi: 10.1086/302672 10577906; PubMed Central PMCID: PMCPMC1288363.

4. Vincent S, Planells R, Defoort C, Bernard MC, Gerber M, Prudhomme J, et al. Genetic polymorphisms and lipoprotein responses to diets. Proc Nutr Soc. 2002;61(4):427–34. 12691171.

5. Hichri H, Stoetzel C, Laurier V, Caron S, Sigaudy S, Sarda P, et al. Testing for triallelism: analysis of six BBS genes in a Bardet-Biedl syndrome family cohort. Eur J Hum Genet. 2005;13(5):607–16. doi: 10.1038/sj.ejhg.5201372 15770229.

6. Abu-Safieh L, Al-Anazi S, Al-Abdi L, Hashem M, Alkuraya H, Alamr M, et al. In search of triallelism in Bardet-Biedl syndrome. Eur J Hum Genet. 2012;20(4):420–7. doi: 10.1038/ejhg.2011.205 22353939; PubMed Central PMCID: PMCPMC3306854.

7. Nakane T, Biesecker LG. No evidence for triallelic inheritance of MKKS/BBS loci in Amish Mckusick-Kaufman syndrome. Am J Med Genet A. 2005;138(1):32–4. doi: 10.1002/ajmg.a.30593 16104012.

8. Katsanis N, Eichers ER, Ansley SJ, Lewis RA, Kayserili H, Hoskins BE, et al. BBS4 is a minor contributor to Bardet-Biedl syndrome and may also participate in triallelic inheritance. Am J Hum Genet. 2002;71(1):22–9. doi: 10.1086/341031 12016587; PubMed Central PMCID: PMCPMC384990.

9. Katsanis N, Ansley SJ, Badano JL, Eichers ER, Lewis RA, Hoskins BE, et al. Triallelic inheritance in Bardet-Biedl syndrome, a Mendelian recessive disorder. Science. 2001;293(5538):2256–9. doi: 10.1126/science.1063525 11567139.

10. Goetz SC, Anderson KV. The primary cilium: a signalling centre during vertebrate development. Nat Rev Genet. 2010;11(5):331–44. doi: 10.1038/nrg2774 20395968; PubMed Central PMCID: PMCPMC3121168.

11. Garcia-Gonzalo FR, Reiter JF. Scoring a backstage pass: mechanisms of ciliogenesis and ciliary access. J Cell Biol. 2012;197(6):697–709. doi: 10.1083/jcb.201111146 22689651; PubMed Central PMCID: PMCPMC3373398.

12. Chih B, Liu P, Chinn Y, Chalouni C, Komuves LG, Hass PE, et al. A ciliopathy complex at the transition zone protects the cilia as a privileged membrane domain. Nat Cell Biol. 2012;14(1):61–72. doi: 10.1038/ncb2410 22179047.

13. Williams CL, Li C, Kida K, Inglis PN, Mohan S, Semenec L, et al. MKS and NPHP modules cooperate to establish basal body/transition zone membrane associations and ciliary gate function during ciliogenesis. J Cell Biol. 2011;192(6):1023–41. doi: 10.1083/jcb.201012116 21422230; PubMed Central PMCID: PMCPMC3063147.

14. Craige B, Tsao CC, Diener DR, Hou Y, Lechtreck KF, Rosenbaum JL, et al. CEP290 tethers flagellar transition zone microtubules to the membrane and regulates flagellar protein content. J Cell Biol. 2010;190(5):927–40. doi: 10.1083/jcb.201006105 20819941; PubMed Central PMCID: PMCPMC2935561.

15. Huang L, Szymanska K, Jensen VL, Janecke AR, Innes AM, Davis EE, et al. TMEM237 is mutated in individuals with a Joubert syndrome related disorder and expands the role of the TMEM family at the ciliary transition zone. Am J Hum Genet. 2011;89(6):713–30. doi: 10.1016/j.ajhg.2011.11.005 22152675; PubMed Central PMCID: PMCPMC3234373.

16. Garcia-Gonzalo FR, Corbit KC, Sirerol-Piquer MS, Ramaswami G, Otto EA, Noriega TR, et al. A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition. Nat Genet. 2011;43(8):776–84. doi: 10.1038/ng.891 21725307; PubMed Central PMCID: PMCPMC3145011.

17. Gilula NB, Satir P. The ciliary necklace. A ciliary membrane specialization. J Cell Biol. 1972;53(2):494–509. 4554367; PubMed Central PMCID: PMCPMC2108734.

18. Perkins LA, Hedgecock EM, Thomson JN, Culotti JG. Mutant sensory cilia in the nematode Caenorhabditis elegans. Dev Biol. 1986;117(2):456–87. 2428682.

19. Dowdle WE, Robinson JF, Kneist A, Sirerol-Piquer MS, Frints SG, Corbit KC, et al. Disruption of a ciliary B9 protein complex causes Meckel syndrome. Am J Hum Genet. 2011;89(1):94–110. doi: 10.1016/j.ajhg.2011.06.003 21763481; PubMed Central PMCID: PMCPMC3135817.

20. Fliegauf M, Horvath J, von Schnakenburg C, Olbrich H, Müller D, Thumfart J, et al. Nephrocystin specifically localizes to the transition zone of renal and respiratory cilia and photoreceptor connecting cilia. J Am Soc Nephrol. 2006;17(9):2424–33. doi: 10.1681/ASN.2005121351 16885411.

21. Sang L, Miller JJ, Corbit KC, Giles RH, Brauer MJ, Otto EA, et al. Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways. Cell. 2011;145(4):513–28. doi: 10.1016/j.cell.2011.04.019 21565611; PubMed Central PMCID: PMCPMC3383065.

22. Williams CL, Winkelbauer ME, Schafer JC, Michaud EJ, Yoder BK. Functional redundancy of the B9 proteins and nephrocystins in Caenorhabditis elegans ciliogenesis. Mol Biol Cell. 2008;19(5):2154–68. doi: 10.1091/mbc.E07-10-1070 18337471; PubMed Central PMCID: PMCPMC2366840.

23. Williams CL, Masyukova SV, Yoder BK. Normal ciliogenesis requires synergy between the cystic kidney disease genes MKS-3 and NPHP-4. J Am Soc Nephrol. 2010;21(5):782–93. doi: 10.1681/ASN.2009060597 20150540; PubMed Central PMCID: PMCPMC2865747.

24. Winkelbauer ME, Schafer JC, Haycraft CJ, Swoboda P, Yoder BK. The C. elegans homologs of nephrocystin-1 and nephrocystin-4 are cilia transition zone proteins involved in chemosensory perception. J Cell Sci. 2005;118(Pt 23):5575–87. doi: 10.1242/jcs.02665 16291722.

25. Jauregui AR, Nguyen KC, Hall DH, Barr MM. The Caenorhabditis elegans nephrocystins act as global modifiers of cilium structure. J Cell Biol. 2008;180(5):973–88. doi: 10.1083/jcb.200707090 18316409; PubMed Central PMCID: PMCPMC2265406.

26. Roberson EC, Dowdle WE, Ozanturk A, Garcia-Gonzalo FR, Li C, Halbritter J, et al. TMEM231, mutated in orofaciodigital and Meckel syndromes, organizes the ciliary transition zone. J Cell Biol. 2015;209(1):129–42. doi: 10.1083/jcb.201411087 25869670; PubMed Central PMCID: PMCPMC4395494.

27. Nachury MV, Loktev AV, Zhang Q, Westlake CJ, Peränen J, Merdes A, et al. A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. Cell. 2007;129(6):1201–13. doi: 10.1016/j.cell.2007.03.053 17574030.

28. Berbari NF, Lewis JS, Bishop GA, Askwith CC, Mykytyn K. Bardet-Biedl syndrome proteins are required for the localization of G protein-coupled receptors to primary cilia. Proc Natl Acad Sci U S A. 2008;105(11):4242–6. doi: 10.1073/pnas.0711027105 18334641; PubMed Central PMCID: PMCPMC2393805.

29. Jin H, White SR, Shida T, Schulz S, Aguiar M, Gygi SP, et al. The conserved Bardet-Biedl syndrome proteins assemble a coat that traffics membrane proteins to cilia. Cell. 2010;141(7):1208–19. doi: 10.1016/j.cell.2010.05.015 20603001; PubMed Central PMCID: PMCPMC2898735.

30. Blacque OE, Reardon MJ, Li C, McCarthy J, Mahjoub MR, Ansley SJ, et al. Loss of C. elegans BBS-7 and BBS-8 protein function results in cilia defects and compromised intraflagellar transport. Genes Dev. 2004;18(13):1630–42. doi: 10.1101/gad.1194004 15231740; PubMed Central PMCID: PMCPMC443524.

31. Leitch CC, Zaghloul NA, Davis EE, Stoetzel C, Diaz-Font A, Rix S, et al. Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome. Nat Genet. 2008;40(4):443–8. doi: 10.1038/ng.97 18327255.

32. Zhang Y, Seo S, Bhattarai S, Bugge K, Searby CC, Zhang Q, et al. BBS mutations modify phenotypic expression of CEP290-related ciliopathies. Hum Mol Genet. 2014;23(1):40–51. doi: 10.1093/hmg/ddt394 23943788; PubMed Central PMCID: PMCPMC3857943.

33. Reiter JF, Skarnes WC. Tectonic, a novel regulator of the Hedgehog pathway required for both activation and inhibition. Genes Dev. 2006;20(1):22–7. doi: 10.1101/gad.1363606 16357211; PubMed Central PMCID: PMCPMC1356097.

34. Swoboda P, Adler HT, Thomas JH. The RFX-type transcription factor DAF-19 regulates sensory neuron cilium formation in C. elegans. Mol Cell. 2000;5(3):411–21. 10882127.

35. Chen N, Mah A, Blacque OE, Chu J, Phgora K, Bakhoum MW, et al. Identification of ciliary and ciliopathy genes in Caenorhabditis elegans through comparative genomics. Genome Biol. 2006;7(12):R126. doi: 10.1186/gb-2006-7-12-r126 17187676; PubMed Central PMCID: PMCPMC1794439.

36. Phirke P, Efimenko E, Mohan S, Burghoorn J, Crona F, Bakhoum MW, et al. Transcriptional profiling of C. elegans DAF-19 uncovers a ciliary base-associated protein and a CDK/CCRK/LF2p-related kinase required for intraflagellar transport. Dev Biol. 2011;357(1):235–47. doi: 10.1016/j.ydbio.2011.06.028 21740898; PubMed Central PMCID: PMCPMC3888451.

37. Colosimo ME, Brown A, Mukhopadhyay S, Gabel C, Lanjuin AE, Samuel AD, et al. Identification of thermosensory and olfactory neuron-specific genes via expression profiling of single neuron types. Curr Biol. 2004;14(24):2245–51. doi: 10.1016/j.cub.2004.12.030 15620651.

38. Ansley SJ, Badano JL, Blacque OE, Hill J, Hoskins BE, Leitch CC, et al. Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome. Nature. 2003;425(6958):628–33. doi: 10.1038/nature02030 14520415.

39. Starich TA, Herman RK, Kari CK, Yeh WH, Schackwitz WS, Schuyler MW, et al. Mutations affecting the chemosensory neurons of Caenorhabditis elegans. Genetics. 1995;139(1):171–88. 7705621; PubMed Central PMCID: PMCPMC1206316.

40. Jensen VL, Li C, Bowie RV, Clarke L, Mohan S, Blacque OE, et al. Formation of the transition zone by Mks5/Rpgrip1L establishes a ciliary zone of exclusion (CIZE) that compartmentalises ciliary signalling proteins and controls PIP2 ciliary abundance. EMBO J. 2015. doi: 10.15252/embj.201488044 26392567.

41. Caspary T, Larkins CE, Anderson KV. The graded response to Sonic Hedgehog depends on cilia architecture. Dev Cell. 2007;12(5):767–78. doi: 10.1016/j.devcel.2007.03.004 17488627.

42. Cevik S, Hori Y, Kaplan OI, Kida K, Toivenon T, Foley-Fisher C, et al. Joubert syndrome Arl13b functions at ciliary membranes and stabilizes protein transport in Caenorhabditis elegans. J Cell Biol. 2010;188(6):953–69. doi: 10.1083/jcb.200908133 20231383; PubMed Central PMCID: PMCPMC2845074.

43. Cevik S, Sanders AA, Van Wijk E, Boldt K, Clarke L, van Reeuwijk J, et al. Active transport and diffusion barriers restrict Joubert Syndrome-associated ARL13B/ARL-13 to an Inv-like ciliary membrane subdomain. PLoS Genet. 2013;9(12):e1003977. doi: 10.1371/journal.pgen.1003977 24339792; PubMed Central PMCID: PMCPMC3854969.

44. Sengupta P, Chou JH, Bargmann CI. odr-10 encodes a seven transmembrane domain olfactory receptor required for responses to the odorant diacetyl. Cell. 1996;84(6):899–909. 8601313.

45. Dwyer ND, Troemel ER, Sengupta P, Bargmann CI. Odorant receptor localization to olfactory cilia is mediated by ODR-4, a novel membrane-associated protein. Cell. 1998;93(3):455–66. 9590179.

46. Lee BH, Liu J, Wong D, Srinivasan S, Ashrafi K. Hyperactive neuroendocrine secretion causes size, feeding, and metabolic defects of C. elegans Bardet-Biedl syndrome mutants. PLoS Biol. 2011;9(12):e1001219. doi: 10.1371/journal.pbio.1001219 22180729; PubMed Central PMCID: PMCPMC3236739.

47. Xu Q, Zhang Y, Wei Q, Huang Y, Li Y, Ling K, et al. BBS4 and BBS5 show functional redundancy in the BBSome to regulate the degradative sorting of ciliary sensory receptors. Sci Rep. 2015;5:11855. doi: 10.1038/srep11855 26150102; PubMed Central PMCID: PMCPMC4493597.

48. Mollet G, Salomon R, Gribouval O, Silbermann F, Bacq D, Landthaler G, et al. The gene mutated in juvenile nephronophthisis type 4 encodes a novel protein that interacts with nephrocystin. Nat Genet. 2002;32(2):300–5. doi: 10.1038/ng996 12244321.

49. Otto E, Hoefele J, Ruf R, Mueller AM, Hiller KS, Wolf MT, et al. A gene mutated in nephronophthisis and retinitis pigmentosa encodes a novel protein, nephroretinin, conserved in evolution. Am J Hum Genet. 2002;71(5):1161–7. doi: 10.1086/344395 12205563; PubMed Central PMCID: PMCPMC385091.

50. Won J, Marín de Evsikova C, Smith RS, Hicks WL, Edwards MM, Longo-Guess C, et al. NPHP4 is necessary for normal photoreceptor ribbon synapse maintenance and outer segment formation, and for sperm development. Hum Mol Genet. 2011;20(3):482–96. doi: 10.1093/hmg/ddq494 21078623; PubMed Central PMCID: PMCPMC3016909.

51. Hildebrandt F, Otto E, Rensing C, Nothwang HG, Vollmer M, Adolphs J, et al. A novel gene encoding an SH3 domain protein is mutated in nephronophthisis type 1. Nat Genet. 1997;17(2):149–53. doi: 10.1038/ng1097-149 9326933.

52. Konrad M, Saunier S, Heidet L, Silbermann F, Benessy F, Calado J, et al. Large homozygous deletions of the 2q13 region are a major cause of juvenile nephronophthisis. Hum Mol Genet. 1996;5(3):367–71. 8852662.

53. Parisi MA, Bennett CL, Eckert ML, Dobyns WB, Gleeson JG, Shaw DW, et al. The NPHP1 gene deletion associated with juvenile nephronophthisis is present in a subset of individuals with Joubert syndrome. Am J Hum Genet. 2004;75(1):82–91. doi: 10.1086/421846 15138899; PubMed Central PMCID: PMCPMC1182011.

54. Gorden NT, Arts HH, Parisi MA, Coene KL, Letteboer SJ, van Beersum SE, et al. CC2D2A is mutated in Joubert syndrome and interacts with the ciliopathy-associated basal body protein CEP290. Am J Hum Genet. 2008;83(5):559–71. doi: 10.1016/j.ajhg.2008.10.002 18950740; PubMed Central PMCID: PMCPMC2668034.

55. Noor A, Windpassinger C, Patel M, Stachowiak B, Mikhailov A, Azam M, et al. CC2D2A, encoding a coiled-coil and C2 domain protein, causes autosomal-recessive mental retardation with retinitis pigmentosa. Am J Hum Genet. 2008;82(4):1011–8. doi: 10.1016/j.ajhg.2008.01.021 18387594; PubMed Central PMCID: PMCPMC2427291.

56. Tallila J, Jakkula E, Peltonen L, Salonen R, Kestilä M. Identification of CC2D2A as a Meckel syndrome gene adds an important piece to the ciliopathy puzzle. Am J Hum Genet. 2008;82(6):1361–7. doi: 10.1016/j.ajhg.2008.05.004 18513680; PubMed Central PMCID: PMCPMC2427307.

57. Haycraft CJ, Banizs B, Aydin-Son Y, Zhang Q, Michaud EJ, Yoder BK. Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLoS Genet. 2005;1(4):e53. doi: 10.1371/journal.pgen.0010053 16254602; PubMed Central PMCID: PMCPMC1270009.

58. Liu A, Wang B, Niswander LA. Mouse intraflagellar transport proteins regulate both the activator and repressor functions of Gli transcription factors. Development. 2005;132(13):3103–11. doi: 10.1242/dev.01894 15930098.

59. May SR, Ashique AM, Karlen M, Wang B, Shen Y, Zarbalis K, et al. Loss of the retrograde motor for IFT disrupts localization of Smo to cilia and prevents the expression of both activator and repressor functions of Gli. Dev Biol. 2005;287(2):378–89. doi: 10.1016/j.ydbio.2005.08.050 16229832.

60. Frank-Kamenetsky M, Zhang XM, Bottega S, Guicherit O, Wichterle H, Dudek H, et al. Small-molecule modulators of Hedgehog signaling: identification and characterization of Smoothened agonists and antagonists. J Biol. 2002;1(2):10. 12437772; PubMed Central PMCID: PMCPMC137065.

61. Chen JK, Taipale J, Young KE, Maiti T, Beachy PA. Small molecule modulation of Smoothened activity. Proc Natl Acad Sci U S A. 2002;99(22):14071–6. doi: 10.1073/pnas.182542899 12391318; PubMed Central PMCID: PMCPMC137838.

62. Mukhopadhyay S, Wen X, Ratti N, Loktev A, Rangell L, Scales SJ, et al. The ciliary G-protein-coupled receptor Gpr161 negatively regulates the Sonic hedgehog pathway via cAMP signaling. Cell. 2013;152(1–2):210–23. doi: 10.1016/j.cell.2012.12.026 23332756.

63. Davis RE, Swiderski RE, Rahmouni K, Nishimura DY, Mullins RF, Agassandian K, et al. A knockin mouse model of the Bardet-Biedl syndrome 1 M390R mutation has cilia defects, ventriculomegaly, retinopathy, and obesity. Proc Natl Acad Sci U S A. 2007;104(49):19422–7. doi: 10.1073/pnas.0708571104 18032602; PubMed Central PMCID: PMCPMC2148305.

64. Garcia-Gonzalo FR, Phua SC, Roberson EC, Garcia G, Abedin M, Schurmans S, et al. Phosphoinositides Regulate Ciliary Protein Trafficking to Modulate Hedgehog Signaling. Dev Cell. 2015;34(4):400–9. doi: 10.1016/j.devcel.2015.08.001 26305592; PubMed Central PMCID: PMCPMC4557815.

65. Domire JS, Green JA, Lee KG, Johnson AD, Askwith CC, Mykytyn K. Dopamine receptor 1 localizes to neuronal cilia in a dynamic process that requires the Bardet-Biedl syndrome proteins. Cell Mol Life Sci. 2011;68(17):2951–60. doi: 10.1007/s00018-010-0603-4 21152952; PubMed Central PMCID: PMCPMC3368249.

66. Zhang Q, Nishimura D, Seo S, Vogel T, Morgan DA, Searby C, et al. Bardet-Biedl syndrome 3 (Bbs3) knockout mouse model reveals common BBS-associated phenotypes and Bbs3 unique phenotypes. Proc Natl Acad Sci U S A. 2011;108(51):20678–83. doi: 10.1073/pnas.1113220108 22139371; PubMed Central PMCID: PMCPMC3251145.

67. Lechtreck KF, Johnson EC, Sakai T, Cochran D, Ballif BA, Rush J, et al. The Chlamydomonas reinhardtii BBSome is an IFT cargo required for export of specific signaling proteins from flagella. J Cell Biol. 2009;187(7):1117–32. doi: 10.1083/jcb.200909183 20038682; PubMed Central PMCID: PMCPMC2806276.

68. Lechtreck KF, Brown JM, Sampaio JL, Craft JM, Shevchenko A, Evans JE, et al. Cycling of the signaling protein phospholipase D through cilia requires the BBSome only for the export phase. J Cell Biol. 2013;201(2):249–61. doi: 10.1083/jcb.201207139 23589493; PubMed Central PMCID: PMCPMC3628507.

69. Liew GM, Ye F, Nager AR, Murphy JP, Lee JS, Aguiar M, et al. The intraflagellar transport protein IFT27 promotes BBSome exit from cilia through the GTPase ARL6/BBS3. Dev Cell. 2014;31(3):265–78. doi: 10.1016/j.devcel.2014.09.004 25443296; PubMed Central PMCID: PMCPMC4255629.

70. Awata J, Takada S, Standley C, Lechtreck KF, Bellvé KD, Pazour GJ, et al. NPHP4 controls ciliary trafficking of membrane proteins and large soluble proteins at the transition zone. J Cell Sci. 2014;127(21):4714–27. doi: 10.1242/jcs.155275 25150219; PubMed Central PMCID: PMCPMC4215714.

71. Frazer KA, Murray SS, Schork NJ, Topol EJ. Human genetic variation and its contribution to complex traits. Nat Rev Genet. 2009;10(4):241–51. doi: 10.1038/nrg2554 19293820.

72. Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, et al. Finding the missing heritability of complex diseases. Nature. 2009;461(7265):747–53. doi: 10.1038/nature08494 19812666; PubMed Central PMCID: PMCPMC2831613.

73. Bloom JS, Ehrenreich IM, Loo WT, Lite TL, Kruglyak L. Finding the sources of missing heritability in a yeast cross. Nature. 2013;494(7436):234–7. doi: 10.1038/nature11867 23376951; PubMed Central PMCID: PMCPMC4001867.

74. Beales PL, Badano JL, Ross AJ, Ansley SJ, Hoskins BE, Kirsten B, et al. Genetic interaction of BBS1 mutations with alleles at other BBS loci can result in non-Mendelian Bardet-Biedl syndrome. Am J Hum Genet. 2003;72(5):1187–99. doi: 10.1086/375178 12677556; PubMed Central PMCID: PMCPMC1180271.

75. Hoefele J, Wolf MT, O'Toole JF, Otto EA, Schultheiss U, Dêschenes G, et al. Evidence of oligogenic inheritance in nephronophthisis. J Am Soc Nephrol. 2007;18(10):2789–95. doi: 10.1681/ASN.2007020243 17855640.

76. Brenner S. The genetics of Caenorhabditis elegans. Genetics. 1974;77(1):71–94. 4366476; PubMed Central PMCID: PMCPMC1213120.

77. Inglis PN, Blacque OE, Leroux MR. Functional genomics of intraflagellar transport-associated proteins in C. elegans. Methods Cell Biol. 2009;93:267–304. doi: 10.1016/S0091-679X(08)93014-4 20409822.

78. Finney M, Ruvkun G. The unc-86 gene product couples cell lineage and cell identity in C. elegans. Cell. 1990;63(5):895–905. 2257628.

79. Culotti JG, Russell RL. Osmotic avoidance defective mutants of the nematode Caenorhabditis elegans. Genetics. 1978;90(2):243–56. 730048; PubMed Central PMCID: PMCPMC1213887.

80. Bargmann CI, Hartwieg E, Horvitz HR. Odorant-selective genes and neurons mediate olfaction in C. elegans. Cell. 1993;74(3):515–27. 8348618.

81. Louie CM, Caridi G, Lopes VS, Brancati F, Kispert A, Lancaster MA, et al. AHI1 is required for photoreceptor outer segment development and is a modifier for retinal degeneration in nephronophthisis. Nat Genet. 2010;42(2):175–80. doi: 10.1038/ng.519 20081859; PubMed Central PMCID: PMCPMC2884967.

82. Nagy A, Gertsensten M, Vintersten K, Behringer R. Manipulating the Mouse Embryo: A Laboratory Manual. Cold Spring Harbor, New York: Cold Spring Harbor Press; 2003.