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A Variant in the Neuropeptide Receptor is a Major Determinant of Growth and Physiology


The mechanistic basis for how genetic variants cause differences in phenotypic traits is often elusive. We identified a quantitative trait locus in Caenorhabditis elegans that affects three seemingly unrelated phenotypic traits: lifetime fecundity, adult body size, and susceptibility to the human pathogen Staphyloccus aureus. We found a QTL for all three traits arises from variation in the neuropeptide receptor gene npr-1. Moreover, we found that variation in npr-1 is also responsible for differences in 247 gene expression traits. Variation in npr-1 is known to determine whether animals disperse throughout a bacterial lawn or aggregate at the edges of the lawn. We found that the allele that leads to aggregation is associated with reduced growth and reproductive output. The altered gene expression pattern caused by this allele suggests that the aggregation behavior might cause a weak starvation state, which is known to reduce growth rate and fecundity. Importantly, we show that variation in npr-1 causes each of these phenotypic differences through behavioral avoidance of ambient oxygen concentrations. These results suggest that variation in npr-1 has broad pleiotropic effects mediated by altered exposure to bacterial food.


Vyšlo v časopise: A Variant in the Neuropeptide Receptor is a Major Determinant of Growth and Physiology. PLoS Genet 10(2): e32767. doi:10.1371/journal.pgen.1004156
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004156

Souhrn

The mechanistic basis for how genetic variants cause differences in phenotypic traits is often elusive. We identified a quantitative trait locus in Caenorhabditis elegans that affects three seemingly unrelated phenotypic traits: lifetime fecundity, adult body size, and susceptibility to the human pathogen Staphyloccus aureus. We found a QTL for all three traits arises from variation in the neuropeptide receptor gene npr-1. Moreover, we found that variation in npr-1 is also responsible for differences in 247 gene expression traits. Variation in npr-1 is known to determine whether animals disperse throughout a bacterial lawn or aggregate at the edges of the lawn. We found that the allele that leads to aggregation is associated with reduced growth and reproductive output. The altered gene expression pattern caused by this allele suggests that the aggregation behavior might cause a weak starvation state, which is known to reduce growth rate and fecundity. Importantly, we show that variation in npr-1 causes each of these phenotypic differences through behavioral avoidance of ambient oxygen concentrations. These results suggest that variation in npr-1 has broad pleiotropic effects mediated by altered exposure to bacterial food.


Zdroje

1. RockmanMV, SkrovanekSS, KruglyakL (2010) Selection at linked sites shapes heritable phenotypic variation in C. elegans. Science 330: 372–376 doi:10.1126/science.1194208

2. SeidelHS, AilionM, LiJ, van OudenaardenA, RockmanMV, et al. (2011) A novel sperm-delivered toxin causes late-stage embryo lethality and transmission ratio distortion in C. elegans. Plos Biol 9: e1001115 doi:10.1371/journal.pbio.1001115

3. SeidelHS, RockmanMV, KruglyakL (2008) Widespread genetic incompatibility in C. elegans maintained by balancing selection. Science 319: 589–594 doi:10.1126/science.1151107

4. GhoshR, AndersenEC, ShapiroJA, GerkeJP, KruglyakL (2012) Natural variation in a chloride channel subunit confers avermectin resistance in C. elegans. Science 335: 574–578 doi:10.1126/science.1214318

5. BendeskyA, TsunozakiM, RockmanMV, KruglyakL, BargmannCI (2011) Catecholamine receptor polymorphisms affect decision-making in C. elegans. Nature 472: 313–318 doi:10.1038/nature09821

6. PalopoliMF, RockmanMV, TinMaungA, RamsayC, CurwenS, et al. (2008) Molecular basis of the copulatory plug polymorphism in Caenorhabditis elegans. Nature 454: 1019–1022 doi:10.1038/nature07171

7. 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 doi:10.1016/j.neuron.2009.02.012

8. ReddyKC, AndersenEC, KruglyakL, KimDH (2009) A polymorphism in npr-1 is a behavioral determinant of pathogen susceptibility in C. elegans. Science 323: 382–384 doi:10.1126/science.1166527

9. 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 doi:10.1534/genetics.111.127100

10. DuveauF, FélixM-A (2012) Role of pleiotropy in the evolution of a cryptic developmental variation in Caenorhabditis elegans. Plos Biol 10: e1001230 doi:10.1371/journal.pbio.1001230

11. GAERTNERBE, ParmenterMD, RockmanMV, KruglyakL, PhillipsPC (2012) More than the sum of its parts: a complex epistatic network underlies natural variation in thermal preference behavior in Caenorhabditis elegans. Genetics 192: 1533–1542 doi:10.1534/genetics.112.142877

12. BendeskyA, PittsJ, RockmanMV, ChenWC, TanM-W, et al. (2012) Long-range regulatory polymorphisms affecting a GABA receptor constitute a quantitative trait locus (QTL) for social behavior in Caenorhabditis elegans. PLoS Genet 8: e1003157 doi:10.1371/journal.pgen.1003157

13. KammengaJE, DoroszukA, RiksenJAG, HazendonkE, SpiridonL, et al. (2007) A Caenorhabditis elegans wild type defies the temperature-size rule owing to a single nucleotide polymorphism in tra-3. PLoS Genet 3: e34 doi:10.1371/journal.pgen.0030034

14. AndersenEC, GerkeJP, ShapiroJA, CrissmanJR, GhoshR, et al. (2012) Chromosome-scale selective sweeps shape Caenorhabditis elegans genomic diversity. Nat Genet 1–8 doi:10.1038/ng.1050

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

16. GAERTNERBE, PhillipsPC (2010) Caenorhabditis elegans as a platform for molecular quantitative genetics and the systems biology of natural variation. Genet Res 92: 331–348 doi:10.1017/S0016672310000601

17. YvertG, BremRB, WhittleJ, AkeyJM, FossE, et al. (2003) Trans-acting regulatory variation in Saccharomyces cerevisiae and the role of transcription factors. Nat Genet 35: 57–64 doi:10.1038/ng1222

18. BremRB, YvertG, ClintonR, KruglyakL (2002) Genetic dissection of transcriptional regulation in budding yeast. Science 296: 752–755 doi:10.1126/science.1069516

19. van ZantenM, SnoekLB, ProveniersMCG, PeetersAJM (2009) The many functions of ERECTA. Trends Plant Sci 14: 214–218 doi:10.1016/j.tplants.2009.01.010

20. RogersC, RealeV, KimK, ChatwinH, LiC, et al. (2003) Inhibition of Caenorhabditis elegans social feeding by FMRFamide-related peptide activation of NPR-1. Nat Neurosci 6: 1178–1185 doi:10.1038/nn1140

21. 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.

22. 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 doi:10.1038/nature07886

23. ReddyKC, AndersenEC, KruglyakL, KimDH (2009) A polymorphism in npr-1 is a behavioral determinant of pathogen susceptibility in C. elegans. Science 323: 382–384 doi:10.1126/science.1166527

24. ChangAJ, ChronisN, KarowDS, MarlettaMA, BargmannCI (2006) A distributed chemosensory circuit for oxygen preference in C. elegans. Plos Biol 4: e274 doi:10.1371/journal.pbio.0040274

25. DaviesAG, BettingerJC, ThieleTR, JudyME, McIntireSL (2004) Natural variation in the npr-1 gene modifies ethanol responses of wild strains of C. elegans. Neuron 42: 731–743 doi:10.1016/j.neuron.2004.05.004

26. JangH, KimK, NealSJ, MacoskoE, KimD, et al. (2012) Neuromodulatory State and Sex Specify Alternative Behaviors through Antagonistic Synaptic Pathways in C. elegans. Neuron 75: 585–592 doi:10.1016/j.neuron.2012.06.034

27. HallemEA, SternbergPW (2008) Acute carbon dioxide avoidance in Caenorhabditis elegans. Proceedings of the National Academy of Sciences 105: 8038–8043 doi:10.1073/pnas.0707469105

28. ChoiS, ChatzigeorgiouM, TaylorKP, SchaferWR, KaplanJM (2013) Analysis of NPR-1 Reveals a Circuit Mechanism for Behavioral Quiescence in C. elegans. Neuron 78: 869–880 doi:10.1016/j.neuron.2013.04.002

29. YookK, HarrisTW, BieriT, CabunocA, ChanJ, et al. (2012) WormBase 2012: more genomes, more data, new website. Nucleic Acids Res 40: D735–D741 doi:10.1093/nar/gkr954

30. KamathRS, FraserAG, DongY, PoulinG, DurbinR, et al. (2003) Systematic functional analysis of the Caenorhabditis elegans genome using RNAi. Nature 421: 231–237 doi:10.1038/nature01278

31. CheungBHH, 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 doi:10.1016/j.cub.2004.06.027

32. 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 doi:10.1038/nature02714

33. RockmanMV, KruglyakL (2006) Genetics of global gene expression. Nat Rev Genet 7: 862–872 doi:10.1038/nrg1964

34. SeidelHS, KimbleJ (2011) The oogenic germline starvation response in C. elegans. PLoS ONE 6: e28074 doi:10.1371/journal.pone.0028074

35. JoH, ShimJ, LeeJH, LeeJ, KimJB (2009) IRE-1 and HSP-4 contribute to energy homeostasis via fasting-induced lipases in C. elegans. Cell Metab 9: 440–448 doi:10.1016/j.cmet.2009.04.004

36. AveryL, HorvitzHR (1990) Effects of starvation and neuroactive drugs on feeding in Caenorhabditis elegans. J Exp Zool 253: 263–270 doi:10.1002/jez.1402530305

37. LuedtkeS, O'ConnorV, Holden-DyeL, WalkerRJ (2010) The regulation of feeding and metabolism in response to food deprivation in Caenorhabditis elegans. Invert Neurosci 10: 63–76 doi:10.1007/s10158-010-0112-z

38. HubbardEJA, KortaDZ, DalfóD (2013) Physiological control of germline development. Adv Exp Med Biol 757: 101–131 doi:_10.1007/978-1-4614-4015-4_5

39. DalfóD, MichaelsonD, HubbardEJA (2012) Sensory regulation of the C. elegans germline through TGF-β-dependent signaling in the niche. Curr Biol 22: 712–719 doi:10.1016/j.cub.2012.02.064

40. Gloria-SoriaA, AzevedoRBR (2008) npr-1 Regulates foraging and dispersal strategies in Caenorhabditis elegans. Curr Biol 18: 1694–1699 doi:10.1016/j.cub.2008.09.043

41. ToriiKU, MitsukawaN, OosumiT, MatsuuraY, YokoyamaR, et al. (1996) The Arabidopsis ERECTA gene encodes a putative receptor protein kinase with extracellular leucine-rich repeats. Plant Cell 8: 735–746 doi:10.1105/tpc.8.4.735

42. WeberKP, DeS, KozarewaI, TurnerDJ, BabuMM, et al. (2010) Whole genome sequencing highlights genetic changes associated with laboratory domestication of C. elegans. PLoS ONE 5: e13922 doi:10.1371/journal.pone.0013922

43. McGrathPT, XuY, AilionM, GarrisonJL, ButcherRA, et al. (2011) Parallel evolution of domesticated Caenorhabditis species targets pheromone receptor genes. Nature 477: 321–325 doi:10.1038/nature10378

44. RockmanMV (2011) THE QTN PROGRAM AND THE ALLELES THAT MATTER FOR EVOLUTION: ALL THAT'S GOLD DOES NOT GLITTER. Evolution no–no doi:10.1111/j.1558-5646.2011.01486.x

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

46. LanderE, BotsteinD (1989) Mapping Mendelian Factors Underlying Quantitative Traits Using RFLP Linkage Maps. Genetics 121: 185.

47. DoergeRW, ChurchillGA (1996) Permutation tests for multiple loci affecting a quantitative character. Genetics 142: 285–294.

48. HaleyCS, KnottSA (1992) A simple regression method for mapping quantitative trait loci in line crosses using flanking markers. Heredity 69: 315–324.

49. BloomJS, EhrenreichIM, LooWT, LiteT-LV, KruglyakL (2013) Finding the sources of missing heritability in a yeast cross. Nature 494: 234–237 doi:10.1038/nature11867

50. BremRB, KruglyakL (2005) The landscape of genetic complexity across 5,700 gene expression traits in yeast. Proc Natl Acad Sci USA 102: 1572–1577 doi:10.1073/pnas.0408709102

51. SmythGK (2005) Limma: linear models for microarray data. Bioinformatics and Computational Biology Solutions Using R and Bioconductor Statistics for Biology and Health 397–420.

52. CapraEJ, SkrovanekSM, KruglyakL (2008) Comparative developmental expression profiling of two C. elegans isolates. PLoS ONE 3: e4055 doi:10.1371/journal.pone.0004055

53. AntonovAV, SchmidtT, WangY, MewesHW (2008) ProfCom: a web tool for profiling the complex functionality of gene groups identified from high-throughput data. Nucleic Acids Res 36: W347–W351 doi:10.1093/nar/gkn239

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