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Agrawal N, Lawler K, Davidson CM, et al. Predicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila. PLoS Biol. 2021;19(11):e3001255doi: 10.1371/journal.pbio.3001255.
Agrawal, N., Lawler, K., Davidson, C. M., Keogh, J. M., Legg, R., Barroso, I., Farooqi, I. S., & Brand, A. H. (2021). Predicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila. PLoS biology, 19(11), e3001255. https://doi.org/10.1371/journal.pbio.3001255
Agrawal, Neha, et al. "Predicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila." PLoS biology vol. 19,11 (2021): e3001255. doi: https://doi.org/10.1371/journal.pbio.3001255
Agrawal N, Lawler K, Davidson CM, Keogh JM, Legg R, Barroso I, Farooqi IS, Brand AH. Predicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila. PLoS Biol. 2021 Nov 08;19(11):e3001255. doi: 10.1371/journal.pbio.3001255. eCollection 2021 Nov. PMID: 34748544; PMCID: PMC8575313.
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PLoS Biol. 2021 Nov 08;19(11):e3001255. doi: 10.1371/journal.pbio.3001255. eCollection 2021 Nov.

Predicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila.

PLoS biology

Neha Agrawal, Katherine Lawler, Catherine M Davidson, Julia M Keogh, Robert Legg, Inês Barroso, I Sadaf Farooqi, Andrea H Brand

Affiliations

  1. The Gurdon Institute and Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom.
  2. University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom.
  3. MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.

PMID: 34748544 PMCID: PMC8575313 DOI: 10.1371/journal.pbio.3001255

Abstract

The discovery of human obesity-associated genes can reveal new mechanisms to target for weight loss therapy. Genetic studies of obese individuals and the analysis of rare genetic variants can identify novel obesity-associated genes. However, establishing a functional relationship between these candidate genes and adiposity remains a significant challenge. We uncovered a large number of rare homozygous gene variants by exome sequencing of severely obese children, including those from consanguineous families. By assessing the function of these genes in vivo in Drosophila, we identified 4 genes, not previously linked to human obesity, that regulate adiposity (itpr, dachsous, calpA, and sdk). Dachsous is a transmembrane protein upstream of the Hippo signalling pathway. We found that 3 further members of the Hippo pathway, fat, four-jointed, and hippo, also regulate adiposity and that they act in neurons, rather than in adipose tissue (fat body). Screening Hippo pathway genes in larger human cohorts revealed rare variants in TAOK2 associated with human obesity. Knockdown of Drosophila tao increased adiposity in vivo demonstrating the strength of our approach in predicting novel human obesity genes and signalling pathways and their site of action.

Conflict of interest statement

The authors have declared that no competing interests exist.

References

  1. Dev Cell. 2011 Nov 15;21(5):888-95 - PubMed
  2. Hum Mol Genet. 2019 Nov 21;28(R2):R207-R214 - PubMed
  3. Prog Mol Biol Transl Sci. 2013;116:215-35 - PubMed
  4. PLoS Biol. 2019 Dec 5;17(12):e3000522 - PubMed
  5. Proc Natl Acad Sci U S A. 2007 May 15;104(20):8253-6 - PubMed
  6. Mol Psychiatry. 2015 Feb;20(1):140-7 - PubMed
  7. Curr Opin Cell Biol. 2020 Feb;62:96-103 - PubMed
  8. Dis Model Mech. 2016 Mar;9(3):229-31 - PubMed
  9. Sci Rep. 2018 Aug 1;8(1):11536 - PubMed
  10. Genetics. 2018 Dec;210(4):1163-1184 - PubMed
  11. Dev Cell. 2015 Apr 6;33(1):36-46 - PubMed
  12. Genome Biol. 2016 Jun 06;17(1):122 - PubMed
  13. Dis Model Mech. 2011 Nov;4(6):842-9 - PubMed
  14. PLoS Genet. 2013;9(1):e1003175 - PubMed
  15. Nature. 2020 May;581(7809):434-443 - PubMed
  16. Int J Mol Sci. 2018 Jul 13;19(7): - PubMed
  17. Lancet. 2017 Nov 25;390(10110):2360-2371 - PubMed
  18. Cell. 2015 Mar 26;161(1):119-132 - PubMed
  19. Development. 2011 May;138(10):1877-92 - PubMed
  20. PLoS One. 2011;6(9):e23796 - PubMed
  21. PLoS Genet. 2018 Apr 2;14(4):e1007222 - PubMed
  22. Physiology (Bethesda). 2013 Mar;28(2):117-24 - PubMed
  23. Nat Neurosci. 2016 Apr;19(4):571-7 - PubMed
  24. Nucleic Acids Res. 2010 Sep;38(16):e164 - PubMed
  25. Nature. 2010 Feb 4;463(7281):666-70 - PubMed
  26. BMC Neurosci. 2013 Dec 18;14:157 - PubMed
  27. BMC Bioinformatics. 2011 Aug 31;12:357 - PubMed
  28. Science. 2016 Apr 22;352(6284):474-7 - PubMed
  29. Bioinformatics. 2014 Oct 15;30(20):2852-9 - PubMed
  30. Dis Model Mech. 2013 May;6(3):734-44 - PubMed
  31. J Bacteriol. 1978 May;134(2):446-57 - PubMed
  32. Sci Rep. 2017 Jun 29;7(1):4394 - PubMed
  33. Genes Dev. 1995 Jun 15;9(12):1530-42 - PubMed
  34. J Clin Invest. 2018 Oct 1;128(10):4313-4328 - PubMed
  35. Curr Top Dev Biol. 2017;123:143-179 - PubMed
  36. Neuron. 2009 Aug 13;63(3):329-41 - PubMed
  37. Oncogene. 2009 Apr 30;28(17):1916-27 - PubMed
  38. Dev Cell. 2011 Nov 15;21(5):896-906 - PubMed
  39. J Exp Biol. 2008 Oct;211(Pt 19):3103-10 - PubMed
  40. Curr Opin Cell Biol. 2018 Apr;51:73-80 - PubMed
  41. N Engl J Med. 2017 Jan 19;376(3):254-266 - PubMed
  42. Science. 2003 Dec 5;302(5651):1765-8 - PubMed
  43. Nature. 1994 Dec 1;372(6505):425-32 - PubMed
  44. J Exp Biol. 2018 Mar 7;221(Pt Suppl 1): - PubMed
  45. Development. 1997 Sep;124(17):3303-12 - PubMed
  46. Nat Rev Mol Cell Biol. 2017 Feb;18(2):73-89 - PubMed
  47. Int J Epidemiol. 2020 Feb 1;49(1):20-21i - PubMed
  48. Science. 2012 Feb 17;335(6070):823-8 - PubMed
  49. Nature. 1997 Jun 26;387(6636):903-8 - PubMed
  50. Cell Metab. 2005 May;1(5):323-30 - PubMed
  51. Mitochondrion. 2010 Aug;10(5):433-48 - PubMed
  52. J Biol Chem. 2006 Apr 21;281(16):11214-24 - PubMed
  53. Development. 1993 Jun;118(2):401-15 - PubMed
  54. Mol Cell Biol. 1995 Feb;15(2):824-34 - PubMed
  55. Nat Genet. 2015 Aug;47(8):856-60 - PubMed
  56. Cell Metab. 2020 Jun 2;31(6):1107-1119.e12 - PubMed
  57. Curr Protoc Bioinformatics. 2013;43:11.10.1-11.10.33 - PubMed
  58. Cell Metab. 2014 Feb 4;19(2):331-43 - PubMed
  59. Med Res Rev. 2014 Jan;34(1):190-221 - PubMed
  60. Am J Hum Genet. 2012 Aug 10;91(2):224-37 - PubMed
  61. Nature. 1998 Mar 26;392(6674):398-401 - PubMed
  62. Nature. 2020 Oct;586(7831):749-756 - PubMed
  63. J Vis Exp. 2015 Jun 13;(100):e52741 - PubMed
  64. Neural Dev. 2018 Aug 13;13(1):18 - PubMed
  65. Nature. 2015 Feb 12;518(7538):197-206 - PubMed
  66. Diabetes. 2016 Dec;65(12):3805-3811 - PubMed
  67. PLoS One. 2013 Apr 18;8(4):e61740 - PubMed
  68. Dev Cell. 2015 May 4;33(3):272-84 - PubMed
  69. Cell. 2010 Jan 8;140(1):148-60 - PubMed

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