Using transcriptome profiling to characterize QTL regions on chicken chromosome 5

BackgroundAlthough many QTL for various traits have been mapped in livestock, location confidence intervals remain wide that makes difficult the identification of causative mutations. The aim of this study was to test the contribution of microarray data to QTL detection in livestock species. Three different but complementary approaches are proposed to improve characterization of a chicken QTL region for abdominal fatness (AF) previously detected on chromosome 5 (GGA5).ResultsHepatic transcriptome profiles for 45 offspring of a sire known to be heterozygous for the distal GGA5 AF QTL were obtained using a 20 K chicken oligochip. mRNA levels of 660 genes were correlated with the AF trait. The first approach was to dissect the AF phenotype by identifying animal subgroups according to their 660 transcript profiles. Linkage analysis using some of these subgroups revealed another QTL in the middle of GGA5 and increased the significance of the distal GGA5 AF QTL, thereby refining its localization. The second approach targeted the genes correlated with the AF trait and regulated by the GGA5 AF QTL region. Five of the 660 genes were considered as being controlled either by the AF QTL mutation itself or by a mutation close to it; one having a function related to lipid metabolism (HMGCS1). In addition, a QTL analysis with a multiple trait model combining this 5 gene-set and AF allowed us to refine the QTL region. The third approach was to use these 5 transcriptome profiles to predict the paternal Q versus q AF QTL mutation for each recombinant offspring and then refine the localization of the QTL from 31 cM (100 genes) at a most probable location confidence interval of 7 cM (12 genes) after determining the recombination breakpoints, an interval consistent with the reductions obtained by the two other approaches.ConclusionThe results showed the feasibility and efficacy of the three strategies used, the first revealing a QTL undetected using the whole population, the second providing functional information about a QTL region through genes related to the trait and controlled by this region (HMGCS1), the third could drastically refine a QTL region.

[1]  B. Leclercq,et al.  Selecting broilers for low or high abdominal fat: initial observations. , 1980 .

[2]  E. Lander,et al.  Mapping mendelian factors underlying quantitative traits using RFLP linkage maps. , 1989, Genetics.

[3]  H. Miziorko,et al.  Avian liver 3-hydroxy-3-methylglutaryl-CoA synthase: distinct genes encode the cholesterogenic and ketogenic isozymes. , 1990, Archives of biochemistry and biophysics.

[4]  Didier Boichard,et al.  Alternative models for QTL detection in livestock. I. General introduction , 1999, Genetics Selection Evolution.

[5]  L. McIntyre,et al.  Combining mapping and arraying: An approach to candidate gene identification , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[6]  S. Dudoit,et al.  Normalization for cDNA microarray data: a robust composite method addressing single and multiple slide systematic variation. , 2002, Nucleic acids research.

[7]  L. Kruglyak,et al.  Genetic Dissection of Transcriptional Regulation in Budding Yeast , 2002, Science.

[8]  H. Gilbert,et al.  Comparison of three multitrait methods for QTL detection , 2003, Genetics Selection Evolution.

[9]  Rachel B. Brem,et al.  Trans-acting regulatory variation in Saccharomyces cerevisiae and the role of transcription factors , 2003, Nature Genetics.

[10]  M. Georges,et al.  Positional identification of structural and regulatory quantitative trait nucleotides in domestic animal species. , 2003, Cold Spring Harbor symposia on quantitative biology.

[11]  Eric S. Lander,et al.  Identification of a gene causing human cytochrome c oxidase deficiency by integrative genomics , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[12]  Leif Andersson,et al.  A regulatory mutation in IGF2 causes a major QTL effect on muscle growth in the pig , 2003, Nature.

[13]  B. Yandell,et al.  Dimension reduction for mapping mRNA abundance as quantitative traits. , 2003, Genetics.

[14]  R. Stoughton,et al.  Genetics of gene expression surveyed in maize, mouse and man , 2003, Nature.

[15]  R. Sederoff,et al.  Coordinated Genetic Regulation of Growth and Lignin Revealed by Quantitative Trait Locus Analysis of cDNA Microarray Data in an Interspecific Backcross of Eucalyptus1 , 2004, Plant Physiology.

[16]  Michel Georges,et al.  Genetic and functional confirmation of the causality of the DGAT1 K232A quantitative trait nucleotide in affecting milk yield and composition. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[17]  A. Vignal,et al.  Genetic linkage and expression analysis of SREBP and lipogenic genes in fat and lean chicken. , 2004, Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology.

[18]  E. Schadt,et al.  Genetic inheritance of gene expression in human cell lines. , 2004, American journal of human genetics.

[19]  Jean YH Yang,et al.  Bioconductor: open software development for computational biology and bioinformatics , 2004, Genome Biology.

[20]  R. Sederoff,et al.  Genetic Architecture of Transcript-Level Variation in Differentiating Xylem of a Eucalyptus Hybrid , 2005, Genetics.

[21]  Andrew I Su,et al.  Uncovering regulatory pathways that affect hematopoietic stem cell function using 'genetical genomics' , 2005, Nature Genetics.

[22]  E. Petretto,et al.  Integrated transcriptional profiling and linkage analysis for identification of genes underlying disease , 2005, Nature Genetics.

[23]  Eric E. Schadt,et al.  Integrating genotypic and expression data in a segregating mouse population to identify 5-lipoxygenase as a susceptibility gene for obesity and bone traits , 2005 .

[24]  Eric E Schadt,et al.  Cis-acting expression quantitative trait loci in mice. , 2005, Genome research.

[25]  Sandrine Lagarrigue,et al.  Mapping quantitative trait loci affecting fatness and breast muscle weight in meat-type chicken lines divergently selected on abdominal fatness , 2005, Genetics Selection Evolution.

[26]  Maki Moritani,et al.  Identification of candidate genes in the type 2 diabetes modifier locus using expression QTL. , 2005, Genomics.

[27]  E E Schadt,et al.  Integrating genotypic and expression data in a segregating mouse population to identify 5-lipoxygenase as a susceptibility gene for obesity and bone traits , 2005, Nature Genetics.

[28]  J. Castle,et al.  An integrative genomics approach to infer causal associations between gene expression and disease , 2005, Nature Genetics.

[29]  Tomoko Nomoto,et al.  Expression Quantitative Trait Loci Analysis of 13 Genes in the Rat Prostate , 2005, Genetics.

[30]  Elisabeth Le Bihan-Duval,et al.  Fatness QTL on chicken chromosome 5 and interaction with sex , 2006, Genetics Selection Evolution.

[31]  S. Lamont,et al.  Review of quantitative trait loci identified in the chicken. , 2006, Poultry science.

[32]  A. Ghazalpour,et al.  Complex Inheritance of the 5-Lipoxygenase Locus Influencing Atherosclerosis in Mice , 2006, Genetics.

[33]  Dan Nettleton,et al.  Genetic Regulation of Gene Expression During Shoot Development in Arabidopsis , 2006, Genetics.

[34]  Eric E Schadt,et al.  Cis-regulatory variations: A study of SNPs around genes showing cis-linkage in segregating mouse populations , 2006, BMC Genomics.

[35]  Florian Caiment,et al.  A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep , 2006, Nature Genetics.

[36]  J. Weller,et al.  From QTL to QTN identification in livestock--winning by points rather than knock-out: a review. , 2007, Animal genetics.

[37]  M. Georges.  Mapping, fine mapping, and molecular dissection of quantitative trait Loci in domestic animals. , 2007, Annual review of genomics and human genetics.

[38]  Robert W. Williams,et al.  An integrative genomics strategy for systematic characterization of genetic loci modulating phenotypes. , 2007, Human molecular genetics.

[39]  Dennis B. Troup,et al.  NCBI GEO: mining tens of millions of expression profiles—database and tools update , 2006, Nucleic Acids Res..

[40]  Helen E. Parkinson,et al.  ArrayExpress—a public database of microarray experiments and gene expression profiles , 2006, Nucleic Acids Res..

[41]  Christophe Klopp,et al.  Transcriptome profiling of the feeding-to-fasting transition in chicken liver , 2008, BMC Genomics.

[42]  L. Holdt,et al.  Increased ADAM17 mRNA Expression and Activity Is Associated With Atherosclerosis Resistance in LDL-Receptor Deficient Mice , 2008, Arteriosclerosis, thrombosis, and vascular biology.

[43]  Klaus Wimmers,et al.  Trait correlated expression combined with expression QTL analysis reveals biological pathways and candidate genes affecting water holding capacity of muscle , 2008, BMC Genomics.

[44]  Christophe Klopp,et al.  sigReannot: an oligo-set re-annotation pipeline based on similarities with the Ensembl transcripts and Unigene clusters , 2009, BMC proceedings.

[45]  S. Horvath,et al.  Genetic dissection of a major mouse obesity QTL (Carfhg2): integration of gene expression and causality modeling. , 2009, Physiological genomics.

[46]  S Lagarrigue,et al.  A comprehensive analysis of QTL for abdominal fat and breast muscle weights on chicken chromosome 5 using a multivariate approach. , 2009, Animal genetics.

[47]  Hongyu Zhao,et al.  Susceptibility loci for murine HIV-associated nephropathy encode trans-regulators of podocyte gene expression. , 2009, The Journal of clinical investigation.