Long-Range Regulatory Polymorphisms Affecting a GABA Receptor Constitute a Quantitative Trait Locus (QTL) for Social Behavior in

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Aggregation is a social behavior that varies between and within species, providing a model to study the genetic basis of behavioral diversity. In the nematode Caenorhabditis elegans, aggregation is regulated by environmental context and by two neuromodulatory pathways, one dependent on the neuropeptide receptor NPR-1 and one dependent on the TGF-β family protein DAF-7. To gain further insight into the genetic regulation of aggregation, we characterize natural variation underlying behavioral differences between two wild-type C. elegans strains, N2 and CB4856. Using quantitative genetic techniques, including a survey of chromosome substitution strains and QTL analysis of recombinant inbred lines, we identify three new QTLs affecting aggregation in addition to the two known N2 mutations in npr-1 and glb-5. Fine-mapping with near-isogenic lines localized one QTL, accounting for 5%–8% of the behavioral variance between N2 and CB4856, 3′ to the transcript of the GABA neurotransmitter receptor gene exp-1. Quantitative complementation tests demonstrated that this QTL affects exp-1, identifying exp-1 and GABA signaling as new regulators of aggregation. exp-1 interacts genetically with the daf-7 TGF-β pathway, which integrates food availability and population density, and exp-1 mutations affect the level of daf-7 expression. Our results add to growing evidence that genetic variation affecting neurotransmitter receptor genes is a source of natural behavioral variation.

Vyšlo v časopise: Long-Range Regulatory Polymorphisms Affecting a GABA Receptor Constitute a Quantitative Trait Locus (QTL) for Social Behavior in. PLoS Genet 8(12): e32767. doi:10.1371/journal.pgen.1003157
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003157

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Zdroje

1. BendeskyA, BargmannCI (2011) Genetic contributions to behavioural diversity at the gene-environment interface. Nat Rev Genet 12: 809–820.

2. FlintJ (2003) Analysis of quantitative trait loci that influence animal behavior. J Neurobiol 54: 46–77.

3. FlintJ, MackayTF (2009) Genetic architecture of quantitative traits in mice, flies, and humans. Genome Res 19: 723–733.

4. MundyP, SigmanM, UngererJ, ShermanT (1986) Defining the social deficits of autism: the contribution of non-verbal communication measures. J Child Psychol Psychiatry 27: 657–669.

5. TandonR, NasrallahHA, KeshavanMS (2009) Schizophrenia, “just the facts” 4. Clinical features and conceptualization. Schizophr Res 110: 1–23.

6. Wilson EO (2000) Sociobiology: the new synthesis. Cambridge: The Belknap Press of Harvard University Press.

7. DierickHA, GreenspanRJ (2006) Molecular analysis of flies selected for aggressive behavior. Nat Genet 38: 1023–1031.

8. WangL, DankertH, PeronaP, AndersonDJ (2008) A common genetic target for environmental and heritable influences on aggressiveness in Drosophila. Proc Natl Acad Sci U S A 105: 5657–5663.

9. EdwardsAC, RollmannSM, MorganTJ, MackayTF (2006) Quantitative genomics of aggressive behavior in Drosophila melanogaster. PLoS Genet 2: e154 doi:10.1371/journal.pgen.0020154..

10. HaigD (2008) Huddling: brown fat, genomic imprinting and the warm inner glow. Curr Biol 18: R172–174.

11. Székely T, Moore Aj, Komdeur J (2010) Social behavior: genes, ecology and evolution: Cambridge University Press.

12. ParrishJK, Edelstein-KeshetL (1999) Complexity, pattern, and evolutionary trade-offs in animal aggregation. Science 284: 99–101.

13. HodgkinJ, DoniachT (1997) Natural variation and copulatory plug formation in Caenorhabditis elegans. Genetics 146: 149–164.

14. GrayJM, KarowDS, LuH, ChangAJ, ChangJS, et al. (2004) Oxygen sensation and social feeding mediated by a C. elegans guanylate cyclase homologue. Nature 430: 317–322.

15. RogersC, PerssonA, CheungB, de BonoM (2006) Behavioral motifs and neural pathways coordinating O2 responses and aggregation in C. elegans. Curr Biol 16: 649–659.

16. Croll NA, Matthews BE (1977) Biology of nematodes. London: Wiley & Sons.

17. SrinivasanJ, KaplanF, AjrediniR, ZachariahC, AlbornHT, et al. (2008) A blend of small molecules regulates both mating and development in Caenorhabditis elegans. Nature 454: 1115–1118.

18. de BonoM, BargmannCI (1998) Natural variation in a neuropeptide Y receptor homolog modifies social behavior and food response in C. elegans. Cell 94: 679–689.

19. MacoskoEZ, PokalaN, FeinbergEH, ChalasaniSH, ButcherRA, et al. (2009) A hub-and-spoke circuit drives pheromone attraction and social behaviour in C. elegans. Nature 458: 1171–1175.

20. ThomasJH, BirnbyDA, VowelsJJ (1993) Evidence for parallel processing of sensory information controlling dauer formation in Caenorhabditis elegans. Genetics 134: 1105–1117.

21. de BonoM, TobinDM, DavisMW, AveryL, BargmannCI (2002) Social feeding in Caenorhabditis elegans is induced by neurons that detect aversive stimuli. Nature 419: 899–903.

22. CoatesJC, de BonoM (2002) Antagonistic pathways in neurons exposed to body fluid regulate social feeding in Caenorhabditis elegans. Nature 419: 925–929.

23. CheungBH, Arellano-CarbajalF, RybickiI, de BonoM (2004) Soluble guanylate cyclases act in neurons exposed to the body fluid to promote C. elegans aggregation behavior. Curr Biol 14: 1105–1111.

24. McGrathPT, RockmanMV, ZimmerM, JangH, MacoskoEZ, et al. (2009) Quantitative mapping of a digenic behavioral trait implicates globin variation in C. elegans sensory behaviors. Neuron 61: 692–699.

25. PerssonA, GrossE, LaurentP, BuschKE, BretesH, et al. (2009) Natural variation in a neural globin tunes oxygen sensing in wild Caenorhabditis elegans. Nature 458: 1030–1033.

26. RenP, LimCS, JohnsenR, AlbertPS, PilgrimD, et al. (1996) Control of C. elegans larval development by neuronal expression of a TGF-beta homolog. Science 274: 1389–1391.

27. SchackwitzWS, InoueT, ThomasJH (1996) Chemosensory neurons function in parallel to mediate a pheromone response in C. elegans. Neuron 17: 719–728.

28. GreerER, PerezCL, Van GilstMR, LeeBH, AshrafiK (2008) Neural and molecular dissection of a C. elegans sensory circuit that regulates fat and feeding. Cell Metab 8: 118–131.

29. NolanKM, Sarafi-ReinachTR, HorneJG, SafferAM, SenguptaP (2002) The DAF-7 TGF-beta signaling pathway regulates chemosensory receptor gene expression in C. elegans. Genes Dev 16: 3061–3073.

30. ShawWM, LuoS, LandisJ, AshrafJ, MurphyCT (2007) The C. elegans TGF-beta dauer pathway regulates longevity via insulin signaling. Curr Biol 17: 1635–1645.

31. RockmanMV, KruglyakL (2009) Recombinational landscape and population genomics of Caenorhabditis elegans. PLoS Genet 5: e1000419 doi:10.1371/journal.pgen.1000419..

32. GlauserDA, ChenWC, AginR, MacinnisBL, HellmanAB, et al. (2011) Heat avoidance is regulated by transient receptor potential (TRP) channels and a neuropeptide signaling pathway in Caenorhabditis elegans. Genetics 188: 91–103.

33. AndersenEC, GerkeJP, ShapiroJA, CrissmanJR, GhoshR, et al. (2012) Chromosome-scale selective sweeps shape Caenorhabditis elegans genomic diversity. Nat Genet 44: 285–290.

34. LetticeLA, HorikoshiT, HeaneySJ, van BarenMJ, van der LindeHC, et al. (2002) Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly. Proc Natl Acad Sci U S A 99: 7548–7553.

35. EnattahNS, SahiT, SavilahtiE, TerwilligerJD, PeltonenL, et al. (2002) Identification of a variant associated with adult-type hypolactasia. Nat Genet 30: 233–237.

36. TishkoffSA, ReedFA, RanciaroA, VoightBF, BabbittCC, et al. (2007) Convergent adaptation of human lactase persistence in Africa and Europe. Nat Genet 39: 31–40.

37. ConradtB, HorvitzHR (1999) The TRA-1A sex determination protein of C. elegans regulates sexually dimorphic cell deaths by repressing the egl-1 cell death activator gene. Cell 98: 317–327.

38. MauranoMT, HumbertR, RynesE, ThurmanRE, HaugenE, et al. (2012) Systematic localization of common disease-associated variation in regulatory DNA. Science 337: 1190–1195.

39. MackayTF (2001) Quantitative trait loci in Drosophila. Nat Rev Genet 2: 11–20.

40. BegAA, JorgensenEM (2003) EXP-1 is an excitatory GABA-gated cation channel. Nat Neurosci 6: 1145–1152.

41. McIntireSL, JorgensenE, HorvitzHR (1993) Genes required for GABA function in Caenorhabditis elegans. Nature 364: 334–337.

42. JinY, JorgensenE, HartwiegE, HorvitzHR (1999) The Caenorhabditis elegans gene unc-25 encodes glutamic acid decarboxylase and is required for synaptic transmission but not synaptic development. J Neurosci 19: 539–548.

43. KimK, SatoK, ShibuyaM, ZeigerDM, ButcherRA, et al. (2009) Two chemoreceptors mediate developmental effects of dauer pheromone in C. elegans. Science 326: 994–998.

44. ColbertHA, SmithTL, BargmannCI (1997) OSM-9, a novel protein with structural similarity to channels, is required for olfaction, mechanosensation, and olfactory adaptation in Caenorhabditis elegans. J Neurosci 17: 8259–8269.

45. JoseAM, BanyIA, ChaseDL, KoelleMR (2007) A specific subset of transient receptor potential vanilloid-type channel subunits in Caenorhabditis elegans endocrine cells function as mixed heteromers to promote neurotransmitter release. Genetics 175: 93–105.

46. AgarwalS, AvniO, RaoA (2000) Cell-type-restricted binding of the transcription factor NFAT to a distal IL-4 enhancer in vivo. Immunity 12: 643–652.

47. NaganawaS, GinsbergHN, GlickmanRM, GinsburgGS (1997) Intestinal transcription and synthesis of apolipoprotein AI is regulated by five natural polymorphisms upstream of the apolipoprotein CIII gene. J Clin Invest 99: 1958–1965.

48. LoehlinDW, WerrenJH (2012) Evolution of shape by multiple regulatory changes to a growth gene. Science 335: 943–947.

49. SternDL, OrgogozoV (2008) The loci of evolution: how predictable is genetic evolution? Evolution 62: 2155–2177.

50. WittkoppPJ, KalayG (2012) Cis-regulatory elements: molecular mechanisms and evolutionary processes underlying divergence. Nat Rev Genet 13: 59–69.

51. VeyrierasJB, KudaravalliS, KimSY, DermitzakisET, GiladY, et al. (2008) High-resolution mapping of expression-QTLs yields insight into human gene regulation. PLoS Genet 4: e1000214 doi:10.1371/journal.pgen.1000214..

52. SanyalA, LajoieBR, JainG, DekkerJ (2012) The long-range interaction landscape of gene promoters. Nature 489: 109–113.

53. KellyWG, XuS, MontgomeryMK, FireA (1997) Distinct requirements for somatic and germline expression of a generally expressed Caernorhabditis elegans gene. Genetics 146: 227–238.

54. HobertO, TessmarK, RuvkunG (1999) The Caenorhabditis elegans lim-6 LIM homeobox gene regulates neurite outgrowth and function of particular GABAergic neurons. Development 126: 1547–1562.

55. Tobacco and Genetics Consortium (2010) Genome-wide meta-analyses identify multiple loci associated with smoking behavior. Nat Genet 42: 441–447.

56. BendeskyA, TsunozakiM, RockmanMV, KruglyakL, BargmannCI (2011) Catecholamine receptor polymorphisms affect decision-making in C. elegans. Nature 472: 313–318.

57. VacicV, McCarthyS, MalhotraD, MurrayF, ChouHH, et al. (2011) Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia. Nature 471: 499–503.

58. BevilacquaL, DolyS, KaprioJ, YuanQ, TikkanenR, et al. (2010) A population-specific HTR2B stop codon predisposes to severe impulsivity. Nature 468: 1061–1066.

59. ResslerKJ, MercerKB, BradleyB, JovanovicT, MahanA, et al. (2011) Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor. Nature 470: 492–497.

60. WuJ, XiaoH, SunH, ZouL, ZhuLQ (2012) Role of dopamine receptors in ADHD: a systematic meta-analysis. Mol Neurobiol 45: 605–620.

61. MacDermottAB, RoleLW, SiegelbaumSA (1999) Presynaptic ionotropic receptors and the control of transmitter release. Annu Rev Neurosci 22: 443–485.

62. BrennerS (1974) The genetics of Caenorhabditis elegans. Genetics 77: 71–94.

63. BromanKW, WuH, SenS, ChurchillGA (2003) R/qtl: QTL mapping in experimental crosses. Bioinformatics 19: 889–890.

64. HoogewijsD, HouthoofdK, MatthijssensF, VandesompeleJ, VanfleterenJR (2008) Selection and validation of a set of reliable reference genes for quantitative sod gene expression analysis in C. elegans. BMC Mol Biol 9: 9.

65. MelloC, FireA (1995) DNA transformation. Methods Cell Biol 48: 451–482.