title: Combined QTL and selective sweep mappings with coding SNP annotation and cis-eQTL analysis revealed PARK2 and JAG2 as new candidate genes for adiposity regulation.
abstract: Very few causal genes have been identified by quantitative trait loci (QTL) mapping because of the large size of QTL, and most of them were identified thanks to functional links already known with the targeted phenotype. Here, we propose to combine selection signature detection, coding SNP annotation, and cis-expression QTL analyses to identify potential causal genes underlying QTL identified in divergent line designs. As a model, we chose experimental chicken lines divergently selected for only one trait, the abdominal fat weight, in which several QTL were previously mapped. Using new haplotype-based statistics exploiting the very high SNP density generated through whole-genome resequencing, we found 129 significant selective sweeps. Most of the QTL colocalized with at least one sweep, which markedly narrowed candidate region size. Some of those sweeps contained only one gene, therefore making them strong positional causal candidates with no presupposed function. We then focused on two of these QTL/sweeps. The absence of nonsynonymous SNPs in their coding regions strongly suggests the existence of causal mutations acting in cis on their expression, confirmed by cis-eQTL identification using either allele-specific expression or genetic mapping analyses. Additional expression analyses of those two genes in the chicken and mice contrasted for adiposity reinforces their link with this phenotype. This study shows for the first time the interest of combining selective sweeps mapping, coding SNP annotation and cis-eQTL analyses for identifying causative genes for a complex trait, in the context of divergent lines selected for this specific trait. Moreover, it highlights two genes, JAG2 and PARK2, as new potential negative and positive key regulators of adiposity in chicken and mice.
authors: INRA, UMR1348 Pegase, Saint-Gilles, 35590, France Agrocampus Ouest, UMR1348 Pegase, Rennes, 35000, France Université Européenne de Bretagne, France.
authors: Pierre-François
authors: http://orcid.org/0000-0002-0695-4206
authors: PF
authors: Roux
authors: UMR 7205 OSEB (MNHN-CNRS-EPHE-UPMC), Paris, 75005, France INRA/AgroParisTech, UMR1313 GABI, Jouy-en-Josas, 78352, France.
authors: Simon
authors: S
authors: Boitard
authors: Department of Medicine/Division of Cardiology, UCLA, Los Angeles, California.
authors: Yuna
authors: Y
authors: Blum
authors: Department of Medicine/Division of Cardiology, UCLA, Los Angeles, California.
authors: Brian
authors: B
authors: Parks
authors: UMR1331, INP, UPS, TOXALIM, INRA, Toulouse, France.
authors: Alexandra
authors: A
authors: Montagner
authors: INSERM, UMR 1048 I2MC, 31432 Toulouse, France.
authors: Etienne
authors: E
authors: Mouisel
authors: INRA, SIGENAE, Castanet-Tolosan, 31326, France.
authors: Anis
authors: A
authors: Djari
authors: INRA, Plateforme GENOTOUL, Castanet-Tolosan, 31326, France.
authors: Diane
authors: D
authors: Esquerré
authors: INRA, UMR1348 Pegase, Saint-Gilles, 35590, France Agrocampus Ouest, UMR1348 Pegase, Rennes, 35000, France Université Européenne de Bretagne, France.
authors: Colette
authors: C
authors: Désert
authors: INRA, UMR1348 Pegase, Saint-Gilles, 35590, France Agrocampus Ouest, UMR1348 Pegase, Rennes, 35000, France Université Européenne de Bretagne, France.
authors: Morgane
authors: M
authors: Boutin
authors: UMR INRA, INPT ENSAT, INPT ENVT-GENPHYSE, Castanet-Tolosan, 31326, France.
authors: Sophie
authors: S
authors: Leroux
authors: INRA, UMR1348 Pegase, Saint-Gilles, 35590, France.
authors: Frédéric
authors: F
authors: Lecerf
authors: INRA, UR83 Recherches Avicoles, Nouzilly, 37380, France.
authors: Elisabeth
authors: E
authors: Le Bihan-Duval
authors: INRA, SIGENAE, Castanet-Tolosan, 31326, France.
authors: Christophe
authors: C
authors: Klopp
authors: UMR INRA, INPT ENSAT, INPT ENVT-GENPHYSE, Castanet-Tolosan, 31326, France.
authors: Bertrand
authors: B
authors: Servin
authors: UMR INRA, INPT ENSAT, INPT ENVT-GENPHYSE, Castanet-Tolosan, 31326, France.
authors: Frédérique
authors: F
authors: Pitel
authors: INRA, UR83 Recherches Avicoles, Nouzilly, 37380, France.
authors: Michel Jean
authors: MJ
authors: Duclos
authors: UMR1331, INP, UPS, TOXALIM, INRA, Toulouse, France.
authors: Hervé
authors: H
authors: Guillou
authors: Department of Medicine/Division of Cardiology, UCLA, Los Angeles, California Department of Human Genetics, UCLA, Los Angeles, California.
authors: Aldons J
authors: AJ
authors: Lusis
authors: INRA, UMR1348 Pegase, Saint-Gilles, 35590, France Agrocampus Ouest, UMR1348 Pegase, Rennes, 35000, France Université Européenne de Bretagne, France.
authors: Olivier
authors: O
authors: Demeure
authors: INRA, UMR1348 Pegase, Saint-Gilles, 35590, France Agrocampus Ouest, UMR1348 Pegase, Rennes, 35000, France Université Européenne de Bretagne, France sandrine.lagarrigue@agrocampus-ouest.fr.
authors: Sandrine
authors: S
authors: Lagarrigue
mesh_terms: D052436:Adipose Tissue, White / Q000378:metabolism; D050154:Adiposity / Q000235:genetics*; D000483:Alleles; D000818:Animals; D002460:Cell Line; D002645:Chickens; D002874:Chromosome Mapping; D016678:Genome; D059014:High-Throughput Nucleotide Sequencing; D000072101:Jagged-2 Protein; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D058977:Molecular Sequence Annotation; D009218:Myosins / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D017422:Sequence Analysis, DNA; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: C490503:Jag2 protein, mouse; D000072101:Jagged-2 Protein; D008565:Membrane Proteins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D009218:Myosins
keywords: JAG2; PARK2; QTL; adiposity; cis-eQTLs; divergent lines; selective sweeps
references: Mol Ecol. 2004 Apr;13(4):969-80
references: 15012769
references: PLoS Genet. 2012;8(7):e1002791
references: 22807686
references: Genetics. 1973 May;74(1):175-95
references: 4711903
references: Biochemistry. 1979 Nov 27;18(24):5294-9
references: 518835
references: J Biol Chem. 2008 Oct 31;283(44):29650-7
references: 18728004
references: Genetics. 2008 Oct;180(2):977-93
references: 18780740
references: Genes Dev. 1998 Apr 1;12(7):1046-57
references: 9531541
references: J Biol Chem. 2009 Mar 27;284(13):8209
references: 19008216
references: Anim Genet. 2009 Apr;40(2):176-84
references: 19067671
references: Genetics. 2009 Apr;181(4):1567-78
references: 19204373
references: Bioinformatics. 2009 Jul 15;25(14):1754-60
references: 19451168
references: Science. 2009 Jul 3;325(5936):100-4
references: 19520913
references: Bioinformatics. 2009 Aug 15;25(16):2078-9
references: 19505943
references: BMC Genomics. 2009;10:550
references: 19930592
references: Nature. 1998 Apr 9;392(6676):605-8
references: 9560156
references: J Clin Invest. 2004 Nov;114(9):1326-33
references: 15520865
references: Nature. 2004 Dec 9;432(7018):695-716
references: 15592404
references: Nature. 2004 Dec 9;432(7018):717-22
references: 15592405
references: Proc Natl Acad Sci U S A. 2005 Feb 8;102(6):2174-9
references: 15684050
references: Genome Res. 2005 Nov;15(11):1566-75
references: 16251466
references: Genet Sel Evol. 2006 Jan-Feb;38(1):85-97
references: 16451793
references: PLoS Biol. 2006 Mar;4(3):e72
references: 16494531
references: Am J Hum Genet. 2006 Apr;78(4):629-44
references: 16532393
references: Nat Genet. 2006 Jul;38(7):813-8
references: 16751773
references: Ann Hum Genet. 2007 May;71(Pt 3):354-69
references: 17233754
references: Annu Rev Genomics Hum Genet. 2007;8:131-62
references: 17477823
references: Nat Genet. 2008 Mar;40(3):340-5
references: 18246066
references: Genetics. 2008 Mar;178(3):1817-29
references: 18245358
references: Genome Res. 2010 Feb;20(2):281-90
references: 20054062
references: Nature. 2010 Mar 25;464(7288):587-91
references: 20220755
references: J Biol Chem. 2010 Apr 30;285(18):13580-8
references: 20189990
references: Nat Rev Genet. 2012 Sep;13(9):654-66
references: 22868267
references: Mamm Genome. 2012 Oct;23(9-10):680-92
references: 22892838
references: Nucleic Acids Res. 2013 Jan;41(Database issue):D885-91
references: 23175610
references: Nucleic Acids Res. 2013 Jan;41(Database issue):D871-9
references: 23180796
references: PLoS Genet. 2012;8(12):e1003150
references: 23300464
references: BMC Genomics. 2012;13:704
references: 23241142
references: Genetics. 2013 Mar;193(3):929-41
references: 23307896
references: Genetics. 2013 Nov;195(3):1157-66
references: 24026101
references: Am J Hum Genet. 2013 Nov 7;93(5):779-97
references: 24210251
references: PLoS Genet. 2014 Feb;10(2):e1004148
references: 24586189
references: PLoS One. 2014;9(8):e103813
references: 25126940
references: Genetics. 2002 Feb;160(2):765-77
references: 11861577
references: Nature. 2002 Oct 24;419(6909):832-7
references: 12397357
references: Proc Natl Acad Sci U S A. 2003 May 13;100(10):5956-61
references: 12719539
references: J Biol Chem. 2003 Oct 31;278(44):43628-35
references: 12930822
references: Proc Natl Acad Sci U S A. 2004 Feb 24;101(8):2398-403
references: 14983021
references: BMC Genomics. 2010;11:473
references: 20707912
references: Genome Res. 2010 Sep;20(9):1297-303
references: 20644199
references: Genetics. 2010 Sep;186(1):241-62
references: 20855576
references: PLoS Genet. 2010 Nov;6(11):e1001188
references: 21079680
references: Nat Rev Genet. 2011 Apr;12(4):277-82
references: 21386863
references: PLoS Genet. 2011 Apr;7(4):e1002038
references: 21490954
references: BMC Genomics. 2011;12(1):274
references: 21627800
references: PLoS One. 2011;6(7):e14825
references: 21750696
references: Bioinformatics. 2011 Aug 15;27(16):2300-1
references: 21697123
references: Development. 2011 Sep;138(17):3593-612
references: 21828089
references: Nat Methods. 2011;8(10):833-5
references: 21892150
references: Nucleic Acids Res. 2012 Jan;40(Database issue):D881-6
references: 22075990
references: Am J Hum Genet. 2012 Jan 13;90(1):7-24
references: 22243964
references: PLoS Biol. 2012 Feb;10(2):e1001258
references: 22346734
references: ScientificWorldJournal. 2012;2012:365104
references: 22778697
references: Genetics. 2004 Jul;167(3):1513-24
references: 15280259